Cardiac effects of vecuronium and its interaction with autonomic nervous system in isolated perfused canine hearts.

The chronotropic and inotropic effects of vecuronium bromide and its interaction with the autonomic nervous system were investigated in the isolated, cross-circulated right atrial and left ventricular preparations of the dog. Vecuronium, injected into the external jugular vein of the support dog, induced dose-dependent decreases in heart rate and arterial blood pressure, and increased atrial contractile force with no change in sinus rate in isolated atrial preparations. Vecuronium (1-3,000 micrograms), injected into the sinus node artery of the isolated atrium, induced dose-dependent increases in atrial contractile force with small increases in sinus rate. Vecuronium also increased the ventricular contractile force in a dose-dependent manner. The positive inotropic effect was attenuated in part by propranolol, but not by either tetrodotoxin or imipramine. Vecuronium inhibited in a dose-related manner the negative chronotropic and inotropic responses to parasympathetic nerve stimulation and carbachol (CCh) and the negative followed by positive cardiac responses to nicotine, but did not attenuate the positive responses to sympathetic nerve stimulation. The ID50s for the responses to parasympathetic stimulation, CCh, and nicotine were not significantly different. Vecuronium enhanced the positive chronotropic and inotropic responses to sympathetic nerve stimulation, tyramine, norepinephrine, and isoproterenol. These results indicate that (a) vecuronium causes the positive inotropic responses mediated by nonadrenergic mechanisms and beta-adrenoceptors, (b) vecuronium blocks ganglionic and presynaptic nicotinic and postsynaptic muscarinic receptor-mediated responses similarly, and (c) vecuronium enhances beta-adrenoceptor-mediated responses in the dog heart.


A CNS serotonergic mechanism in acute central hypovolemia in conscious rabbits?

We tested whether a brainstem serotonergic mechanism influences the hemodynamic response to acute central hypovolemia. An inferior vena caval cuff was gradually inflated so that mean cardiac index (MCI) fell at a constant rate (approximately 8%/min). Under control conditions, mean systemic vascular conductance index (MSVCI) fell progressively until MCI had fallen by approximately 50% (compensatory phase), at which point MSVCI rose abruptly and arterial pressure fell to approximately 40 mm Hg (decompensatory phase). Intravenous methysergide delayed the decompensatory phase and at a critical dose (300-3,000 nmol) abolished it. Methysergide had similar effects when injected into the fourth ventricle, pontomedullary cistern, or lateral ventricle in doses that were 7-10% of the critical i.v. dose, but had no effect when injected into the spinal subarachnoid space. LY53857 was equipotent to methysergide. None of these treatments attenuated the vasoconstriction of the first, compensatory, phase. Partial depletion of neuronal serotonin (after p-chlorophenylalanine or 5,7-dihydroxytryptamine treatment) had no effect on either phase. We conclude that a serotonergic mechanism, probably located in the brainstem, may be involved in the decompensatory phase of acute central hypovolemia.


Effects of verapamil and Bay K 8644 on defibrillation energy requirements in dogs.

Antiarrhythmic drugs are often required in patients with implantable cardioverter-defibrillator devices. Prior evidence suggests that drugs modulate defibrillation energy requirements by altering ion channel activity. To evaluate the effects of calcium ion channel activity on internal defibrillation energy requirements, the calcium antagonist verapamil and Bay K 8644, a calcium channel activator, were investigated in 30 open-chest, pentobarbital-anesthetized dogs. Defibrillation energies were applied across two epicardial patch electrodes. The likelihood of successful defibrillation was determined at various shock energy levels, and the 50 and 90% effective energy doses were calculated using nonlinear regression. In saline control experiments (n = 10), the stability of the preparation throughout the 6-h duration of the experiments could be demonstrated. Verapamil administration (n = 10) infused to a mean plasma concentration of 69 ng/ml increased the 50 and 90% effective defibrillation energies by 41 and 43% (p less than 0.05), respectively, and to a mean plasma verapamil concentration of 170 ng/ml by 95 and 75% (p less than 0.01), respectively. The mean cycle length during ventricular fibrillation decreased with verapamil and was inversely related to the change in defibrillation energy requirement. Administration of Bay K 8644 (n = 10) produced a slight increase in the 50% effective defibrillation energy (25%; p less than 0.05) and 90% effective defibrillation energy (17%; n.s.). The electrophysiologic effects of verapamil were neither prevented nor reversed by Bay K 8644. In conclusion, intravenous verapamil administration caused an increase in defibrillation energy requirements, but the mechanism by which verapamil exerted this effect remains unclear. These experimental data suggest that verapamil should be used in patients with automatic implantable cardioverter-defibrillator devices only after individual testing.


Effects of NZ-105, a new calcium antagonist, on renal function in anesthetized spontaneously hypertensive rats.

The effects of a new dihydropyridine derivative, NZ-105, on renal function were investigated in anesthetized spontaneously hypertensive rats. Intravenous injection of NZ-105 (0.01 and 0.03 mg/kg of body weight) significantly increased the urine flow rate (UV) and renal absolute excretion of sodium and chloride. Potassium excretion also increased significantly, but it was relatively slight in comparison with sodium or chloride excretion. There was a decrease in mean blood pressure (-14.5 +/- 2.3 and -22.3 +/- 3.4 mm Hg, 20 min after the administration of 0.01 and 0.03 mg/kg of body weight, respectively). The glomerular filtration rate (GFR) was not changed; however, the renal plasma flow (RPF) was significantly increased. The tubular site of action of NZ-105 was investigated by the lithium clearance technique. Intravenous injection of NZ-105 inhibited sodium reabsorption beyond the proximal tubules about four to five times more effectively than at the proximal tubules. In conclusion, intravenous administration of NZ-105 in anesthetized spontaneously hypertensive rats caused diuretic and natriuretic action. The possible site of diuretic action may be mainly at the nephron segments beyond the proximal tubules.


Expression of renal alpha 1-adrenergic receptor subtypes in established hypertension.

Radioligand binding studies were undertaken in renal membranes of normotensive and hypertensive rats in order to test the hypothesis that there are alterations in renal alpha 1-adrenergic subtypes of genetic hypertensive animals. The highly selective competitive compound, (+)-niguldipine, was used to distinguish high-affinity (alpha 1a) from low-affinity (alpha 1b) sites, after initial studies demonstrated that this compound had greater selectivity than 5-methylurapidil in distinguishing alpha 1a and alpha 1b sites in rat renal membranes. In contrast to the significant difference in the blood pressure of the spontaneously hypertensive rats (delta BP = 74 mm Hg), there was no difference in the renal alpha 1-adrenergic receptor density. Membranes from the whole kidneys of spontaneously hypertensive rats (SHRs) possessed 31% alpha 1a and 69% alpha 1b sites with -log(Ki) values of 10.0 +/- 0.3 and 7.1 +/- 0.1, respectively, for (+)-niguldipine. However, these values were not different from those obtained from renal membranes of the normotensive Wistar-Kyoto (WKY) rats. These results indicate that in spite of the elevated blood pressure during the established phase of hypertension, the number, the affinity, and the ratio of the alpha 1a and alpha 1b appear not to be responsible for the manifestation of hypertension during this phase.


Differential effects of enalapril and hydralazine on short-term variability of blood pressure and heart rate in rats.

Using a spectral procedure, we studied the acute and chronic effects of enalapril and hydralazine on the variability of blood pressure (BP) and heart rate (HR) in conscious Wistar rats. In the acute protocol, rats received two injections 25 min apart (saline followed by enalaprilic acid or hydralazine hydrochloride). In the chronic protocol, animals received oral enalapril maleate, hydralazine hydrochloride, or distilled water. A 5-min recording session was initiated on day 12. Acute enalapril and hydralazine amplified the low-frequency (LF) component of the systolic BP (SBP) spectrum. Chronic enalapril reduced the variability of BP, as indicated by the lower variance in SBP distribution. Chronic enalapril preferentially reduced the amplitude of the 400-mHz oscillations of SBP. Acute administration of enalapril or hydralazine resulted in BP variability profiles, suggesting a reflexly mediated vascular sympathetic activation. In contrast, chronic angiotensin-converting enzyme (ACE) blockade with enalapril caused a significant decrease in the LF oscillations of BP. This could reflect a reduced sympathetic outflow to vascular smooth muscles.


Comparison of the safety and efficacy of bisoprolol versus atenolol in stable exercise-induced angina pectoris: a Multicenter International Randomized Study of Angina Pectoris (MIRSA).

Bisoprolol 10 mg and atenolol 100 mg once daily were compared regarding efficacy and safety in stable effort angina in a 12-week, multicenter, double-blind, randomized, parallel-group study. Efficacy was evaluated with angina pectoris diaries and bicycle exercise tests. Spontaneously mentioned complaints and side effects were recorded at each visit. In 11 centers, 147 patients completed the study; 76 received bisoprolol 10 mg, and 71 received atenolol 100 mg. After 12 weeks, weekly anginal attack rate was reduced significantly (p less than 0.05) with bisoprolol (5 +/- 0.5 to 2 +/- 0.6) and with atenolol (4 +/- 0.4 to 1 +/- 0.2). Peak exercise capacity (in W x min) increased significantly (p less than 0.05) with bisoprolol (772 +/- 47 to 878 +/- 52) and with atenolol (891 +/- 46 to 986 +/- 53). Rate pressure product (RPP) at peak exercise (in beats/min x mm Hg) decreased significantly (p less than 0.05) with both bisoprolol (25,003 +/- 692 to 20,116 +/- 637) and atenolol (26,544 +/- 557 to 21,603 +/- 576) (all values are mean +/- SE). The differences between the groups were not statistically significant. There were no significant differences regarding nature and incidence of adverse events between the groups. Thus, bisoprolol 10 mg once daily and atenolol 100 mg once daily are equipotent in their effects on stable effort angina. Both regimens were comparable with respect to incidence and nature of side effects.


Interaction of atrial natriuretic peptide with DA1 receptors in preconstricted isolated perfused rat lungs.

Using an in situ isolated salt-perfused rat lung preparation, we investigated the pulmonary vascular response to atrial natriuretic peptide (ANP). ANP was infused in graded doses ranging from 0.01 to 100.0 micrograms/kg during prostaglandin F2 alpha-induced pulmonary vasoconstriction. These experiments were repeated after selective dopamine1 (DA1) receptor blockade with SCH 23390 and after catecholamine depletion by reserpine. ANP at doses of 0.01, 0.1, 1.0, 10.0, or 100.0 micrograms/kg was injected into the pulmonary artery (n = 5-7/dose). In the unblocked group ANP infusion resulted in a dose-dependent decrease in the mean pulmonary arterial pressure (PAP) with a maximum effect at 10 micrograms/kg (delta PAP = -3.4 +/- 0.2 mm Hg). In the DA1 blockade groups the ANP dose-response curve was shifted to the right, in a parallel fashion. After catecholamine depletion with reserpine, the ANP dose-response curve was identical to that of the unblocked groups. With the parallel, rightward shift of the ANP dose-response curves by SCH 23390 and no attenuation of ANP effect after catecholamine depletion, it appears that ANP vasoactive properties in the pulmonary vasculature involve an interaction with the vascular DA1 receptors. This observation differs from the ANP-dopaminergic interactions seen in the kidney in which ANP action depends on endogenous dopamine transmission.


The effects of cocaine on cardiac electrophysiology in conscious, unsedated dogs.

This study was performed to determine the cardiac electrophysiological effects of cocaine and specifically to determine the time course of these actions. Eighteen chronically instrumented conscious dogs were tested with i.v. cocaine at doses of 1 or 4 mg/kg. The following statistically significant changes were observed 1 min following the 4 mg/kg dose of cocaine: heart rate increased from 135 +/- 8 to 186 +/- 9 beats/min, QRS duration increased from 60 +/- 5 to 74 +/- 5 ms, corrected QT interval increased from 298 +/- 7 to 339 +/- 8 ms, intraatrial conduction time increased from 27 +/- 2 to 31 +/- 3 ms, atrioventricular conduction time increased from 125 +/- 5 to 140 +/- 8 ms, and the atrial effective refractory period (ERP) increased from 101 +/- 6 to 130 +/- 9 ms. All of these parameters had returned to baseline by 10 min after cocaine administration. Corrected sinus node recovery time and the ventricular ERPs were not significantly affected by either cocaine dose. The only significant change produced by the 1 mg/kg cocaine dose was prolongation of the atrial ERP. These results suggest that cocaine causes very transient electrophysiological changes that undoubtedly represent the integrated effects of the adrenergic and local anesthetic actions of this drug.


Effect of E-4031, a class III antiarrhythmic agent, on experimental infarct size in a canine model of myocardial ischemia-reperfusion injury.

Class III antiarrhythmic agents such as E-4031 have demonstrated efficacy in preventing and/or terminating malignant ventricular arrhythmias in experimental models. It has recently been suggested that Class III agents might possess additional antiischemic properties that may translate into a reduction in the frequency or severity of arrhythmia. The potential for the Class III antiarrhythmic agent E-4031 to limit the extent of developing myocardial infarction was assessed in a barbiturate-anesthetized canine model of ischemic-reperfusion injury. Untreated control (n = 13) and E-4031-treated animals (n = 8, 300 micrograms/kg, i.v., immediately preceding myocardial ischemia) were subjected to a 90-min period of left circumflex coronary artery occlusion followed by a 5-h period of reperfusion. The predominant hemodynamic effect displayed by E-4031 was a reduction in heart rate throughout the period of coronary artery occlusion and early reperfusion. Areas at risk of infarction, expressed as percentages of left ventricle, were equivalent in the control and E-4031 treatment groups (38.5 +/- 1.0 and 34.6 +/- 1.9%, respectively). Posterolateral myocardial infarct sizes, expressed either as percentages of risk area or of total left ventricle, were reduced slightly but not significantly in the E-4031 treatment group compared to the control group (35.2 +/- 5.6 and 45.4 +/- 3.0% of risk area, respectively; 12.7 +/- 2.4 and 17.6 +/- 1.4% of left ventricle, respectively). Regional myocardial blood flows in nonischemic and central ischemic zones of myocardium did not differ significantly between the control and E-4031 treatment groups before and during the period of coronary artery occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)


The inhibition of long-chain fatty acyl-CoA synthetase by enoximone in rat heart mitochondria.

The mechanism by which enoximone, a reported phosphodiesterase inhibitor, inhibits the oxidation of long-chain fatty acids was studied in isolated rat heart mitochondria using a series of 14C-labeled substrates. Enoximone decreased palmitate oxidation in a time- and concentration-dependent manner. Fifty percent inhibition of palmitate oxidation was achieved with 250 microM of enoximone. In contrast to its effect on palmitate, enoximone (250 microM) increased octanoate oxidation by 30%, whereas pyruvate oxidation was unaffected by enoximone. At that dose there was no effect on the oxidation of palmitoyl-CoA and palmitoyl carnitine. The degree of palmitate oxidation inhibited by enoximone was parallel to the inhibition of acyl-CoA synthetase in both rat heart mitochondria and microsomes. These results suggest that enoximone is a reversible inhibitor of long-chain fatty acyl-CoA synthetase. Moreover, the reaction, which is catalyzed by this enzyme, is a rate-limiting step in the pathway of fatty acid oxidation in rat heart mitochondria.


Effects of endothelin-1 on antidiuresis and norepinephrine overflow induced by stimulation of renal nerves in anesthetized dogs.

The effects of endothelin-1 (ET-1) on renal function and norepinephrine (NE) overflow induced by renal nerve stimulation (RNS) were examined in anesthetized dogs, and comparisons were made with effects of Bay K 8644, a calcium channel agonist. RNS at a low frequency (0.5-2.0 Hz) produced significant decreases in urine flow and urinary excretion of sodium and increased NE secretion rates without influencing renal hemodynamics. RNS, at a high frequency of 2.5-5.0 Hz which diminishes renal hemodynamics, affected urine formation and NE secretion rate more potently than did low-frequency RNS. Intrarenal arterial infusion of ET-1 (1.0 ng/kg/min) decreased the baseline level of renal blood flow by 25% and that of urinary excretion of sodium by 54-69% but did not alter basal levels of NE secretion rate. During ET-1 infusion, low-frequency RNS-induced antidiuresis was observed to an extent similar to that seen without ET-1 infusion, whereas increase in NE secretion rate elicited by RNS was significantly inhibited by ET-1 infusion (45-65% of the values without ET-1 infusion). In addition, in the case of high-frequency RNS, ET-1 did not affect antidiuretic responses but did inhibit the increase in NE secretion rate by approximately 55%. In contrast, alterations in renal excretory responses and NE secretion rate elicited by RNS were not influenced by Bay K 8644 infusion (1.0 micrograms/kg/min), a dose that decreased renal blood flow to the same degree as did 1.0 ng/kg/min of ET-1.(ABSTRACT TRUNCATED AT 250 WORDS)


Antihypertensive effect of lisinopril assessed by 24-hour ambulatory monitoring: a double-blind, placebo-controlled, cross-over study.

The antihypertensive effect of the angiotensin-converting enzyme (ACE) inhibitor lisinopril administered in a single dose of 20 mg was evaluated by ambulatory blood pressure monitoring (ABPM) in a double-blind, placebo-controlled, cross-over study. Twenty-four patients (21 men and 3 women, mean age 52 +/- 6 years) with mild to moderate hypertension were included in the study and randomly assigned to two consecutive treatments with lisinopril 20 mg and placebo, each administered for 4 weeks. On the last day of each treatment, BP was assessed by noninvasive 24-h ABPM. BP was significantly lower after lisinopril than after placebo in a 24-h period (mean 24-h systolic BP (SBP) with lisinopril 120 +/- 7 mm Hg and with placebo 135 +/- 9 mm Hg; mean day SBP with lisinopril 125 +/- 3 mm Hg and with placebo 142 +/- 5 mm Hg; mean night SBP with lisinopril 112 +/- 4 mm Hg and with placebo 124 +/- 6 mm Hg; mean 24-h diastolic BP (DBP) with lisinopril 76 +/- 6 mm Hg, and with placebo 87 +/- 8 mm Hg; mean day DBP with lisinopril 80 +/- 3 mm Hg and with placebo 93 +/- 4 mm Hg; mean night DBP with lisinopril 69 +/- 2 mm Hg and with placebo 79 +/- 5 mm Hg, p less than 0.001). Mean 24-h, mean day, and mean night heart rate (HR) did not differ significantly between placebo and lisinopril treatments. Repeated-measures analysis of variance (ANOVA) showed a significant influence on SBP (p less than 0.001) and DBP (p less than 0.001) throughout the treatment.(ABSTRACT TRUNCATED AT 250 WORDS)


Comparative effects of diltiazem, nifedipine, and verapamil on large and small coronary artery constriction induced by intracoronary acetylcholine in pigs.

The in vivo protective effects of diltiazem, nifedipine, and verapamil on large and small coronary artery constriction induced by intracoronary injection of acetylcholine were compared by coronary arteriography in pigs. The percent narrowing of the epicardial major right coronary artery was used as an indicator of large coronary artery constriction, and the time required for contrast medium to reach the posterior descending coronary artery from the ostium of the right coronary artery was used as an indicator of small coronary artery constriction. Doses of 12.5, 25, 50, 100, and 200 micrograms of acetylcholine were administered into the right coronary artery under left ventricular pacing to keep the systemic hemodynamics constant. Marked prolongation of the flow time of contrast medium to greater than or equal to 8.1 s (control of less than or equal to 1.8 s) with mild narrowing of the epicardial major right coronary artery (less than or equal to 35%) was observed at doses of 12.5-50 micrograms of acetylcholine and was accompanied by myocardial ischemia. Over 50% narrowing of the epicardial major coronary artery plus markedly slow flow of contrast medium were induced in 12 of the 15 pigs by 100-200 micrograms of acetylcholine. Narrowing of the epicardial major coronary artery and the delay time of contrast medium flow induced by acetylcholine were both significantly reduced to 12-33% (control: 36-81%) and to 4.3-16.8 s (control: 16.2-37.7 s) after intracoronary injection of 100 micrograms of diltiazem.(ABSTRACT TRUNCATED AT 250 WORDS)


Chronic arterial vasodilation, central hemodynamics, and cardiac hypertrophy in spontaneously hypertensive rats.

To determine the possible contribution of cardiac volume overload in the failure of arterial vasodilators to induce regression of left ventricular hypertrophy (LVH), we evaluated in spontaneously hypertensive rats (SHRs) the changes in central hemodynamics caused by treatment with hydralazine or minoxidil. Cardiac output measured by the thermodilution technique and filling pressures were measured in conscious, freely moving rats. Increases in cardiac output were observed after 1 day of treatment, and persisted during chronic treatment; ganglionic blockade did not affect this increase. However, the LV end-diastolic pressure and right atrial pressure of SHRs were not increased by hydralazine or minoxidil. Minoxidil increased the LV weight, and decreased the LV wall thickness to LV internal radius ratio, whereas hydralazine did not change these parameters. We conclude that in SHRs changes in filling pressures do not represent the primary stimulus for the persistence or progression of cardiac hypertrophy during chronic arterial vasodilation.


Effects of nisoldipine upon vasoconstrictor responses and binding of endothelin-1 in ischemic and reperfused rat hearts.

Changes in the vascular response of isolated, perfused rat hearts to endothelin-1 (ET-1) and binding of [125I]ET-1 to cardiac membranes were examined following ischemia (30 min, zero flow) and reperfusion (15 min). Infusion of ET-1 (0, 2.5, 5, 7.5, and 10 x 10(-10) M) increased the control heart perfusion pressure (61, 73, 88, 102, and 117 mm Hg, respectively). Ischemic and reperfused hearts were more sensitive to ET-1 infusion (p less than 0.05 at all concentrations). Nisoldipine (NIS, 1 nM) prevented the rise in sensitivity to ET-1 following ischemia and reperfusion. Two binding sites for [125I]ET-1 were identified in cardiac membranes. High-affinity (Kd = 0.04 nM, Bmax = 0.46 pmol/mg of protein) and low-affinity (Kd = 13.8 nM, Bmax = 5.4 pmol/mg of protein) sites were unchanged by ischemia and reperfusion, and NIS did not change binding constants in control or ischemic and reperfused hearts. Increased ET-1 sensitivity after ischemia may be due to other factors. Endothelium-dependent vasodilation and endothelium-independent vasodilation were significantly reduced following 30 min of ischemia. Inhibition of dilator responses may account for increased ET-1 responses following transient ischemia.


Differential hemodynamic responses to selective inhibitors of cyclic nucleotide phosphodiesterases in conscious rats.

Selective inhibition of either the low Km cyclic AMP (cAMP) or low Km cyclic GMP (cGMP) phosphodiesterase (PDE) promotes vasorelaxation and, consequently, produces depressor effects. To evaluate the systemic and regional hemodynamic effects of selective inhibitors of these PDE isozymes, CI-930 (0.1-10 mg/kg), an inhibitor of low Km cAMP PDE, or zaprinast (3-30 mg/kg), an inhibitor of low Km cGMP PDE, was given i.v. to conscious, normotensive rats. The rats were chronically instrumented with vascular catheters and either an ultrasonic transit-time flow probe around the ascending aorta or miniaturized pulsed Doppler flow probes around the superior mesenteric and left renal arteries and the abdominal aorta. CI-930 and zaprinast, at cumulative doses of 3 and 30 mg/kg, respectively, produced comparable reductions in mean arterial pressure (-22 +/- 3 and -19 +/- 4 mm Hg, respectively) and total peripheral resistance (-0.41 +/- 0.07 and -0.42 +/- 0.06 mm Hg/ml/min, respectively) but affected other hemodynamic variables differently. CI-930 at 3 mg/kg increased the heart rate (HR), maximal aortic flow acceleration (dF/dt), and peak aortic flow and decreased the stroke volume (SV). Cardiac output (CO) was not affected by CI-930. Zaprinast at 30 mg/kg increased the CO, dF/dt, and peak aortic blood flow. The HR and SV were unaffected by zaprinast. Although both CI-930 and zaprinast increased the dF/dt and peak aortic flow, these parameters were affected more by CI-930 than by zaprinast. CI-930 decreased hindquarter, mesenteric, and renal vascular resistances in a dose-dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)


Central cardiovascular effects of rilmenidine and neuropeptide Y in the conscious spontaneously hypertensive rat: haemodynamic and biochemical evidence for a negative interaction.

The possible cardiovascular and biochemical interactions between the imidazoline ligand rilmenidine, a novel antihypertensive agent, and neuropeptide Y (NPY) were examined in spontaneously hypertensive rats (SHR). Rilmenidine (25-225 micrograms/kg) and NPY (1.7-15 micrograms/kg) both produced a significant, dose-dependent reduction in blood pressure (BP) after intracisternal (i.c.) administration in conscious SHR. When submaximal doses of rilmenidine (25 micrograms/kg) and NPY (1.7 micrograms/kg) were coadministered i.c., the resultant hypotension and bradycardia was less than either individual response and significantly less than the sum of their individual responses, suggesting the existence of an inhibitory interaction between these agents. To determine whether this interaction was evident at the second-messenger level, the effect of these agents on cyclic AMP levels was investigated in slices from the medulla oblongata of SHR. NPY (10(-6) and 10(-7) M) significantly inhibited forskolin-stimulated cyclic AMP production. Rilmenidine (10(-8)-10(-5) M) itself had no significant effect on forskolin-stimulated cyclic AMP levels in this system, but rilmenidine (10(-6) M) attenuated the inhibitory effect of NPY (10(-6) M) on cyclic AMP production. Thus, an inhibitory interaction between rilmenidine and NPY was observed at the hemodynamic and second-messenger level in the SHR.


Comparative in vitro study of a series of organic nitroesters: unique biphasic concentration-effect curves for glyceryl trinitrate in isolated bovine arterial smooth muscle and lack of stereoselectivity for some glyceryl trinitrate analogues.

Four different organic nitroesters, constituting a homologous series based on unbranched polyalcohols, were compared with regard to in vitro relaxation of isolated bovine mesenteric arteries contracted with 2.5 microM phenylephrine. The organic nitroesters included ethylene glycol dinitrate (EGDN), dinitratopropane (DPN), glyceryl trinitrate (GTN), and tetranitratobutane. Glyceryl trinitrate exhibited a biphasic concentration-effect relationship, with pD2 values of 11.5 +/- 0.5 and 7.2 +/- 0.2 for the high-pD2 and low-pD2 component of the relaxation curve, respectively. The high-pD2 and low-pD2 component contributed 28 and 72% of the maximal response, respectively. EGDN, DPN, and tetranitratobutane induced monophasic concentration-effect curves with pD2 values of 7.4 +/- 0.1, 7.8 +/- 0.2, and 6.9 +/- 0.6, respectively. Stereoisomeric forms of DPN and tetranitratobutane showed no difference with regard to relaxing potency in bovine mesenteric artery. GTN has a partly unique mechanism for vascular smooth muscle relaxation that distinguishes this compound from other related organic nitroesters.


N-ethylmaleimide diminishes alpha 2-adrenoceptor-mediated effects on norepinephrine release in rat tail arteries.

Isolated tail arteries from Wistar rats, prelabeled with [3H]norepinephrine (NE) were subjected to electrical field stimulation (24 pulses at 0.4 Hz and 200 mA). Both NE release and vasoconstriction were measured in parallel. The selective alpha 2-adrenoceptor agonist B-HT 933 diminished the evoked NE release in a concentration-dependent manner. This effect of B-HT 933 was counteracted by the selective alpha 2-adrenoceptor antagonist rauwolscine, which given alone enhanced evoked transmitter release, indicating the presence of autoinhibition. N-Ethylmaleimide (NEM) (3 microM), which also in itself increased transmitter release, virtually abolished facilitation of release by 0.1 microM rauwolscine and diminished its inhibition by 10 microM B-HT 933. The diminution of the inhibitory effect of B-HT 933 was even more pronounced when the current strength was decreased from 200 mA to 90 mA to compensate for the NEM-induced increase in transmitter release. Treatment of the arteries with NEM did not affect the perfusion pressure. In contrast, however, the B-HT 933-induced increase in basal perfusion pressure was significantly diminished by NEM. Although 10 microM B-HT 933 given alone did not affect stimulation-evoked vasoconstriction, it caused a significant increase in arteries treated with NEM. In conclusion, the observed NEM-sensitivity of the presynaptic and vascular alpha 2-adrenoceptor mechanisms is compatible with the idea that both pre- and postsynaptic alpha 2-adrenoceptors couple to Pertussis toxin (PTX)-sensitive G proteins.


Effect of the phosphodiesterase inhibitor UK 61260 on human myocardial inotropy and diastolic relaxation.

The phosphodiesterase inhibitor UK 61260 exhibits positive inotropic activity in animal studies and is under clinical investigation for treatment of congestive heart failure (CHF). We examined the lusitropic and inotropic responses to UK 61260 in electrically driven (1 Hz, 37 degrees C) human auricular trabeculae (AUT, aortocoronary bypass operation, nonfailing hearts, n = 13) and in papillary muscle strips (PAP) from moderately (New York Heart Association, NYHA II-III, mitral valve replacement, n = 6) and terminally (NYHA IV, heart transplantation, n = 7) failing human hearts. For comparison, we studied the effects of UK 61260 after prestimulation with forskolin (FOR 0.03 microM) and isoprenaline (ISO 0.03 microM), as well as the effects of milrinone (MIL 1-1,000 microM), ISO (0.01-10 microM), ouabain (OUA, 0.1 microM), and Ca2+ (1.8-15 mM) in failing human myocardium alone. UK 61260 increased force of contraction (FOC), peak rate of tension increase (+T) and decay (-T) significantly (p less than 0.01) in AUT but not in PAP of NYHA II-III and NYHA IV. Only after prestimulation (FOR and ISO), was UK 61260 effective in stimulating FOC in NYHA II-III and NYHA IV. UK 61260 increased (p less than 0.01) +T and -T, resulting in a shortening of twitch time. As judged from the EC50 values, UK 61260 increased FOC more potently than MIL. The effectiveness of OUA and Ca2+ in increasing developed tension in human failing myocardium was significantly higher as compared with UK 61260. We conclude that during stimulation of the cardiac beta-adrenoceptor-adenylate-cyclase system, UK 61260 increases myocardial systolic and diastolic function in failing human myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)


Facilitatory role of the renin-angiotensin system in controlling adrenal catecholamine release in hemorrhaged dogs.

Effects of the renin-angiotension system (RAS) on adrenal catecholamine release in response to hemorrhagic hypotension and splanchnic nerve stimulation (SNS) were studied in pentobarbital-anesthetized dogs. In hemorrhage experiments, mean blood pressure (MBP) was maintained at 50 mm Hg for 60 min by bleeding the arterial blood into a pressurized bottle. In the renal intact group (control), epinephrine (EPI) and norepinephrine (NE) output from the adrenal gland increased markedly during hemorrhagic hypotension: from 45 +/- 13 and 4.7 +/- 0.9 to 1,167 +/- 202 and 169 +/- 30 ng/min at 60 min after onset of hemorrhage, respectively. The increases in catecholamine output during hemorrhagic hypotension in the renal-intact group pretreated with captopril (1 mg/kg intravenously, i.v.) and in the renal-ligated group were significantly smaller than those in the control group. The increases in catecholamine output in the renal-ligated group infused with angiotensin II (AngII 10 ng/kg/min i.v.) were comparable to those in the control group. In SNS experiments, AngII infusion (10 ng/kg/min i.v.) enhanced increases in catecholamine output induced by 3 Hz SNS significantly. Captopril (1 mg/kg i.v.) did not affect the SNS-induced increases in catecholamine output. These results suggest that the renal RAS facilitates reflex release of adrenal catecholamines during hemorrhagic hypotension, at least in part, by acting directly on the release process of catecholamines from dog adrenal gland.


Evidence for a role of nitric oxide in hypovolemic hemorrhagic shock.

Hypovolemic hemorrhagic shock was induced in rats by intermittently withdrawing blood from an iliac catheter for 20 min until mean arterial blood pressure (MAP) decreased to 30 mm Hg. Survival rate, survival time, plasma myocardial depressant factor (MDF) activity, MAP, and microscopic gastric alterations were then evaluated. NG-nitro-L-arginine methyl-ester (L-NAME), a selective inhibitor of nitric oxide (NO) production from L-arginine, was injected intravenously (i.v.) after the bleeding was discontinued. Untreated hemorrhagic shocked rats died in 27 +/- 3.3 min, had enhanced plasma activity of MDF, and exhibited hemorrhagic infiltrates in gastric fundus mucosa. L-NAME (5 and 10 mg/kg) significantly increased survival rate and time, blunted the increase in plasma MDF activity, and protected against the gastric lesions induced by hemorrhagic hypovolemic shock. All these protective effects were reversed by a bolus of L-arginine (30 mg/kg/i.v.), given 2 min after administration of L-NAME. Our findings suggest that NO production plays an important role in the pathophysiology of hemorrhagic shock.


Inhibition of granulocyte cAMP-phosphodiesterase by rolipram in vivo is not sufficient to protect the canine myocardium from reperfusion injury.

The purpose of this study was to determine whether the selective type IV cAMP-phosphodiesterase inhibitor rolipram could reduce the reperfusion injury that occurs during myocardial infarction in the anesthetized dog. This question was tested in pentobarbital-anesthetized dogs subject to 90 min of regional myocardial ischemia and 5 h of reperfusion. Dogs were treated with 1 mg/kg of rolipram (i.v., 15 min before reperfusion) followed by a 1 mg/kg/h infusion over the duration of the 5 h of reperfusion. Rolipram was tested in vitro for efficacy in inhibition of isolated human neutrophil superoxide generation. Rolipram produced significant inhibition of superoxide production over the concentration range of 0.1-100 microM rolipram when neutrophils were stimulated with a 10(-7) M concentration of the chemotactic peptide f-Met-Leu-Phe. Rolipram significantly inhibited superoxide generation from human and canine granulocytes in whole blood stimulated by zymosan. Therapeutic concentrations of rolipram in the blood of dogs were achieved during the course of the experiments with a plasma concentration of 0.761 +/- 0.095 micrograms/ml (2.76 +/- 0.34 microM) at the time of reperfusion, and 0.574 +/- 0.098 micrograms/ml (2.08 +/- 0.36 microM) at the end of the reperfusion period. The relative severity of myocardial ischemia between the two treatment groups was similar as assessed with radiolabeled microsphere measurement of myocardial blood flow. Transmural myocardial blood flows were not significantly different between the two groups after coronary occlusion (control, 0.05 +/- 0.01 ml/min/g, n = 6, vs. rolipram, 0.18 +/- 0.07 ml/min/g, n = 6; p = 0.48).(ABSTRACT TRUNCATED AT 250 WORDS)


Alpha-adrenergic and serotonergic receptors and forearm venous compliance in normal human subjects.

The effect of alpha-adrenergic and serotonergic receptor agonists and antagonists on forearm venous capacitance and vascular resistance was studied in normal subjects. Venous volumes were significantly decreased by phenylephrine, an alpha 1-adrenoceptor agonist, and norepinephrine, which stimulates both alpha 1- and alpha 2-adrenoceptors, but not by the alpha 2-adrenoceptor agonist clonidine. Vascular resistance was increased significantly by all three agonists. Both the alpha 2-adrenoceptor antagonist yohimbine and the alpha 1-adrenoceptor antagonist prazosin attenuated the venoconstrictor and vasoconstrictor response to norepinephrine, indicating that both adrenoceptors are present. 5-Hydroxytryptamine significantly decreased venous volumes, while vascular resistance was not affected. Ketanserin, a 5-HT2 and alpha 1-adrenoceptor antagonist, attenuated the venous volume responses to 5-hydroxytryptamine and phenylephrine. It is concluded that there are alpha 1- and alpha 2-adrenoceptors and 5-HT2 receptors in the forearm venous system. However, vasoactive doses of clonidine are not venoconstricting. Forearm veins are sensitive to doses of 5-hydroxytryptamine, which do not change vascular resistance compared to alpha-adrenoceptor agonists, which affect both.


Has antihypertensive treatment prevented vascular disease or vascular events?

Our current knowledge of the effects of antihypertensive therapy is based on a large number of therapeutic trials based on mortal and morbid cardiovascular events. Although these events are indeed "hard" data, extrapolations from the results of trials based on events cannot be applied to possible effects on the underlying cardiovascular disease, particularly coronary artery disease, as the mechanisms responsible for the precipitation of events are often different from the mechanisms leading to disease. Once a distinction between prevention of disease and prevention of events is made, then both must be considered to be different, but essential, goals of antihypertensive therapy. The prevention of events is a short-term goal for patients who already have disease, and can be easily appreciated by traditional event-based trials; the prevention of disease, however, is a long-term goal that can be appreciated clinically only after years of treatment, but can be assessed within a shorter time frame by measuring plaque development, as in new types of randomized trials. Studies of the potential actions of antihypertensive drugs on the mechanisms precipitating events, particularly thrombotic factors, may further supplement our current knowledge in our search for the most appropriate treatment of the hypertensive patient.


Vascular mechanisms in hypertensive cerebrovascular disease.

Hypertension causes vascular changes of essentially three types: structurally adaptative changes, degenerative alterations unrelated to atherosclerosis, and atherosclerosis. Structural changes result in an increased peripheral resistance, even in the relaxed vascular bed, and a reduced collateral capacity, thus predisposing to ischemia distal to an arterial stenosis/occlusion and to "watershed" infarcts in connection with a drop in blood pressure. Degenerative changes in the small intracerebral arteries can lead to plasma extravasation and focal brain edema, lacunar infarcts, and intracerebral hemorrhages. Hypertension also predisposes to saccular aneurysms and subarachnoid hemorrhages. Finally, atherosclerotic changes including stenoses or occlusions of predominantly extracranial and pial arteries give rise to transitory ischemic attacks and brain infarcts by artery-to-artery embolism or distal hemodynamic perfusion insufficiency.


MIDAS: hypertension and atherosclerosis. A trial of the effects of antihypertensive drug treatment on atherosclerosis. MIDAS Research Group.

Although clinical trials of the efficacy of antihypertensive treatment have demonstrated impressive reductions in the incidence of stroke, the reduction in coronary artery disease mortality has been less impressive. It may be that the antihypertensive drugs used in these trials induced metabolic disturbances, or produced inadequate regression of left ventricular hypertrophy, thus blunting the reduction in risk of coronary artery disease expected with blood pressure-lowering. Isradipine, a dihydropyridine calcium antagonist known to be an effective antihypertensive agent, has also displayed pronounced antiatherogenic effects in animals. Thus, a reasonable hypothesis could be that isradipine not only reduces the level of blood pressure, but also may have a positive effect on the evolution of atherosclerotic plaque in coronary and carotid arteries, thereby leading to prevention of clinical sequelae of atherosclerosis. On this basis, a 3-year clinical trial is being carried out in the United States--the Multicenter Isradipine/Diuretic Atherosclerosis Study (MIDAS)--to establish the efficacy of isradipine in inhibiting atherogenesis and retarding the progression of atherosclerosis in carotid arteries of hypertensive patients. The primary end point of the study is intima-media thickness and the extent of atherosclerotic plaque in the carotid arteries, as measured by B-mode ultrasonography.


Enhanced risk of thromboembolic disease in hypertension from platelet hyperfunction and decreased fibrinolytic activity: has antihypertensive therapy any influence?

Enhanced platelet function and a decrease in fibrinolytic activity have been reported in patients with mild hypertension after treatment with various nonselective beta-blockers. Until now, such changes have not been reported during treatment with beta 1-selective drugs or with agents that have intrinsic sympathomimetic activity. The impact of angiotensin-converting enzyme inhibitors and diuretics on platelet function and fibrinolytic activity has not been fully elucidated. Calcium antagonists of various types, however, are known to decrease platelet release in vivo whereas their effects on platelet aggregation and fibrinolytic activity are less clear. The new dihydropyridine calcium antagonist isradipine, when tested in a group of patients with mild hypertension, resulted in a decrease in platelet aggregation, a shortened euglobulin clot-lysis time, and a dramatic increase in t-PA (tissue-plasminogen activator) activity after 14 days of treatment. These changes remained stable throughout the 1-year study period. The fact that antihypertensive therapy does not always result in the hoped-for prolongation of life, despite satisfactory blood pressure reduction, may be in part due to an unfavorable impact on various components of the blood-clotting system.


Platelet activation by low-density lipoprotein and serotonin: effects of calcium antagonists.

Epidemiological studies indicate that there are biological interrelationships between blood pressure and blood lipids that may influence the mechanisms whereby hypertension is associated with an increased risk of coronary artery disease. Serotonin (5-HT) and thromboxane A2, which are released from aggregating platelets, mediate platelet-induced vasoconstriction, which itself significantly contributes to coronary artery constriction in vivo. Platelet aggregatory response to serotonin is modulated by disparate effects of lipoprotein fractions. This corresponds to the recognized differences in degree of atherogenicity of low- (LDL) and high-density lipoprotein (HDL). Amplification of serotonin-induced platelet aggregation by LDL and its inhibition by HDL support the hypothesis that 5-HT-mediated effects represent a mechanism clinically relevant to both chronic progression of atherosclerosis (particularly at sites of vascular injury and atherosclerotic plaques) and acute thrombotic events. Calcium antagonists differ in their platelet-inhibition potency, including their effects on platelet response to 5-HT and LDL. Verapamil and isradipine inhibit platelet aggregation induced by 5-HT at therapeutic concentrations. Isradipine also inhibits the amplifying effect of LDL on 5-HT-induced aggregation. These platelet effects of calcium antagonists appear to be neither group- nor class-specific but, rather, drug-specific.


Antiatherosclerotic actions of isradipine.

Isradipine, a calcium antagonist of the dihydropyridine type, shows antiatherosclerotic actions that interfere with all three main mechanisms of atherosclerosis. These actions are mediated by the release of prostaglandin I2 and endothelium-derived relaxing factor, and the subsequent elevation of intracellular adenosine-3',5'-cyclic phosphate and 3',5'-guanosine monophosphate, respectively. These mechanisms have been proven in vitro and in animal models. Preliminary data in humans suggest that these mechanisms have clinical relevance in the long-term treatment of patients as well.


Effects of the calcium antagonist isradipine on 24-hour ambulatory blood pressure, platelet aggregation, and neutrophil oxygen free radicals in hypertension.

The effects of isradipine on ambulatory blood pressure, platelet aggregation, and oxygen free radicals were assessed in 30 patients with hypertension in a non-comparative 16-week study. After 4 weeks of placebo run-in, patients received isradipine at 2.5 mg twice daily for 12 weeks. The average supine systolic/diastolic blood pressure (155 +/- 17/101 +/- 11 mm Hg) was significantly reduced at the end of treatment (144 +/- 13/95 +/- 9 mm Hg; p less than 0.01). The heart rate was not significantly altered. Isradipine had no adverse effects on red or white blood cells or on plasma viscosity. The thromboxane B2 level and epinephrine-induced platelet aggregation were significantly (p less than 0.05) reduced. High-density lipoprotein cholesterol was significantly (p less than 0.01) increased after vs. before treatment; total cholesterol was significantly (p less than 0.05) increased at midstudy, but this was not significant at the end of the study. Other biochemical parameters were unchanged. Studies of neutrophil oxygen free radicals by serum opsonized zymosan and phorbol myristate acetate were not affected by isradipine. In conclusion, isradipine is an effective antihypertensive agent that also has beneficial effects on platelet aggregation and lipids while having no effects on neutrophil oxygen free radicals or most of the biochemical variables tested, making it an ideal agent for hypertension.


Tolerability of isradipine in the treatment of mild-to-moderate hypertension in general practice: a large-scale surveillance study.

The tolerability of isradipine was evaluated in an open trial of patients with mild-to-moderate essential hypertension as treated in general practice. The primary objective was to identify all adverse reactions, especially those that were newly occurring (greater than or equal to 6 reports), with a frequency greater than 1/1,000. Over 1,100 general practitioners and 5,526 patients participated in this trial. After a 2-week washout period, and a 3-week placebo run-in, patients with diastolic blood pressure (DBP) greater than or equal to 95 mm Hg were initially given isradipine at 1.25 mg twice daily. After 4 weeks, doses were doubled if DBP was greater than 90 mm Hg. If, after a further 4 weeks with doubled dosages, the DBP was still greater than 90 mm Hg, a second (nonspecified free-choice) antihypertensive agent was added to the treatment. Adverse events were recorded by open questioning. The incidence of adverse events was found to be similar to that with placebo; adverse events were generally mild or moderate in intensity and disappeared over time. No newly occurring adverse events were found. In conclusion, isradipine is safe and well tolerated at effective antihypertensive doses in patients with mild-to-moderate hypertension as treated in general practice.


Long-term (2-year) isradipine data in the treatment of mild-to-moderate hypertension.

At the end of a short-term (3-month) study of antihypertensive treatment of mild-to-moderate hypertension, 141 of the 200 study patients continued into a 2-year follow-up of isradipine as monotherapy or in combination with other antihypertensive agents. Although all 141 patients completed the first year, only 102 completed the study. Twenty-four patients dropped out: 2 with flushing; 1 each with arrhythmia, edema, angina, and headache; 12 who were noncompliant; 2 with disease unrelated to the study drug; and 4 for reasons unknown. Before the follow-up, 70% of the 141 patients were taking isradipine; after 2 years, 63% were still taking isradipine as monotherapy. During the follow-up study, the blood pressure remained stable (142.9/86.8 mm Hg after 3 months, and 142.9/86.2 mm Hg after 2 years), whereas the normalization rate was only slightly changed (73 vs. 75.2%). The incidence of reported adverse events decreased with time. At the end of the short-term study, 44.7% of patients had reported one or more adverse events; after 2 years of treatment, only 14.4% reported adverse events. Two patients had ECG signs of left ventricular hypertrophy: one showed no relevant changes while the other presented clear signs of regression. No clinically relevant laboratory abnormalities were noted during the study. In conclusion, isradipine is effective, well tolerated and safe in the long-term treatment of mild-to-moderate hypertension.


Isradipine in the treatment of mild-to-moderate hypertension in Portugal.

A short-term trial of isradipine was conducted to assess its effectiveness and tolerability in the treatment of mild-to-moderate hypertension. The study was carried out by general practitioners and involved 2,702 patients, aged 18-70 years, who had diastolic blood pressures (DBP) of 95-114 mm Hg. Patients completed a pretreatment phase of up to 4 weeks for antihypertensive drug washout and placebo run-in, before entering a 12-week active-treatment phase with 1.25 mg of isradipine twice daily, which was increased after 4 weeks to 2.5 mg twice daily, depending on the blood pressure response. At the end of 12 weeks, the mean systolic blood pressure (SBP) and DBP were 148.1 and 86.7 mm Hg compared with 169.0 and 103.0 mm Hg after placebo, respectively. The majority of patients (89.6%) had a DBP reduction greater than 10 mm Hg, and 86.2% had normalized DBP (less than or equal to 90 mm Hg) at the end of treatment. Adverse events were reported by 2.8% of patients, and 90% of patients and general practitioners reported satisfaction with the treatment. Thus, our results indicate that isradipine is effective and well tolerated, and may deserve a place as first-line treatment in mild-to-moderate hypertension.


Clinical efficacy and tolerability of isradipine in the treatment of mild-to-moderate hypertension in young and elderly patients.

The clinical efficacy and tolerability of isradipine was evaluated in 63 patients with mild-to-moderate hypertension [supine systolic blood pressure (SBP) greater than or equal to 160 mm Hg and diastolic blood pressure (DBP) greater than or equal to 95 mm Hg]. Patients were divided into two groups according to age: group A (n = 41), aged 37-69 years (mean age of 54 +/- 7 years); group B (n = 22), aged 70-80 years (mean age of 72.8 +/- 2.4 years). After a 3-week washout period, group A received 2.5 mg of isradipine twice daily for 6 weeks. Group B received 1.25 mg of isradipine initially, increasing to 2.5 mg twice daily according to treatment response and tolerability. At the end of treatment (week 6), there were statistically significant decreases (p less than 0.01) in supine SBP and DBP in both groups compared with baseline values: the mean SBP in groups A and B decreased from 160.0 +/- 14.7 to 133.6 +/- 10.0 mm Hg and from 161.6 +/- 17.8 to 134.8 +/- 10.9 mm Hg, respectively; the mean DBP in groups A and B decreased from 101.3 +/- 3.0 to 83.6 +/- 5.5 mm Hg and from 101.3 +/- 8.4 to 84.2 +/- 3.6 mm Hg, respectively. Clinical and laboratory parameters did not change significantly during treatment. Side effects (headache, flushing, palpitations, and edema) were mild/moderate and disappeared after the first 2 weeks of treatment. In conclusion, 2.5 mg of isradipine twice daily is effective and well tolerated in the treatment of mild-to-moderate hypertension regardless of patient age.


Metabolic, hematological, and cardiac effects of long-term isradipine treatment in mild-to-moderate essential hypertension.

Twenty-four patients with mild-to-moderate hypertension (19 women, 5 men; mean age of 49 +/- 9.1 years) completed a 2-week washout phase followed by 1 week of single-blind placebo. Patients were then given isradipine at 2.5 mg twice daily, which was increased to up to 7.5 mg twice daily according to the blood pressure response, over a 12-month period. Thirteen patients completed the trial. The supine and sitting blood pressure decreased to normal levels within 6 weeks of starting active treatment. Heart rate remained unchanged. Plasma cholesterol and triglycerides did not change significantly. Plasma high-density lipoprotein (HDL) cholesterol increased significantly (p less than 0.05) and a decrease (NS) was observed in low-density lipoprotein (LDL) cholesterol and in the LDL/HDL cholesterol ratio. Very-low-density lipoprotein (VLDL) cholesterol did not change, nor did other biochemical laboratory tests, or electrocardiographic and echocardiographic parameters. The most notable side effects were headache (n = 1), flushing (n = 1), palpitations (n = 3), and pretibial edema (n = 1). In conclusion, our results indicate that isradipine is safe and effective in the long-term treatment of mild-to-moderate hypertension. It also appears to have beneficial effects on lipid metabolism.


Role of calcium and endothelium in hypertension, cardiovascular disease, and subsequent vascular events.

The response of isolated blood vessels to vasoactive agonists is modulated by endothelial cells. Nitric oxide is probably the major endothelium-derived relaxing factor (EDRF), although an unidentified hyperpolarizing factor and prostacyclin are secreted. Previous studies indicate that the release of EDRF must require an increase in cytoplasmic calcium in the endothelial cells. In perfused arteries, calcium-channel activators also trigger the release of EDRF; thus, the endothelial cell membrane must contain voltage-operated calcium channels. However, the increase in cytoplasmic calcium stimulating EDRF release is not due to activation of these channels. Endothelial cells also release constricting factors (EDCF), most likely superoxide anions, endoperoxides, and endothelin. Endothelium-dependent contractions can be evoked by anoxia. These contractions, as well as the endothelium-dependent increases in tension evoked by stretch in cerebral arteries, are inhibited by calcium antagonists. This inhibitory effect is at the level of vascular smooth muscle, not the endothelium. Thus, calcium antagonists do not prevent the release of either EDRF or EDCF. Indeed, by facilitating the inhibition exerted by the former and preventing the activation of vascular smooth muscle by the latter, they favor dilation.


Clinical equivalence of once-daily administration of a modified-release formulation of isradipine and twice-daily administration of the standard formulation. Multicentre Study Group.

In a double-blind, parallel-group comparative study, once-daily administration of a modified-release formulation of isradipine (Im, n = 189) was compared with twice-daily administration of the standard formulation (Is, n = 191). Following a 3- to 5-week placebo period, patients with a sitting diastolic blood pressure (sDBP) of greater than or equal to 100 mm Hg but less than or equal to 120 mm Hg were randomized to receive either Im at 5 mg once daily or Is at 2.5 mg twice daily for 6 weeks. A double-dummy technique was used to maintain blindness and no dosage titration was made. Blood pressure was always recorded in the morning before drug administration (12 h after the previous administration of Is or 24 h after the previous administration of Im). The mean sDBP was reduced significantly (p less than 0.001) and equally in both groups, and the normalization rate (sDBP less than or equal to 90 mm Hg) was 54% with Im and 55% with Is. Adverse events were slightly less frequent overall in the patients receiving Im than Is (23 vs. 28%, respectively) as was the incidence of typical dihydropyridine side effects such as flushing and headache. The results show that once-daily administration of 5 mg of Im is as effective and better tolerated than 2.5 mg twice daily of Is while providing adequate blood pressure control at the end of the 24-h dosing interval.


Postexercise reflex control of forearm vascular resistance during calcium antagonism with slow-release oral isradipine.

In untreated hypertensive patients, blood pressure is decreased during the hours that follow a single bout of exercise, but the mechanisms involved are as yet unknown. As antihypertensive chemotherapy may interfere with cardiovascular regulation, we investigated the effects of calcium antagonism with isradipine (slow-release oral formulation, SRO) on postexercise blood pressure and on the reflex control of forearm vascular resistance in patients with mild-to-moderate hypertension. The results show that isradipine SRO exerted an additional blood pressure-lowering effect after exercise that was associated with a further decrease in forearm vascular resistance. The reflex changes in forearm vascular resistance were potentiated after exercise, but were not further affected by isradipine SRO. Therefore, isradipine SRO does not interfere with the cardiovascular mechanisms that act to decrease blood pressure after exercise in patients who have hypertension.


Pharmacological modulation of stress-induced cardiovascular hyperreactivity in essential hypertension.

The effects of the calcium antagonist isradipine and the beta-blocker metoprolol, which are based on different antihypertensive therapeutic principles, were evaluated in 52 men with mild-to-moderate hypertension in a 6-week, double-blind, randomized study. Mental stress-testing was performed before and after active treatment. With isradipine (n = 26), the stress-induced responses of cardiac output and total peripheral resistance were not significantly changed, but the blood pressure (BP) response, specifically the diastolic response, was decreased. With metoprolol (n = 26), there was a decreased response of cardiac output and an increased response of total peripheral resistance, and the BP response was even greater than it had been before treatment. Thus, these results indicate that beta-blockade is effective in reducing cardiac responsiveness but, because of vascular counterregulatory mechanisms, BP responsiveness is not decreased. In contrast, calcium antagonism preserves the physiological hemodynamic profile while reducing BP responsiveness to stress.


Does isradipine exert a special early-morning blood pressure-lowering effect?

The blood pressure-lowering effect of isradipine at 1.25-2.5 mg twice daily (taken at 0700 and 1900 h) was assessed in a double-blind study involving 28 men with mild-to-moderate hypertension. After a 4-week placebo period, patients were randomized to receive either isradipine (group I) or placebo (group II) for 8 weeks. At the end of the placebo and active-treatment periods, patients were evaluated by 24-h ambulatory blood pressure monitoring. Data were analyzed according to two time periods: daytime, 1000-2300 h; nighttime and early morning, 2300-1000 h. Intersubject analyses were performed comparing values at the end of placebo with those at the end of active treatment. Intrasubject two-way analysis of variance showed that the time of day or night had no influence on blood pressure changes. Comparison of systolic (SBP) and diastolic (DBP) blood pressures with isradipine indicated that there were significantly greater average decreases in SBP at 0600-0800 h than at 1800-2000 h (p = 0.038), and at 0800-1100 h than at 2000-2300 h (p = 0.045). This was also true for the average decreases in DBP (p = 0.006). In conclusion, isradipine exerts blood pressure control throughout 24 h with a pronounced action during the early morning (0600-0800 h) period.


Isradipine in the treatment of hypertensive crisis in ambulatory patients.

In order to investigate the efficacy of isradipine in the treatment of hypertensive crisis, we treated three groups of patients who had diastolic blood pressure (DBP) greater than 120 mm Hg, and who were without signs of acute target-organ damage. Isradipine was given sublingually in doses of 1.25 mg (group 1; n = 10), 2.5 mg (group 2; n = 10), and 5 mg (group 3; n = 7). Mean arterial pressure (MAP) was reduced in all patients [from 153.4 +/- 4.3 to 124.0 +/- 2.3 mm Hg at 60 min, and to 118.0 +/- 2.1 mm Hg at 2 h after administration (p less than 0.001)]. The heart rate (HR) did not change significantly (from 82.4 +/- 3.7 to 84.0 +/- 6 beats/min; NS). No significant differences were noted in the overall responses of the three groups; however, blood pressure reduction was more rapid in the group receiving 5 mg compared with the other two dosages. These results show that isradipine given sublingually is effective in reducing the elevated blood pressure of a hypertensive crisis and is not accompanied by limiting side effects. Isradipine's onset of action is early (approximately 30 min after dosing) and reaches its maximum blood pressure response within 2 h of administration. No dose-dependent reductions in blood pressure were observed with the dosage range employed in this study.


Regression of cardiac hypertrophy in hypertensive patients by long-term treatment with isradipine.

The aim of this study was to assess the effects of long-term (9-month) treatment with isradipine, alone or combined with bopindolol, on blood pressure, left ventricular hypertrophy (LVH), and diastolic function. Thirty-five hypertensive patients with LVH and supine diastolic blood pressures (DBPs) greater than or equal to 100 and less than or equal to 120 mm Hg received increasing doses of isradipine (1.25, 2.5, and 5 mg twice daily); if blood pressure was not controlled, bopindolol (0.5-2 mg once daily) was added to the treatment. Clinical and laboratory investigations were carried out after placebo for baseline values, and after 5 and 9 months of isradipine treatment alone (n = 11) or combined with bopindolol (n = 24). At the end of the study, blood pressure was significantly decreased while heart rate did not change with isradipine alone, but decreased significantly after the addition of bopindolol. Although the DBP was normalized (less than or equal to 90 mm Hg) in 28 patients (80%), complete reversal of the left ventricular mass index (LVMI) was seen in only 7 patients (20%). The ratio of early to atrial filling did not change, but the deceleration time was significantly decreased after 9 months. No laboratory abnormalities or important side effects were observed. Although isradipine alone or combined with bopindolol was effective in controlling blood pressure and significantly reduced the LVMI after 5 months, improvement in diastolic function was seen only after 9 months of active treatment.


Effects of isradipine on hypertension and renal hemodynamics.

The safety and efficacy of isradipine as well as its long-term effects on renal hemodynamics were evaluated in a study of 17 patients with mild-to-moderate essential hypertension and normal or slightly impaired renal function. After a 4-week placebo period, isradipine was administered according to a schedule of increasing dosages ranging from 1.25 to 5 mg twice daily. During treatment and at the latest follow-up (at 6 months), isradipine was found to lower blood pressure (diastolic and systolic) significantly. There were no significant side effects or changes in blood chemistry during treatment. Plasma renin activity and serum aldosterone were slightly raised whereas the glomerular filtration rate, renal plasma flow, and filtration fraction were significantly raised at the latest follow-up compared with the pretreatment levels.


Hemodynamic effects of isradipine and nifedipine in chronic sustained hypertension.

As isradipine is known to be less cardiodepressant than nifedipine, myocardial wall stress--an important determinant of cardiac oxygen demand--may also be more favorably influenced by isradipine. Therefore, the acute effects of an intravenous (i.v.) infusion of isradipine (0.4 mg) vs. nifedipine (2.0 mg) on cardiac hemodynamics and systolic wall stress were investigated in a crossover study of 12 hypertensive patients. Vasodilation-induced reflex activation was limited by pretreatment with i.v. propranolol at 0.1 mg/kg of body weight. The hemodynamic parameters measured were statistically comparable at baseline and after propranolol with both calcium antagonists, as was blood pressure reduction. However, the end-systolic volume decreased with isradipine, but not with nifedipine [before: 69 +/- 7.0 ml (mean +/- SEM); after: 61 +/- 6.1 ml; 2p less than 0.01 vs. before: 62 +/- 6.1 ml; after: 64 +/- 7.0 ml; NS, (difference between changes in response to treatments: 2p less than 0.05)]. The ejection fraction increased only with isradipine vs. nifedipine [before: 48 +/- 2.3%; after: 54 +/- 2.3%; 2p less than 0.001 vs. before: 52 +/- 2.0%; after: 52 +/- 2.3%; NS (difference between changes in response to treatments: 2p less than 0.05)]. Systolic wall stress decreased significantly more with isradipine than with nifedipine [before: 2,767 +/- 231; after: 2,153 +/- 162 relative units; 2p less than 0.001 vs. before: 2,636 +/- 212; after: 2,310 +/- 199 relative units; 2p less than 0.05 (difference between changes in response to treatments: 2p less than 0.05)]. These results suggest that isradipine, given acutely, unloads the heart more than does nifedipine.


Effects of long-term administration of isradipine on renal hemodynamics and sodium metabolism.

The objective of this double-blind, placebo-controlled study was to evaluate the effects of isradipine on renal hemodynamics and function. Ten patients with mild-to-moderate hypertension were given isradipine at 2.5 mg twice daily for 3 months after 4 weeks of placebo washout. Renal studies were performed 2 h after the morning administration of treatment. The results of these evaluations indicate that isradipine as monotherapy significantly reduced the mean arterial pressure, while the effective renal plasma flow was increased (+16%) and glomerular filtration rate remained virtually unchanged (-8.7 ml/min). The filtration fraction and renal vascular resistance decreased significantly. There was a significant decrease in the absolute rate of proximal sodium reabsorption, and a significant increase in the distal reabsorption. Clearance of sodium remained unchanged. In conclusion, monotherapy with low-dose isradipine was not only effective in controlling blood pressure, but also decreased the renal vascular resistance while avoiding glomerular hyperfiltration, and exerted a protective effect on renal hemodynamics. Natriuresis also remained stable despite the blood pressure reduction.


Long-term antihypertensive and renal effects of isradipine in hypertensive patients with normal and reduced renal function.

The long-term hemodynamic and antihypertensive effects of isradipine were investigated in 11 patients who had normal renal function and 9 who had reduced renal function. The dose regimen was 1.25-5 mg twice daily, depending on blood pressure response. After 24 weeks of active treatment, systolic/diastolic blood pressure decreased from 172/106 to 155/94 mm Hg (p less than 0.05) in the patients with normal renal function, and from 176/105 to 169/93 mm Hg (p less than 0.01) in those with impaired renal function. Contrary to the results of short-term treatment, no changes in inulin and p-aminohippuric acid (PAH) clearances were observed in either study group. There were no significant changes in plasma renin, aldosterone, glucose, or lipids, nor were these changes in protein excretion in either group; however, sodium excretion increased significantly in both groups. On the basis of our results, we conclude that isradipine has a place in the treatment of hypertensive patients with mild renal insufficiency.


Cardiovascular diseases, blood rheology, and dihydropyridine calcium antagonists.

Over the last 10 years, accumulating evidence has confirmed the ability of dihydropyridine calcium antagonists to improve red blood cell deformability. In this review of the literature, particular attention is paid to results obtained with isradipine, a second-generation derivative of the 1,4-dihydropyridine family. Isradipine appears to be more selective in various pharmacological properties, well tolerated, easy to administer, and effective in controlling blood pressure and reducing the frequency of ischemic events. While manifesting these desirable attributes, isradipine retains an unimpaired ability to improve red blood cell deformability. It is suggested that the therapeutic efficacy of dihydropyridine calcium antagonists is attributable, at least in part, to their ability to affect blood rheology by improving red blood cell deformability.


Effect of isradipine on responses to standardized physical stress tests in hypertension of pregnancy.

Fourteen women with hypertension of pregnancy and who were in their last trimester were subjected to three standardized physical stress tests before and after 1-2 weeks of treatment with 5 mg of isradipine twice daily. Their blood pressure and heart rate responses to the isometric handgrip exercise, the cold pressor test, and the orthostatic tilt test were recorded. Treatment with isradipine reduced systolic and diastolic blood pressures significantly at rest. However, although the diastolic blood pressure was reduced during the stress tests, the decrease was significant only during cold pressor testing.


Use of teaching methods within the lecture format.

A survey was carried out at Dorset House School of Occupational Therapy, Oxford, into the perceived effectiveness of different teaching methods used within the lecture format in the Human Biology Courses for Year 1 and Year 2. Results showed that the traditional, didactic lecture was perceived by the students as the least effective method used, yet by involving the students actively within the lecture time the format was enhanced and was regarded as a more effective teaching/learning tool. Experimental tasks and learning packages used within the lecture format were also perceived by the students as effective. Some trends were noted relating to the age of students and the different perceptions of effectiveness of teaching methods. The implication of these results on the planning and financing of courses is discussed.


The use of the liquid crystal display (LCD) panel as a teaching aid in medical lectures.

The liquid crystal display (LCD) panel is designed to project on-screen information of a microcomputer onto a larger screen with the aid of a standard overhead projector, so that large audiences may view on-screen information without having to crowd around the TV monitor. As little has been written about its use as a visual aid in medical teaching, the present report documents its use in a series of pathology lectures delivered, over a 2-year period, to two classes of about 150 medical students each. Some advantages of the LCD panel over the 35mm slide include the flexibility of last-minute text changes and less lead time needed for text preparation. It eliminates the problems of messy last-minute changes in, and improves legibility of, handwritten overhead projector transparencies. The disadvantages of using an LCD panel include the relatively bulky equipment which may pose transport problems, image clarity that is inferior to the 35mm slide, and equipment costs.


Simultaneously occurring alopecia areata and Hodgkin's lymphoma: complete remission of both diseases with MOPP/ABV chemotherapy.

A 43-year-old man presented with simultaneously occurring alopecia areata and stage IIIB nodular sclerosing Hodgkin's disease. Systemic symptoms of Hodgkin's disease were present for 6 months, and rapidly developing patchy hair loss of the scalp was present for 2 weeks prior to presentation. The patient was treated with eight cycles of MOPP-ABV chemotherapy that resulted in complete remission of Hodgkin's-disease. Four months after the completion of chemotherapy, the patient had normal hair regrowth with no evidence of alopecia areata. Alopecia areata may be an autoimmune disease and may respond to chemotherapy.


CNQX binding to non-NMDA glutamate receptors in canine cerebro-cortical crude synaptosomal membranes: pharmacological characterization and comparison of binding parameters in dogs with congenital portosystemic encephalopathy and control dogs.

The pharmacological profile and binding characteristics of the non-NMDA antagonist of glutamate receptors [3H]6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX), were investigated in triton-washed crude synaptosomal membranes prepared from canine cerebral cortex. [3H]CNQX binding was inhibited by various glutamate agonists and antagonists, the rank order of potency being CNQX greater than alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) = quisqualate = kainate greater than glutamate. Two binding sites for [3H]CNQX were apparent when non-specific binding (NSB) was defined with unlabelled CNQX. In contrast, when NSB was defined with saturating concentrations of unlabelled AMPA and kainate, only one binding site was identified which corresponded to the high affinity site identified when CNQX was used to define NSB. No physiologically relevant differences were found in binding parameters for [3H]CNQX membranes from dogs with congenital portosystemic encephalopathy (PSE) when compared with control dogs. The affinity constant (Ki) of AMPA displacement of [3H]CNQX binding was not significantly different in PSE dogs compared with control dogs. These results suggest that the antagonist site on cortical non-NMDA receptors is not perturbed in dogs with congenital PSE.


Cranial metastasis of hepatocellular carcinoma associated with chronic epidural hematoma--case report.

A case of cranial metastasis of hepatocellular carcinoma associated with epidural hematoma in a 58-year-old male is presented. The epidural hematoma demonstrated an unusual chronic clinical course and computed tomographic appearance. Associated bleeding from either the diploic marrow or emissary veins might be a cause of the slowly expanding hematoma, and the outward displacement of the artificial bone-flap implanted previously may also have contributed to the chronic course.


Radiation-induced bilateral cystic frontal lobe necroses demonstrating a fluid-blood level--case report.

A 41-year-old male developed radiation-induced bilateral cystic frontal lobe necroses after irradiation for an olfactory neuroblastoma. Computed tomography (CT) and magnetic resonance (MR) imaging revealed the lesions, one containing a fluid-blood level on CT scans and niveau formation on MR images. It was proved to be a coagulated hematoma within the cyst at surgery. Such a fluid-blood level in a radiation-induced cyst has never been reported, although hemorrhage frequently accompanies delayed radiation necrosis. Positron emission tomography with multiple tracers may be useful in differentiating cerebral radiation necrosis from tumor recurrence, because of absence of abnormal tracer accumulation.


Experimental investigation of a new liquid embolization method: enhancing effect of 25% ethanol on conjugated estrogen.

A new liquid embolization material applicable to intracranial lesions was evaluated by selective renal artery embolization in mongrel dogs. Absolute and diluted ethanol, estrogen, and estrogen in 25% ethanol (ethanol-estrogen) were injected. The embolization and side effects were investigated angiographically and histologically. Ethanol-estrogen caused similar embolization to absolute ethanol, but no direct damage to perivascular tissue, and is considered a promising embolization agent in intravascular surgery.


Peritumoral brain edema associated with meningioma--histological study of the tumor margin and surrounding brain.

Thirty-nine cases of intracranial meningiomas were analyzed to identify factors causing brain edema. Edema was significantly correlated with tumor size and the destruction of the leptomeninges and cortex. Meningotheliomatous meningioma tended to have more peritumoral edema. There was no correlation between the presence of edema and location of the tumor or histological features including lymphocytic infiltration and the presence of glial fibrillary acidic protein-positive cells in the tumor tissue. Larger tumors destroy the leptomeninges and cerebral cortex, allowing direct transmission of humoral edema-promoting factor or edema fluid into the white matter, resulting in vasogenic edema.


Postoperative neurosurgical infection and antibiotic prophylaxis.

The most suitable antibiotics for chemoprophylaxis in neurosurgery and risk factors for postoperative neurosurgical infection were investigated by retrospective analysis of 807 neurosurgical procedures in 566 patients between 1980 and 1989. Prophylactic antibiotics were administered intravenously for 6 or 7 postoperative days in all instances. The 807 operations were classified according to the antibiotics used into: 1) penicillin, 2) cephem-I, 3) cephem-II, 4) cephem-III, and 5) others. Postoperative neurosurgical infections occurred in 27 of 807 operations (3.3%), or 27 of 566 patients (4.8%). Hypertension and surgery performed in summer carried a significantly higher risk of infection. Diabetes mellitus, steroid administration, prolonged surgery, re-exploration, and surgery for hemorrhagic cerebrovascular diseases were associated with increased risk, but were not statistically significant. Infection rates by type of chemoprophylaxis were: 3.6% in the penicillin group, 3.7% in the cephem-I group, 1.7% in the cephem-II group, 5.7% in the cephem-III group, and 2.8% in the others group. This result indicates that the best choice for prophylactic antibiotic therapy may be a second-generation cephem.


Acute subdural hematoma in young patient with moyamoya disease--case report.

A 17-year-old boy with known moyamoya disease developed an acute subdural hematoma after a mild head trauma. He had been confined to a wheelchair with contracture in the upper and lower extremities due to juvenile rheumatoid arthritis since age 1 year. He had undergone encephalo-duro-arterio-synangiosis (EDAS) on the right and encephalo-myo-synangiosis (EMS) on the left at 13 years of age. He was admitted with headache, nausea, and vomiting after a fall from his wheelchair at age 17. Computed tomography on admission showed a large acute subdural hematoma in the right fronto-temporal region but no bleeding at the EDAS or EMS sites. Cerebral angiography 12 weeks after the head trauma revealed a remarkable reduction in the spontaneous transdural external-internal carotid anastomoses in the right frontal region. The acute subdural hematoma was probably caused by rupture of the spontaneous transdural anastomoses.


Spontaneous disappearance of arteriovenous fistula between the vertebral artery and deep cervical vein--case report.

A 58-year-old female was readmitted with pulsatile tinnitus in the right ear 8 months after subtemporo-occipital transtentorial clipping of a peripheral superior cerebellar artery aneurysm. On examination, she was normal except for pulsatile bruit over the right mastoid region. Angiography showed a fistulous communication between the muscular branches of the right vertebral artery and the deep cervical vein. The incision of the aneurysm surgery was supratentorial, so the only possible cause of the upper cervical arteriovenous (AV) fistula was fine gold acupuncture needles implanted for bronchial asthma 18 years before. The AV fistula disappeared spontaneously after 1 month, possibly because of thrombosis of the affected veins.


Bilateral symmetrical cerebral arteriovenous malformations in the basal ganglia--case report.

A 21-year-old male presented with visual disturbance followed by severe headache. Computed tomography showed right thalamic hemorrhage entering the right lateral ventricle. Cerebral angiography revealed bilateral symmetrical arteriovenous malformations (AVMs) fed by the lenticulostriate, anterior choroidal, and lateral posterior choroidal arteries and draining into the vein of Galen. Partial removal of the right AVM induced bleeding on the left side, probably due to postoperative hemodynamic changes. Bilateral symmetrical cerebral AVMs are extremely rare, but provide serious problems for surgical intervention in the deep cerebrum.


Intracavernous cavernous hemangioma: dynamic CT findings and effectiveness of irradiation--case report.

An intracavernous cavernous hemangioma occurred in a 34-year-old female presenting with amenorrhea and hyperprolactinemia. Computed tomography (CT) showed a homogeneously enhanced mass in the right cavernous sinus. The time-density curve detected by dynamic CT showed significant delayed flow in the lesion. The mass was significantly reduced in size by local irradiation (50 Gy). Dynamic CT may be useful in differentiating cavernous hemangioma, and radiation therapy should be considered for preferred treatment to surgical intervention.


Sacral nerve root cysts manifesting as localized unilateral perineal pain--case report.

A 62-year-old female presented with multiple sacral nerve root cysts manifesting as localized unilateral perineal pain. Myelography just after contrast material injection revealed multiple cysts at the sacral level. However, perioperative dye injection showed hardly any flow in the reverse direction. Only the S3 nerve was constricted by hyperplasia of the dura mater, and adhered to the cyst wall. Other nerves were not constricted, nor adhered to cyst walls. The S3 nerve constriction and tight adhesion was the cause of the pain. The one-way flow of spinal fluid from the spinal subarachnoid space to the cysts is probably closely correlated with cyst formation.


Distribution of HSP72 induction and neuronal death following limbic seizures.

A small area of deep prepiriform cortex is uniquely susceptible to convulsant and anticonvulsant drugs in the rat. We have studied the pattern of expression of the non-constitutive stress protein (HSP72) following seizures induced by unilateral microinjection of bicuculline into this area. HSP was seen first in ipsilateral dorsal medial thalamus, amygdala and associated piriform cortex, and with more sustained seizures was seen bilaterally in these structures as well as in other projection sites. Neuronal cell death, as assessed by acid-fuchsin staining, occurred in the same brain regions. Frank necrosis was found in the ipsilateral piriform cortex with prolonged seizures. Behaviorally, the seizures induced are characteristic of involvement of the limbic system and, therefore, may be a model of human complex partial seizures.


Induction by nerve growth factor (NGF) of NGF receptor-like immunoreactivity in the preoptic area and hypothalamus of neonatal rats.

Nerve growth factor (NGF) was injected in the brain of neonatal rats. In eleven of thirty-one rats that received 1 microgram of mouse NGF (2.5S form) on postnatal day 3, NGF receptor-like immunoreactivity was found in the preoptic area (POA) and hypothalamus until 12 days after birth. However, no immunoreactivity was seen in the region of rats in the same group examined on day 20 or 45 and of uninjected control rats on days 1-45. These results indicate that NGF induces the transient appearance of the receptor for NGF in the POA and hypothalamus of neonatal rats.


Chronic treatment with D600 enhances development of sodium channels in cultured chick skeletal muscle cells.

We have studied the long-term effects of D600, a blocker of L-type voltage-dependent Ca channels (VDCC), on the development of voltage-dependent Na channels (VDNC) that are sensitive to tetrodotoxin (TTX), by electrophysiological measurements of the maximum rate of rise of the TTX-sensitive Na spike in cultured chick skeletal muscle cells. Chronic treatment with D600 (2-20 microM) caused a dose-dependent increase in the density of VDNC. The density of VDNC was increased by 150-250% when D600 was added to the cultures at 20 microM from the second day of culture onward. Co-treatment with an inhibitor of the transcription of RNA from DNA, alpha-amanitin, or with cycloheximide, an inhibitor of protein synthesis, prevented the up-regulation by D600. Nifedipine, a different type of blocker of L-type VDCC, was also effective in increasing the density of VDNC, and BAY K 8644, an agonist of L-type VDCC, had the opposite effect. It is suggested that the effect of D600 was mediated via a mechanism specific for L-type VDCC that involves regulation of cytosolic levels of Ca2+ and protein synthesis de novo.


Adenosine receptor link in an adrenal opioid-induced antinociception in the rat tail-flick test.

Intrathecal administration of substance P at the lower thoracic spinal level has an antinociceptive effect on reaction time in the tail-flick test; this response is blocked by naloxone i.v. but not by i.v. administration of opiate antagonists which do not cross the blood-brain barrier. As morphine-induced analgesia is blocked by adenosine antagonists, to determine whether this substance P-induced, opioid-mediated antinociception also includes a purine link, the adenosine receptor antagonist, caffeine, was given systemically 10 min prior to substance P administration. In control rats pretreated with saline, substance P (6.5 nmol) produced an increase in reaction time to about 160% of preadministration values at one min after intrathecal injection. The effect could also be observed at 6 min after this injection. Pretreatment with 16 or with 32 mg/kg of caffeine i.p. blocked the response to substance P, and produced a hyperalgesia similar to that reported in studies at the lumbo-sacral spinal level. These results indicate that the adrenal opioid-induced antinociception observed upon intrathecal administration of substance P at the lower thoracic level occurs via an adenosine link. This is the first demonstration of a purine link in the expression of antinociceptive effects of an endogenously released opioid.


Pyramidal neurons are immunoreactive for calbindin D28k in the CA1 subfield of the human hippocampus.

The calcium binding protein calbindin D28k (CaBP) is localized in the granule cells of the dentate gyrus, in pyramidal neurons of the CA1 and CA2 subfields of the Ammon's horn as well as in distinct groups of local circuit neurons in both parts of the human hippocampal formation. Immunostaining was performed on human brain perfused 2 h after death. The localization of CaBP in the human was found to be similar to that in the monkey hippocampus suggesting that there is no species difference in the cellular localization of CaBP among different primates.


Stimulation of locomotor activity by intra-accumbens AMPA is not inhibited by neonatal 6-hydroxydopamine-induced lesions.

The involvement of dopamine in the hypermotility responses to amphetamine s.c. or AMPA injected into the nucleus accumbens was evaluated in adult rats depleted of dopamine as neonates with 6-hydroxydopamine. The hypermotility response to amphetamine was markedly inhibited in the lesioned animals, while that to AMPA was enhanced. In addition, the hypermotility produced by AMPA in these rats was not inhibited by sulpiride+SCH-23390; however, it was inhibited completely by alpha-methyl-p-tyrosine. These results suggest that the hypermotility produced by AMPA requires endogenous dopamine, but is mediated by a different mechanism than that produced by amphetamine.


Demonstration of a direct projection from the retina to the hypothalamic supraoptic nucleus of the hamster.

Hamsters were injected in the left eye with unconjugated cholera toxin subunit B (CHB) and the tracer was localized using immunohistochemistry. A large number of immunoreactive fibers was found in the suprachiasmatic nuclei and the contralateral lateral hypothalamic area. Labeled fibers coursed around the supraoptic nucleus and nerve terminals accumulated in a zone dorsally and laterally to the nucleus. Single fibers from this plexus penetrated into the supraoptic nucleus, where few fibers arborized into delicate immunoreactive profiles possessing varicosities. Labeled fibers were identified only in the dorsal and lateral parts of the nucleus, and mostly at the caudal level of the optic chiasm. These results show a direct retinal innervation of the magnocellular neurons of the supraoptic nucleus, and indicate a direct photic influence on the hypothalamo-neurohypophysial system.


Differential effect of immunosympathectomy on the expression of rat enteric neurotransmitters.

The effect of immunosympathectomy on the pattern of distribution of catecholamine- and peptide-containing nerve fibres and neurones in the myenteric and submucous plexuses of rat ileum was investigated. There was an increase in vasoactive intestinal polypeptide (VIP)-, galanin (GAL)- and substance P-like immunoreactivity in the myenteric plexus of ileum from rats treated with nerve growth factor (NGF) antiserum compared with controls. A similar increase in immunoreactivity was observed in VIP-, GAL- and neuropeptide Y (NPY)-containing submucous neurones and nerve fibres. In contrast, the immunosympathectomy had no effect on the pattern of distribution of catecholamine-, calcitonin gene-related peptide (CGRP)- and NPY-containing nerve fibres in the myenteric plexus or on substance P- and CGRP-containing neurones and nerve fibres of the submucous plexus. The findings of the present study suggest that NGF may differentially regulate the expression of enteric neuropeptides at a postnatal stage of development.


Effects of McN-A-343 on insect neurosecretory cells: evidence for muscarinic-like receptor subtypes.

The muscarinic agonist McN-A-343 has been used to characterize the muscarinic receptors on somata of adult cockroach dorsal unpaired median (DUM) neurones maintained in short-term culture. Pressure application of McN-A-343 onto isolated DUM neurones induced a dose- and voltage-dependent biphasic response composed of a fast initial hyperpolarization followed by a slow depolarizing phase, recorded with the patch-clamp technique in the whole-cell recording configuration. The fast hyperpolarization reversed at an extrapolated potential value of -91.04 mV and was fully antagonized by the M2 muscarinic antagonist methoctramine. The slow depolarizing component reversed at an extrapolated value of -28.33 mV and was inhibited by the M1 muscarinic antagonist pirenzepine. These results demonstrate both a specific effect for McN-A-343 on DUM neurones and the existence of two functionally distinct muscarinic-like receptor subtypes governing this McN-A-343-induced biphasic response.


ATP activates junctional and extrajunctional acetylcholine receptor channels in isolated adult rat muscle fibres.

Single-channel recordings in the cell-attached configuration were made on freshly dissociated and cultured rat muscle fibers. We demonstrate that ATP (50-100 microM) elicits single channel currents in freshly isolated fibres. These ATP-activated channels have a slope conductance similar to that determined for ACh-activated channels but exhibit a shorter open time. We also show that ATP activates extrajunctional AChR-channels in the membrane of long-term cultured muscle fibres. Here the ATP activated channel has a slope conductance and open time characteristics similar to those of the ACh-activated channel.


A comparative HRP study of the neuronal supply to the inferior and superior nasal meatus in the cat.

Neurons supplying the nasal mucosa in the cat were retrogradely labelled with horseradish peroxidase. Sensory trigeminal neurons to the inferior and superior nasal meati are somatotopically organized, according to the ophthalmic or maxillary origin of the afferents studied. Whatever their relative location, the cell bodies from nasal afferents were, on average, smaller than the overall cell population in the ganglion, in keeping with the high proportion of nasal receptors innervated by thin fibers. Postganglionic neurons from parasympathetic origin could be labelled in the sphenopalatine ganglion. These neurons probably supply mucosal secretory glands. They are in the same size range as the bulk of neurons in the same ganglia.


Presence of gastrin-releasing peptide in neurons of the geniculate ganglion in rat and man.

Gastrin-releasing peptide (GRP) was demonstrated by immunohistochemistry and high-performance liquid chromatography to be present in the great majority of neurons in the geniculate ganglion of rat and man. This was in contrast to findings in the sphenopalatine ganglion of rat, where only little GRP was found, and in the otic, trigeminal, glossopharyngeal-vagal and internal carotid ganglia, where no GRP-containing cells could be demonstrated. The peptide was not detected by immunohistochemistry in nerve fibers within structures innervated from the ganglion (tongue, soft palate, retroauricular skin and facial musculature). The retrograde axonal tracer True blue accumulated in these neurons of rat after application not only in the tongue and soft palate but also in the retroauricular skin.


Hippocampal and neocortical ubiquitin-immunoreactive inclusions in amyotrophic lateral sclerosis with dementia.

Amyotrophic lateral sclerosis (ALS) patients with dementia were found to have ubiquitin-immunoreactive (IR) inclusions in the dentate granule cells of the hippocampus. These inclusions were also present in some patients with minor cognitive changes but otherwise typical ALS. Ubiquitin-IR inclusions were also found in neurons of superficial layers of the frontal and temporal cortex and in the entorhinal cortex in patients with ALS and dementia. These ubiquitin-IR inclusions were non-argyrophilic, and were not labelled by antibodies which identify Alzheimer's neurofibrillary tangles and Pick bodies, nor were they typical of cortical Lewy bodies. Our findings indicate that ubiquitin-IR inclusions in small neurons of the hippocampus, entorhinal area and neocortex are a characteristic feature of degeneration of non-motor cortex in ALS, and are particularly associated with cognitive impairment and dementia of frontal lobe type.


Comparison of the inhibitory roles of neuropeptide Y and galanin on cardiac vagal action in the dog.

Prolonged attenuation of cardiac vagal action occurs following cardiac sympathetic nerve stimulation or intravenous neuropeptide Y (NPY) injections in anaesthetised dogs. Equimolar intravenous injections of galanin (GAL) had no effect on cardiac vagal action in this species. Immunohistochemical analysis of dog stellate ganglia and cardiac muscle showed that most nerve cell bodies showing tyrosine hydroxylase immunoreactivity (TH-IR) also showed immunoreactivity to both NPY and GAL. The results are consistent with the proposal that NPY released from cardiac sympathetic nerves is responsible for the prolonged inhibition of cardiac vagal action known to be caused by such stimulation. A role for GAL, shown here to exist in cardiac sympathetic nerves in the dog, has yet to be determined.


Fastigiofugal fibers encoding horizontal and vertical components of saccades as determined by microstimulation in monkeys.

To identify the routes by which oculomotor vermis signals control eye movements (saccadic signals), saccades evoked by microstimulation were studied in the region of the uncinate fasciculus (UF) and juxtarestiform body (JB) in the macaque monkey. Anatomical pathways of axons from the fastigial oculomotor region (FOR) were studied by anterograde transport of wheatgerm agglutinin conjugated horseradish peroxidase (WGA-HRP). The routes were identified by comparing maps of low threshold for evoking saccades with the anatomical map of anterogradely labeled axons arising from the FOR. Microstimulation of a region of the UF and JB demonstrated that saccadic signals are carried exclusively by decussated FOR axons which leave the cerebellum via the contralateral UF. The fibers in the JB do not carry saccadic signals. The horizontal component of saccadic signals is conveyed by fibers in the descending limb of the UF, while the vertical component is conveyed by a smaller group of fibers which separate from the UF and enter the midbrain with the contralateral superior cerebellar peduncle.


Initial uncoordinated expression of three types of voltage-gated currents in cultured Xenopus myocytes.

The expression of three types of voltage-gated ionic currents, namely the Na+ inward current, K+ outward rectifier current and K+ inward rectifier current, was examined in cultured developing Xenopus myocytes. In the population of myocytes, the Na+ inward current and K+ outward rectifier current appeared at around 32 h after fertilization (stage 27) and gradually increased during the period of observation, up to more than 44 h after fertilization (stage 33/34). The developmental time course of these two types of currents was similar. However, during the transition period individual myocytes did not necessarily express these two types of currents in a coordinated fashion. Some myocytes had a large Na+ inward current and small K+ outward rectifier current or vice versa. The K+ inward rectifier current was observed in some cells earlier than stage 27 and also gradually increased during the observation period. The initial expression of this current was not correlated with the K+ outward rectifier current or with the Na+ inward current.