**2.4 Ca2+ channels in the adrenal gland**

30 Antihypertensive Drugs

gated Ca2+ channels play a key role in this process, which is a pharmacological target molecule for so-called Ca2+ channel blockers. In excitatory cells such as smooth and cardiac muscle cells and neurons, high voltage-activated (HVA) Ca2+ channels are well known to regulate a variety of cellular events, which include muscle contraction, neuronal electrical activity, the release of neurotransmitters and hormones as well as gene expressions. On the other hand, low voltage-activated (LVA) Ca2+ channels are expressed throughout the body, including nervous tissue, heart, kidney, smooth muscle and many endocrine organs. The channels in the brain are considered to be involved in repetitive low threshold firing and nociception. In the heart, they are expressed in the sino-atrial node and are considered to

Ca2+ channels are classified into at least 6 subtypes; namely, L-, N-, P-, Q-, R-, and T-type, based on electrophysiological and pharmacological evidences (Varadi et al., 1995). The Ttype Ca2+ channels are known as low-voltage-activated Ca2+ channels that activate and deactivate slowly, but inactivate rapidly. The other five types of Ca2+ channels are all highvoltage-activated Ca2+ channels, which depolarize at approximately –40 mV. Molecular biological techniques have shown that Ca2+ channels are composed of α1, α2-δ, β, and γ subunits using L-type Ca2+ channels from skeletal muscles. In particular, the αl subunit forms the Ca2+ transmission pore, which fulfills the most important function. Furthermore, 10 α1 subunits have been cloned and classified into 3 subfamilies: Cav1.x; Cav2.x; and Cav3.x, based on their gene sequence similarity (Catterall et al., 2003). More importantly, the

In the cardiovascular system, L-type Ca2+ channels are predominantly expressed in the heart and vessels, which regulate cardiac contractility, sinus nodal function and vascular tone. βadrenergic stimulation enhances the force of cardiac contraction through activation of cAMPmediated activation of protein kinase A that in turn increases the L-type Ca2+ channel currents, causing a greater rate of release of Ca2+ from the sarcoplasmic reticulum. In the arterial vessels, receptor stimulation or membrane depolarization activates Ca2+ influx through Ca2+ channels and myosin light chain kinase, leading to smooth muscle contraction. Thus, L-type Ca2+ channels have been recognized as a pharmacological target for the treatment of cardiovascular disease. Most of Ca2+ channel blockers are well known to have selectivity for vascular tissues rather than cardiac function. On the other hand, verapamil, diltiazem and bepridil have been shown to possess less vascular selectivity, which are used for supraventricular and/or ventricular arrhythmias. The selectivity of Ca2+ channel blockers for cardiac and vascular actions may be associated with that the membrane potential in vascular smooth muscle cells is definitely less negative than the diastolic membrane potential of working cardiac muscle cells. In the vascular system, arterioles appear to be more sensitive to Ca2+ channel blockers than

The most thoroughly characterized role of Ca2+ in the nerve is the triggering of exocytosis. The synaptic vesicle cycles at nerve endings could be divided into the following processes:

participate in cardiac pacemaking (Tanaka & Shigenobu, 2005).

α1 subunit has a binding site for Ca2+ channel blockers.

venules; orthostatic hypotension is not a common adverse effect.

**2.3 Ca2+ channels in the sympathetic nerve system**

**2.2 Ca2+ channels in the cardiovascular system**

**2.1 Classification of Ca2+ channels**

Chromaffin cells in the medulla of the adrenal gland are innervated by the splanchnic nerve and secrete catecholamines into the blood stream. In anesthetized dogs, the splanchnic nerve stimulation increased the catecholamine secretion from adrenal gland, which was effectively inhibited by an N-type Ca2+ channel blocker ω-conotoxin GVIA but not by L-type Ca2+ channel blockers nifedipine or verapamil (Kimura et al., 1994). Many in vitro studies also support that N-type Ca2+ channels are localized at chromaffin cells to regulate the release of catecholamine. Recently, it is shown that N-type Ca2+ channels are also localized at the human adrenocortical cells, playing an important role in the secretion of adrenocortical hormones (Aritomi et al., 2011a). Furthermore, N-type Ca2+ channels may offer the different way of controlling corticosteroid production in adrenocortical cells than other types of voltage-gated Ca2+ channels.