Calcium Ion Channels and Their Blockers - Ion Channels and Their Inhibitors - page 268

cardiac and smooth muscle. They block the entry of calcium into the muscle cells of
the heart and the arteries. By blocking the entry of calcium, calcium channel
blockers decrease the contraction of the heart and dilate the arteries. This may
partially explain their rather selective effects on the cardiovascular system.
Calcium channel blockers are primarily used for treating cardiac arrythmia and
pulmonary hypertension and for prevention of reperfusion injury as well as athero-
sclerosis (particularly the lipophilic agents). They also slow the rate at which
calcium passes into the heart muscle and into the vessel walls. This relaxes the
vessels. The relaxed vessels let blood flow more easily through them, thereby
lowering blood pressure. Unlike -blockers, calcium channel blockers do not

decrease the responsiveness of the heart.
Different classes of Calcium channel blockers bind to different sites on the a1-
subunit. Recent clinical evidence in patients with microvascular disease suggests
that blockade of the T-type calcium ion channel has additional benefit. Blockade of
these channels slows the sinus rate and prolongs atrioventricular nodal conduction,
in addition to causing vasodilation, without adverse negative inotropic or positive
chronotropic cardiac actions [ 29 , 30 ].
Recently, some of the classical L -type calcium channel blockers were found to
have a potent inhibitory activity against the N-type as well. The N-type channel has
been shown to play a significant role in the pathophysiological processes of stroke
and neuropathic pain [ 31 - 33 ], in addition to physiological regulation. Over the last
decade, synthetic efforts have focused on the development of both peptidic and
nonpeptidic-based small molecule N-type calcium channel blockers for analgesia
or neuroprotection.

b

2.2 Classification of Calcium Ion Channel Blockers

• Dihydropyridines (DHPs)
• Nondihydropyridines:

- Phenylalkylamines
- Benzothiazepine

• Nonselective (Fig. 1 )

All the above-mentioned blockers differ not only in their basic chemical structure,
but also in their relative selectivity toward cardiac versus vascular L -type calcium
channels. All of them bind reversibly with the L -type Calcium channel, but each class
binds to different binding sites of the same channel in a stereoselective manner and
with dissociation constants in the nanomolar range (0.1-50 nM). Verapamil binds to
the V binding site. Diltiazem binds to the D binding site in the L -type Ca 2 þ channel.
However, it shows cardiovascular effects similar to those of verapamil. Calcium
channel antagonists block the inward movement of calcium by binding to the L -type
calcium channels in the heart and in smooth muscle of the peripheral vasculature.