three positive charges out of the cell for each Ca^2 +; the resulting negative inside charge
of the resting cell therefore favours Ca efflux. Binding of an L-type channel antago-
nist produces a reduction in cardiac muscle contractility throughout the heart and a
decrease in the sinus node pacemaker rate and in atrioventricular node conduction
velocity; it also produces a prolonged relaxation of the smooth muscles within arterial
walls.
The 1,4-dihydropyridines enjoy widespread clinical use for a variety of cardiovascu-
lar problems, with angina and arterial hypertension being the two most common. One
of the 1,4-dihydropyridines, nimodipine (7.37), has a greater effect on cerebral arteries
than on other arteries. Consequently, nimodipine is sometimes indicated for treating
spasm of blood vessels in the brain following rupture of an intracranial aneurysm that
produces a subarachnoid hemorrhage. The side effects of the L-type Ca^2 +channel
blockers include flushing, nasal congestion, tachycardia, headache, constipation, shortness
of breath, and excessively slow heart rate (bradycardia). Given the mechanism of action of
these agents, such side effects are to be expected. Also, as expected, 1,4-dihydropyridines
do not tend to produce skeletal muscle weakness. Skeletal muscle is not depressed by
Ca^2 +channel antagonists because it uses intracellular stores of Ca^2 +to enable excitation–
contraction coupling and is not dependent upon Ca^2 +being supplied by a transmembrane
ion influx.
From a chemical perspective, there are four classes of L-type Ca^2 +channel blockers
that have been developed for clinical indications:
- 1,4-Dihydropyridines (e.g., nifedipine,7.38)
- Phenylalkylamines (e.g., verapamil,7.25)
- Benzothiazepines (e.g., diltiazem,7.26)
- Diaminopropanol ethers (e.g., bepridil,7.39)
Nifedipine is just one of many 1,4-dihydropyridines; in contrast, the remaining three
classes have only one representative agent. Nifedipine is selective for vascular smooth
muscle and is therefore an excellent hypotensive. However, it can cause tachycardia
(i.e.,an excessive increase in heart rate), and is therefore prescribed with β-adrenergic
blockers. Verapamil and diltiazem have a direct effect on the heart, do not cause tachy-
cardia, and are therefore the ideal antianginal agents. Phenylalkylamines need a 1- to
2-week lag period until their antianginal effect is evident. Bepridil has a relatively
non-selective action.
ENDOGENOUS CELLULAR STRUCTURES 427