Pharmacological basis for use of calcium antagonists in hypertension

Many different classification systems for Ca2+ antagonists were proposed. They are mostly based on structural aspects or profiles of biological activity. 1,4-dihydropyridines, with Ca2+ channel antagonistic activity, including nifedipine and nitrendipine, are highly effective as antihypertensive agents. Although Ca2+ antagonists have multiple sites of antihypertensive action, their main mechanism of action is inhibition of Ca2+ entry into the vascular smooth muscle cells. Ca2+ channel antagonists bind to specific receptors at Ca2+ channels and stabilize the channels in a mode unavailable for opening. Their effect is enhanced by depolarization of the cell membrane. Currently used pharmacological methods for detection of Ca2+ antagonistic action of drugs include: (1) inhibition of 45Ca2(+)-uptake; (2) displacement of [3H]nitrendipine from isolated membranes, and (3) inhibition of Ca2+ current in single cells or channels. Ca2+ antagonists were reported to prevent hypertension-induced vascular changes and other vascular pathology, probably related to Ca2+ overload. Vascular lesions in Dahl salt-sensitive hypertensive rats and in spontaneously hypertensive rats were prevented by chronic administration of nifedipine or nitrendipine. Hemodynamic effects of Ca2+ antagonists are characterized by reduction in total peripheral vascular resistance, increase in cardiac output, reduction in systemic left ventricular end-diastolic, pulmonary arterial and capillary wedge pressures. Ca2+ antagonists differ in potency, duration of action and their therapeutic ratios. DHPs enhance sympathetic tone and have little or no negative dromotropic action. They are, therefore, safer in combination with beta-adrenoceptor antagonists than either verapamil or diltiazem. In comparison with other Ca2+ antagonists nitrendipine is highly potent as a vasodilator. As a negative inotropic agent, it is, however, less potent than either verapamil or nifedipine. Nitrendipine has, therefore, a better therapeutic ratio than some of the other well-known Ca2+ antagonists. Unlike older vasodilators, e.g. hydralazine and minoxidil, Ca2+ antagonists have diuretic properties which are primarily due to inhibition of tubular reabsorption of salt and water. Under certain experimental conditions, e.g. infusion of angiotensin II, DHPs can increase GFR. Nitrendipine has also renal cytoprotective activity. It protected rats from aminoglycoside-induced nephrotoxicity and antagonized proliferative glomerular changes in nephritic rats.(ABSTRACT TRUNCATED AT 400 WORDS)