CLINICAL EXPERIENCE WITH BLOCKADE OF RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM BY AN ORAL CONVERTING-ENZYME INHIBITOR (SQ 14,225, CAPTOPRIL) IN HYPERTENSIVE PATIENTS

Nineteen patents with treatment-resistant essential (13) or renovascular (6) hypertension were treated with an orally active inhibitor of angiotensin-converting enzyme, D-2-methyl-3-mercaptopropanoyl-L-proline (captopril), for periods up to 6 mo. The compound alone produced moderate to marked sustained reductions in blood pressure, often to normal levels. One patient who had a low renin level exhibited no significant response. In four patients with a partial response, addition of a diuretic produced satisfactory blood pressure control. No serious side-effects were noted. A syndrome of rash and fever was observed in two patients, which resolved following reduction of the dose or withdrawal of drug. The mechanism of action remains to be fully elucidated, but the data indicate that a major action involves suppression of the reninangiotensin-aldosterone system. Thus, the degree of blood pressure reduction was correlated (1) with the level of pretreatment plasma renin activity, (2) with the induced suppression of urinary aldosterone excretion, and (3) with the consequent changes in potassium balance and serum potassium. Sustained coverting-enzyme blockade produced natriuresis in a majority of patients on a normal sodium intake, a factor that may contribute to the blood pressure response. The evidence suggests that at the doses currently used the induced blockade of angiotensin II formation is incomplete, since during therapy aldosterone appears to remain responseive to physiologic changes in renin activity, although at a lower level. Indeed, reactive increases in renin secretion may, in some patients, diminish the antihypertensive action of the drug. These results with an oral agent over a longer time closely resemble the acute effects of the intravenous nonapeptide inhibitor. The effects of these two agents in turn are in many respects similar to those obtained with other agents that block the renin system, namely saralasin and beta-adrenergic blockers. Accordingly, from a conceptual standpoint, these new findings provide another dimension in the growing body of evidence, idicating a significant in involvement of the renin-angiotensin-aldosterone system in most hypertensive patients. This in turn provides the basis for a new approach to therapy based on the identification and containment of the renin factor by specific pharmacologic agents. © 1978.