Converting enzyme inhibitors in hypertension and heart failure.

Abstract

The renin-angiotensin-aldosterone system is intimately involved in the regulation of vascular tone, and is central to sodium homeostasis; the octapeptide angiotensin II, formed by the action of converting enzyme on the inactive precursor decapeptide angiotensin I, constricts arterioles, enhances sympathetic activity, and promotes sodium retention, both by direct renal actions and through the release of aldosterone.Hypertension and cardiac failure are characterised by increased peripheral vascular tone and abnormal sodium and water excretion, though to what extent these changes reflect activity of the reninangiotensin-aldosterone system is unclear. Both conr ditions respond to diuretics and vasodilators even though consequent stimulation of the reninangiotensin-aldosterone system may ensue. Not surprisingly, therefore, the recent introduction of orally active converting enzyme inhibitors' 2 has generated much renewed interest in the role of the reninangiotensin-aldosterone system in hypertension and cardiac failure. These drugs prevent the conversion of angiotensin I to angiotensin II. They may also have additional effects such as inhibition of degradation of the vasodilator peptide bradykinin. Though most of our knowledge concerning the effects of converting enzyme inhibitors in man stems from the use of captopril, preliminary work with the newer compound enalapril (MK421) suggests that it has similar pharmacological effects.3 Both drugs reduce plasma angiotensin II and aldosterone with reciprocal changes in plasma renin and angiotensin I concentrations. Sustained suppression of plasma angiotensin II has been seen using 150 mg captopril three times a day.4 Enalapril, which has a longer action, may be given less frequenly.3 The associated early fall in blood pressure is the result of reduction in peripheral vascular resistance which is probably largely, though perhaps not entirely, the result of the reduction in plasma angiotensin II since restoration of 305 the latter by infusion of exogenous angiotensin II does not reverse completely the hypotensive effects of captopril.5 With prolonged use, a further fall of pressure may occur over one to three weeks; this may be the partial result of antagonism of a slow pressor effect of angiotensin II3Thus, there may be actions of converting enzyme inhibition on the systemic vasculature other than loss of the direct vasoconstrictor effect of angiotensin II; candidates for involvement in these mechanisms include bradykinin, prostaglandins, and the sympathetic nervous system, while resetting of baroreflexes has also been suggested.' 6-8 Inhibition of bradykinin degradation by converting enzyme inhibitors could have two principal results; firstly, increased levels of bradykinin could directly result in vasodilatation; and, secondly, stimulation of prostaglandin E production could result in further vasodilatation. The evidence, however, for involvement of kinins or prostaglandins in the pharmacological effects of converting enzyme inhibitors is confficting.9 10 In hypertension,...

Captopril: 4 years of post marketing surveillance of all patients in New Zealand.

“…The only two patients without heart failure who developed hypotension in the event monitoring study had renal failure. Postural dizziness has been noted previously when heart failure was treated and it has been postulated that angiotensin-converting enzyme inhibition may be harmful in the early stages of cardiac failure (Dargie et al, 1983).…”

Enalapril (MK421) and its lysine analogue (MK521): a comparison of acute and chronic effects on blood pressure, renin‐angiotensin system and sodium excretion in normal man.

“…Captopril, the first orally active converting enzyme inhibitor, is effective in the treatment of hypertension and congestive cardiac failure (Atkinson & Robertson, 1979;Dargie et al, 1983). Recently, a new group of proline derivatives, lacking a sulphydryl group, has been developed (Patchett et al, 1980).…”

A dose‐response study of HOE 498, a new non‐sulphydryl converting enzyme inhibitor, on blood pressure, pulse rate and the renin‐ angiotensin‐aldosterone system in normal man.

“…Angiotensin converting enzyme (ACE) inhibi-introduction of longer acting non-sulphydryl tors have proved effective therapy for hyperten-containing ACE-inhibitors, with potentially less sion (Atkinson & Robertson, 1979;Brunner et toxicity (Dollery, 1983), seems likely to widen Hodsman et al, 1983a) and heart the indications for ACE-inhibitors (Ball & failure (Atkinson & Robertson, 1979;Dargie et Robertson 1985Robertson ). al, 1983Wenting et al, 1983).…”