Kinin- and Non-Kinin-Mediated Interactions of Converting Enzyme Inhibitors with Vasoactive Hormones

The antihypertensive effect of inhibitors of the ngiotensin I-converting enzyme (ACE = kininase II) results from their vasodilatory and natriuretic effects as well s their effect on baroreceptor function. In addition to the ihibition of systemic and local angiotensin II formation, ther local hormonal systems may also be involved in this Elect at multiple target sites. Thus, potentiation of the vasodilator and natriuretic kinin system following inhibition f kininase II is thought to contribute to the persistent hyotensive effect of ACE inhibitors despite normalization of irculating ACE activity. Although increased plasma braykinin levels cannot be detected, we found that the enanced kinin-dependent local vascular prostacyclin prouction can be blunted in vitro by aprotinin, a kallikrein inhibitor. ACE inhibition may affect the atrial natriuretic peptide (ANP) system as the renin-angiotensin system and ANP appear to play antagonistic roles at the peripheral and entral nervous system levels. Inhibition of kallikrein or of ininase II were both shown to modulate the natriuretic nd vasorelaxant effects of ANP. In hypertensive subjects, we found that ACE inhibition with blood pressure normalization reduces basal and stimulated plasma ANP and blunts the renal sodium excretion in response to saline loading. In contrast, we did not observe effects of acute ACE inhibition in healthy sodium-depleted volunteers on plasma vasopressin under basal conditions or in response to passive tilt. Finally, we investigated the interaction of ACE inhibition with substance P, a powerful endogenous diuretic and natriuretic peptide that may have a transmitter function in the baroreceptor reflex arch. Although plasma levels of substance P remained unaffected, captopril caused a fourfold rise in renal substance P clearance in the rat, suggesting that ACE inhibition may increase local concentrations of this potent vasoactive undecapeptide. These examples suggest that a number of circulating hormones other than angiotensin II and autacoids may participate in the vasodilator, natriuretic, and tissue protecting, but also in some unwanted, effects of ACE inhibitors.