MECHANISMS INVOLVED IN THE ANGIOTENSIN II-INDEPENDENT HYPOTENSIVE ACTION OF ACE-INHIBITORS

1. The blood pressure-lowering and cardioprotective actions of angiote nsin converting enzyme (ACE) inhibitors are thought to be based primar ily on a reduction in vascular angiotensin II (Ang-II) formation. Howe ver, since ACE also degrades the potent endothelium-dependent vasodila tor bradykinin, it has been proposed that the local accumulation of th is peptide represents an additional mechanism by which ACE inhibitors exert their cardiovascular effects. 2. Incubation of endothelial cells with ACE inhibitors indeed causes an enhanced formation of nitric oxi de (NO) and prostacyclin (PGI(2)) which can be completely blocked by t he B-2-kinin receptor antagonist Hoe 140, suggesting that the vascular endothelium is capable of generating vasoactive kinins from an endoge nous source. 3. Moreover, ACE inhibitors not only prevent the breakdow n of bradykinin but, by virtue of an as yet unidentified mechanism, al so enhance the potency of bradykinin at the receptor level and reverse the desensitization of the B-2-kinin receptor following continuous ex posure to bradykinin. Both of these effects may enhance or sustain the bradykinin-induced formation of NO and PGI(2) by the endothelium. 4. Furthermore, ACE inhibition leads to the accumulation of Ang-I which c an be metabolised to Ang-(1-7) by another endothelial enzyme, neutral endopeptidase 24.11. By activating an as yet unidentified angiotensin receptor, Ang-(1-7), but not other known angiotensin peptides, stimula tes endothelial NO release in porcine coronary arteries as well as in the isolated perfused rat heart. This effect is, albeit to a different degree, dependent on the release of vasoactive kinins from the endoth elium. The shift in Ang-I metabolism towards an enhanced formation of Ang(1-7) in the presence of an ACE inhibitor may thus contribute to th e hypotensive action of this class of compounds as well.