[Endothelial mechanisms in vasomotor effects of ACE inhibitors]

The beneficial cardiovascular effects of ACE inhibitors are thought to be based primarily on a reduction in vascular angiotensin II formation. However, since ACE also degrades the potent endothelium-dependent vasodilator bradykinin, it has been proposed that the local accumulation of this peptide in the vascular wall represents an additional mechanism by which ACE inhibitors exert their cardiovascular effects. In this context it has been demonstrated that incubation of cultured endothelial cells with ACE inhibitors leads to an enhanced formation of nitric oxide (NO) and prostacyclin (PGI2). This effect is believed to be the consequence of an accumulation of endothelium-derived bradykinin in the vicinity of the endothelial cells. Moreover, by virtue of an as yet unidentified mechanism, ACE inhibitors may also enhance the potency of bradykinin at the receptor level and/or activate the B2-kinin receptor following pre-exposure to bradykinin. Both of these effects may enhance or sustain the bradykinin-induced formation of NO and PGI2 by the endothelium. ACE inhibition also leads to the accumulation of angiotensin I which can be metabolized to angiotensin-(1-7) by another endothelial enzyme, the neutral endopeptidase 24.11. Activating an as yet unidentified receptor, angiotensin-(1-7) (but not other known angiotensin peptides) stimulates endothelial NO release in coronary arteries from different species as well as in the isolated perfused rat heart. This effect also seems to involve the release of vasoactive kinins from the endothelium. The shift in angiotensin I metabolism towards an enhanced formation of angiotensin-(1-7) in the presence of an ACE inhibitor may thus also contribute to the hypotensive action of this class of compounds.