ENDOTHELIUM-DERIVED BRADYKININ - IMPLICATIONS FOR ANGIOTENSIN-CONVERTING ENZYME-INHIBITOR THERAPY

The effects of angiotensin-converting enzyme (ACE) inhibitors on endothelial autacoid formation were determined in human cultured endothelial cells and in endothelium-intact bovine coronary arteries under resting conditions and after stimulation with bradykinin. Incubation of cultured human endothelial cells with moexiprilat or ramiprilat (0.3 muM) caused a maintained increase in resting intracellular calcium [Ca2+]i, which was prevented by the selective B2-receptor antagonist Hoe 140 (0.1 muM). Both ACE inhibitors also significantly enhanced the increase in [Ca2+]i elicited by bradykinin (3 nM). In parallel with their effect on resting [Ca2+]i, Moexiprilat and ramiprilat both induced an increase in intracellular cyclic GMP (cGMP). This increase was prevented by Hoe 140 (0.1 muM) and was abolished by N(G)-nitro-L-arginine (30 muM), indicating a kinin-induced nitric oxide (NO) formation in this response. The elevation in [Ca2+]i also led to an enhanced production of prostacyclin (PGI2), as indicated by an increase in the concentration of 6-keto prostaglandin F1alpha (PGF1alpha) in the cell supernatant. Similar effects of the ACE inhibitors on endothelial autacoid production were observed in endothelium-intact bovine coronary arteries. Like bradykinin (30 nM), moexiprilat (0.3 muM) elicited a nearly twofold increase in the cGMP content of these arteries, which was abolished by both N(G)-nitro-L-arginine and removal of the endothelium. The functional consequences of this ACE inhibitor-induced increase in vascular cGMP were reflected by a distinct relaxation of arteries preconstricted with PGF2alpha. These findings support the hypothesis that native as well as cultured endothelial cells from different species are capable of producing vasoactive kinins, the release of which leads, in an autocrine and a paracrine manner, to a sustained stimulation of NO and PGI2 formation provided that kinin degradation is prevented by ACE inhibition.