RAMIPRIL PREVENTS ENDOTHELIAL DYSFUNCTION INDUCED BY OXIDIZED LOW-DENSITY LIPOPROTEINS - A BRADYKININ-DEPENDENT MECHANISM

We wished to determine whether the acute toxic effects of oxidized LDL are attenuated in aortas isolated from rats chronically treated with an angiotensin-converting enzyme (ACE) inhibitor. In aortic rings incu bated with human oxidized LDL (300 mu g/mL), the endothelium-dependent relaxations to acetylcholine were attenuated, but not those to A23187 and to nitroprusside. This toxic effect of oxidized LDL was completel y prevented in preparations coincubated with oxidized LDL and the nitr ic oxide (NO) precursor L-arginine (0.3 mmol/L). In aortas isolated fr om rats orally treated for 6 weeks with 10 mg/kg ramipril (group 1) or 1 mg/kg ramipril (group 2), this toxic effect of oxidized LDL was als o markedly attenuated. In contrast, in aortas isolated from rats cotre ated with ramipril (10 mg/kg) for 6 weeks and subcutaneous injections of Hoe 140 (a B-2 kinin antagonist), 500 mu g/kg per day for the last 2 weeks (group 3) or from rats orally treated for 6 weeks with losarta n (an AT(1)-type angiotensin II receptor antagonist), 20 mg/kg (group 4), the inhibitory effect of oxidized LDL on acetylcholine-induced rel axations was similar to that observed in the control group (group 5). Moreover, long-term treatment with ramipril increased relaxations to a cetylcholine in groups 1 and 2 and also relaxations to A23187 and aort ic cGMP content in group 1, suggesting an enhanced NO availability. Th us, the protective effect of long-term ACE inhibition against the acut e vascular toxicity of oxidized LDL is bradykinin dependent and seems to involve a facilitation of NO release via endothelial B-2 kinin rece ptors.