Acute and chronic angiotensin-1 receptor antagonism reverses endothelial dysfunction in atherosclerosis

Background-The renin-angiotensin system may contribute to atherogenesis thr ough the promotion of endothelial dysfunction. The present study was perfor med to determine whether angiotensin-1 (AT(1)) receptor inhibition improves endothelial dysfunction. Methods and Results-In the femoral circulation of 19 patients with atherosc lerosis and of 9 control subjects, we studied microvascular responses to re active hyperemia, angiotensin II, acetylcholine, and sodium nitroprusside b efore and after the administration of intra-arterial losartan (10 mg), Femo ral artery flow velocity was measured with a Doppler flow wire, and the fem oral vascular resistance index (FVRI) was calculated as mean arterial press ure divided by flow velocity. Losartan induced a minor (5.9+/-2%, P=0.02) r eduction in FVRI and inhibited angiotensin II-mediated vasoconstriction in both patient groups (P<0.01). After the administration of losartan, acetylc holine-mediated vasodilation was augmented in patients (44+/-5% to 58+/-4% reduction in FVRI with infusion at a rate of 150 mu g/min, P<0.001) but not control subjects. Vasodilation during reactive hyperemia was also greater after AT(1) receptor inhibition (P=0.03) in patients, but the response to s odium nitroprusside remained unchanged. In a separate group of 31 patients with atherosclerosis, we investigated the effect of 8 weeks of oral losarta n therapy on brachial artery flow-mediated vasodilation with the use of hig h-resolution ultrasound. Oral losartan therapy improved flow-mediated brach ial artery dilation (1.4+/-0.9% to 3.2+/-0.8%, P=0.03) but had no effect on the nitroglycerin response. Serum nitrogen oxide levels increased from 21. 6+/-1.7 to 26.7+/-2.4 mu mol/L (P=0.008). Conclusions-The results of the present study indicate that inhibition of th e AT(1) receptor in patients with atherosclerosis reverses endothelial dysf unction by improving NO availability and therefore may have long-term thera peutic benefits.