Arterial function in nitric oxide-deficient hypertension: influence of long-term angiotensin II receptor antagonism

Objective: Since the effects of angiotensin II receptor antagonism on arter ial function in nitric oxide (NO)-deficient hypertension are unknown, we in vestigated the influence of losartan therapy (20 mg kg(-1) day(-1)) on the control of arterial tone in N-G-nitro-L-arginine methyl ester (L-NAME; 20 m g kg(-1) day(-1))-induced hypertension. Methods: Forty Wistar rats were div ided into four groups: control, losartan, L-NAME, and losartan+L-NAME. The responses of isolated mesenteric arterial rings were examined in standard o rgan chambers after 8 treatment weeks. Results: Losartan therapy prevented the development of L-NAME-induced hypertension and the associated impairmen ts of endothelium-independent relaxations to nitroprusside, isoprenaline, a nd cromakalim, vasodilators acting via the formation of NO, activation of b eta-adrenoceptors and opening of K+ channels, respectively. In addition, en dothelium-dependent relaxations of noradrenaline-precontracted rings to ace tylcholine during NO synthase inhibition in vitro were decreased in L-NAME rats, and clearly improved by losartan therapy. The inhibition of cyclooxyg enase by diclofenac improved the responses to acetylcholine more effectivel y in L-NAME than losartan+L-NAME rats, but the relaxations remained decreas ed in L-NAME rats when compared with losartan+L-NAME rats. When hyperpolari zation of smooth muscle was prevented by precontractions induced by high co ncentration of KCl, the responses to acetylcholine during combined NO synth ase and cyclooxygenase inhibition were similar and almost abolished in all groups. Furthermore, superoxide dismutase, a scavenger of superoxide anions , enhanced the acetylcholine-induced relaxations more effectively in L-NAME than losartan+L-NAME rats, although plasma antioxidant capacity was simila r in all study groups. Conclusion: Chronic L-NAME-induced hypertension was associated with attenuated arterial relaxation via endothelium-dependent an d -independent mechanisms, both of which were improved by the losartan trea tment. The mechanisms whereby losartan enhanced arterial relaxation in this model of experimental hypertension may have included enhanced hyperpolariz ation and increased sensitivity to NO in smooth muscle, and decreased vascu lar production of superoxide and vasoconstrictor prostanoids. (C) 1999 Else vier Science B.V. All rights reserved.