L-NAME Hypertension Alters Endothelial and Smooth Muscle Function in Rat Aorta

Abstract

Abstract Nitric oxide is an important regulator of vascular function and blood pressure. Chronic administration of nitric oxide inhibitors provides a new model of hypertension with pronounced target organ damage. We investigated the effects of oral treatment with N ω -nitro- l -arginine methyl ester (L-NAME) for 6 weeks on vascular reactivity of the aorta in Wistar-Kyoto rats. Certain rats received verapamil or trandolapril in addition to L-NAME. Systolic blood pressure increased in the L-NAME group (by ≈80 mm Hg systolic) but not in controls or rats treated with verapamil or trandolapril. Isometric tension changes of aortic rings were recorded. Endothelium-dependent relaxations to acetylcholine were reduced in the L-NAME group (58±6% versus 104±1% in placebo, P <.05) but were normalized by treatment with verapamil or trandolapril. In contrast, endothelium-independent relaxations to sodium nitroprusside were not significantly reduced in L-NAME hypertension but were slightly enhanced by trandolapril therapy ( P <.05). Acute in vitro incubation of vessels with the thromboxane receptor antagonist SQ 30741 enhanced the relaxation to acetylcholine ( P <.05) in the L-NAME group only. In quiescent rings, acetylcholine caused endothelium-dependent contractions in particular after in vitro incubation with L-NAME. These contractions tended to be enhanced in L-NAME hypertension (23±4% versus 14±3% in the placebo group; P =NS) and were significantly reduced after treatment with verapamil or trandolapril ( P <.05). Contractions to norepinephrine and angiotensin I and II were unaffected by L-NAME hypertension, whereas those to endothelin-1 were reduced ( P <.05). Thus, in the aorta, L-NAME–induced hypertension is associated with impaired endothelium-dependent relaxations, unmasking the effects of endothelium-derived vasoconstrictor prostanoids, and with a specific reduction of the contraction induced by endothelin-1. Chronic antihypertensive therapy with verapamil or trandolapril prevented this imbalance of endothelium-dependent relaxations and contractions and, in turn, normalized vascular function.