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

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.