Roles of Nitric Oxide and Endothelium-Derived Hyperpolarizing Factor in Vasorelaxant Effect of Acetylcholine as Influenced by Aging and Hypertension

Abstract

We investigated vasodilator responses to acetylcholine (ACh) in isolated mesenteric vascular bed preparations (preconstricted with methoxamine) of young (2 months) and old (18 months) normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). ACh produced a similar dose-dependent vasorelaxant effect in preparations from both 2-month old normotensive and hypertensive rats. This vasodilator response to ACh decreased with age, especially in hypertensive animals. In preparations from young WKY, the vasorelaxant effect of ACh was not affected by 100 microM NG-nitro-L-arginine methyl ester (L-NAME), and was only slightly reduced by 500 microM L-NAME. The K+ channel blocker tetraethylammonium (TEA 2.5-10 mM) concentration-dependently antagonized the ACh-induced vasodilation in the same preparations. In preparations obtained from aged WKY animals, as well as in those from young and aged SHR animals, ACh-induced vasodilation was significantly and concentration-dependently reduced by 100 and 500 microM L-NAME. On the other hand, TEA induced a lesser antagonistic effect than that observed in young normotensive animals. In preparations preconstricted with 80 mM KCl, ACh caused vasodilation that was weaker in preparations from young WKY than in those from aged WKY; on the contrary, ACh was more effective in young than in aged SHR. These results confirm that the vasodilating response to ACh decreases with age and hypertension and suggest that the main mechanism responsible for the effect of ACh in vessels of young normotensive animals consists of activation of K+ channels. In preparations from old normotensive, as well as in those from young and old hypertensive animals, ACh induces vasorelaxation mainly through nitric oxide (NO) release.