The vasorelaxing action of rutaecarpine: direct paradoxical effects on intracellular calcium concentration of vascular smooth muscle and endothelial cells

Abstract

We have examined both the hypotensive effect and the mechanism of intracellular Ca++ regulation, underlying rutaecarpine (Rut)-induced vasodilatation. An i.v. bolus injection of Rut in anesthetized Sprague-Dawley rats produced a dose-dependent hypotensive effect. In isolated rat aorta rings, Rut (0.1-3 mu M) inhibited the phasic and tonic responses of norepinephrine- and phyenylephrine-induced contractions, respectively, mainly through an endothelium-dependent mechanism. However, the vasorelaxing effect of Rut (3 microM) persisted in denuded aorta, although to a much less extent than in intact tissue. As determined by the fura-2/AM (1-[2-(5-carboxyoxazol-2-yl)-6-aminobenzofuran-5-oxy]-2-(2'- amino-5'-methylphenoxy)-ethane-N,N,N,N-tetraacetic acid pentaacetoxymethyl ester) method, Rut (10 microM), in the presence of extracellular Ca++, suppressed the KCI-induced increment in the intracellular Ca++ concentration ([Ca++]i) of cultured vascular smooth muscle cells (VSMC). Rut (10 microM) also attenuated the norepinephrine-induced peak rise of [Ca++]i in VSMC placed in Ca++-free solution. On the other hand, Rut (1 and 10 microM) increased the level of [Ca++]i of cultured endothelial cells (EC) in the presence of extracellular Ca++. In conclusion, Rut acts on both VSMC and EC directly. In VSMC, it reduces [Ca++]i through the inhibition of Ca++ influx and Ca++ release from intracellular stores. In EC, Rut augments EC [Ca++]i by increasing Ca++ influx, possibly leading to nitric oxide release. The paradoxical regulation of Ca++ in both VSMC and EC acts simultaneously to cause vasorelaxation which could account, at least in part, for the hypotensive action. This is a most significant and a unique feature of this study.