ENDOTHELIN SUBTYPE-B-RECEPTOR-MEDIATED CALCIUM AND CONTRACTILE RESPONSES IN SMALL ARTERIES OF HYPERTENSIVE RATS

Endothelin-1 elicits vasoconstrictor responses through endothelin subtype A receptors, which are located on vascular smooth muscle cells, and vasodilator responses through endothelin subtype B receptors, which occur predominantly on endothelial cells. Endothelin subtype B receptors also may be present on vascular smooth muscle cells, in which they may mediate vasoconstriction. The aims of this study were to determine the presence of vascular smooth muscle vasoconstrictor endothelin subtype B receptors in mesenteric resistance arteries and to assess whether endothelin subtype B receptor-mediated responses differ between spontaneously hy pertensive rats and Wistar-Kyoto rats. Contractile responses to the endothelin subtype B receptor agonist sarafotoxin S6c and endothelin-1 were measured simultaneously with [Ca2+](i) in endothelium-denuded mesenteric resistance arteries from adult spontaneously hypertensive rats and Wistar-Kyoto rats. To simulate in vivo conditions matched as closely as possible to in vitro conditions, vessels were mounted in a vessel flow chamber in which intraluminal pressure was maintained at 60 mm Hg. Contraction was determined by video imaging to record lumen diameter, and [Ca2+](i) was measured by the fura 2 method. Basal [Ca2+](i) was significantly higher (P<.01) in hypertensive (170+/-4 nmol/L) compared with normotensive rats (134+/-3 nmol/L). The endothelin subtype B receptor agonist sarafotoxin S6c increased [Ca2+](i) in a concentration-dependent manner. Sarafotoxin S6c-induced [Ca2+](i) and contractile responses were significantly lower in hypertensive compared with normotensive rats. These data demonstrate that endothelin subtype B receptors are present in vascular smooth muscle of small arteries and that endothelin subtype B receptor-mediated vasoconstriction occurs through intracellular calcium signaling pathways. Although the contribution of endothelin subtype B receptor-induced contraction is small, responses mediated by this receptor subtype in spontaneously hypertensive rats are attenuated compared with age-matched Wistar-Kyoto rats.