Microvascular responsiveness to endothelin in normal and deoxycorticostereone acetate-salt hypertensive rats

The objective of the present study was to determine if the vasoactive agent, endothelin-1, plays a role in regulation of peripheral resistance in normotensive and hypertensive states.;In the first study, we assessed the ability of endothelin-1 to induce dilation of small arterioles in the normotensive rat cremaster muscle. The response to topical application of endothelin-1 was assessed by using intravital microscopy. Exposure to increasing concentrations of endothelin-1 produced a dose-dependent constriction of third-order arterioles. Pretreatment with antagonists of nitric oxide production caused a significant potentiation of the contractile responses of third-order arterioles to endothelin-1. In addition, we observed a significant vasodilation to low levels of endothelin-1 in the presence of the endothelin type A receptor (ET-A) antagonist. This dilation was abolished in the presence of nitric oxide blockade. These results indicate that endothelin-1-induced vasodilation is mediated by the endothelin type B receptor (ET-B) via the stimulation of endogenous nitric oxide production. This nitric oxide stimulating effect of endothelin-1 appears to attenuate the ET-A receptor-mediated constricting effects on small resistance vessels in striated muscle.;In the second study, we compared the vascular responses to endothelin-1 in both normotensive and deoxycorticosterone acetate (DOCA)-salt hypertensive rats. By using radioimmunoassay, we also measured tissue and plasma endothelin-1 levels in both groups of rats. DOCA-salt hypertension was induced by subcutaneous injection of DOCA (twice per week, 30 mg/kg) while maintaining the rats on a high sodium chloride and high potassium diet. ET-A and ET-B receptor antagonists were used in these experiments to clarify whether or not there is an alteration in endothelin-1-induced vascular responses during hypertension. The results indicate that during DOCA-salt hypertension, tissue levels of endothelin-1 are increased, ET-A tissue levels of endothelin-1 are increased, ET-A receptor-induced vasoconstriction is blunted, and the major effect of the ET-B receptor is to mediate vasoconstriction.