Endothelin receptor B is Required for the Blood Pressure lowering Effect of G Protein-coupled Estrogen Receptor 1 in Ovariectomized Rats.

ABSTRACT

Activation of the G protein-coupled estrogen receptor 1 (GPER1) elicits antihypertensive actions in different animal models. The endothelin-1 signaling system plays a fundamental role in blood pressure regulation. Lack of functional endothelin receptor B receptors (ETB) evokes hypertension and salt sensitivity. GPER1 and ETB interact to promote urinary sodium excretion in female rats. We hypothesized that activation of GPER1 protects against hypertension and salt sensitivity induced by ETB antagonism in female rats. Female Sprague Dawley rats were implanted with radiotelemetry. Then, animals were subjected to ovariectomy and simultaneously implanted with minipumps to deliver either the GPER1 agonist, G1, or its corresponding vehicle (Veh). Two weeks post-surgery, we initiated treatment of rats with the ETB antagonist, A-192621. Animals were maintained on a normal salt (NS) diet then challenged with a high salt (HS) diet for an additional 5 days. Assessment of mean arterial blood pressure revealed an increase in Veh-treated, but not G1-treated, rats in response to ovariectomy. A-192621 increased blood pressure in NS-fed Veh and G1-treated rats. G1 improved the circadian blood pressure rhythms which were disrupted in A-192621-treated ovariectomized rats. Thus, although systemic GPER1 activation did not protect ovariectomized rats from hypertension and salt sensitivity induced by ETB antagonism, it maintained the circadian blood pressure rhythms. Functional ETB is required to elicit the antihypertensive actions of GPER1. Additional studies are needed to improve our understanding of the interaction between G protein-coupled receptors in regulating circadian blood pressure rhythm.