Functional Interaction of Endothelin Receptors in Mediating Natriuresis Evoked by G Protein-Coupled Estrogen Receptor 1.

The G protein-coupled estrogen receptor 1 (GPER1) mediates rapid estrogenic signaling. We recently reported that activation of GPER1 in the renal medulla evokes endothelin-1-dependent natriuresis in female, but not male, rats. However, the involvement of the ET receptors, ET_A and ET_B, underlying GPER1 natriuretic action remain unclear. In this study, we used genetic and pharmacologic methods to identify the contributions of ET_A and ET_B in mediating this female-specific natriuretic effect of renal medullary GPER1. Infusion of the GPER1-selective agonist G1 (5 pmol/kg per minute) into the renal medulla for 40 minutes increased Na⁺ excretion and urine flow in anesthetized female ET_B-deficient (ET_B def) rats and littermate controls but did not affect blood pressure or urinary K⁺ excretion in either group. Pretreatment with the selective ET_A inhibitor ABT-627 (5 mg/kg, intravenous) abolished G1-induced natriuresis in ET_B def rats. To further isolate the effects of inhibiting either receptor alone, we conducted the same experiments in anesthetized female Sprague-Dawley (SD) rats pretreated or not with ABT-627 and/or the selective ET_B inhibitor A-192621 (10 mg/kg, intravenous). Neither antagonism of ET_A nor antagonism of ET_B receptor alone affected the G1-induced increase in Na⁺ excretion and urine flow in SD rats. However, simultaneous antagonism of both receptors completely abolished these effects. These data suggest that ET_A and ET_B receptors can mediate the natriuretic and diuretic response to renal medullary GPER1 activation in female rats. SIGNIFICANCE Activation of G protein-coupled estrogen receptor 1 (GPER1) in the renal medulla of female rats evokes natriuresis via endothelin receptors A and/or B, suggesting that GPER1 and endothelin signaling pathways help efficient sodium excretion in females. Thus, GPER1 activation could be potentially useful to mitigate salt sensitivity in females.

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