ROLE OF ENDOTHELIN RECEPTOR SUBTYPES IN THE SYSTEMIC AND RENAL RESPONSES TO ENDOTHELIN-1 IN HUMANS

The authors recently reported that infusion of endothelin-1 in humans to obtain pathophysiological plasma levels causes profound renal vasoc onstriction and sodium retention. The relative roles of the ETA- and E TB-receptor subtypes in these effects in humans is unknown. Such infor mation is essential in view of the recent introduction of endothelin-r eceptor blockers in clinical medicine. The study presented here was de signed to define the role of the ETA- and ETB-receptor subtypes in the renal actions of endothelin-1 in humans. Systemic infusion of endothe lin-1, a nonselective receptor agonist, was compared with infusion of equimolar dosages of the ETB-selective agonist endothelin-3 in healthy volunteers. Endothelin-1 infusion was associated with an approximate 2.5-fold increase in plasma levels of endothelin-l. This was accompani ed by an increase in blood pressure by approximately 6 mm Hg (P < 0.05 ). During endothelin-1 infusion, RPF decreased from 642 +/- 42 to 480 +/- 36 mL/min (P < 0.05) and GFR from 121 +/- 4 to 109 +/- 7 mL/min (P < 0.05). Sodium excretion rate decreased during endothelin-1 infusion , from a baseline value of 182 +/- 33 to 84 +/- 28 mu mol/min at the e nd of the endothelin-1 infusion. Endothelin-3 infusion also resulted i n a approximate 2.5-fold increase of plasma levels of endothelin-3. Ho wever, in contrast to the endothelin-1 infusion, endothelin-3 had no e ffect on blood pressure, renal hemodynamics, and electrolyte excretion . These results suggest that the systemic and renal vasoconstrictor ef fects of endothelin-1 in humans are predominantly mediated by the ETA receptors.