Abstract—Endothelin (ET) exerts powerful pressor actions primarily through activation of the ET_A receptor subtype. The ET_B receptor (ET_BR) subtype, on the other hand, is generally thought to initiate physiological actions that decrease arterial pressure. Such actions include clearing ET from the bloodstream, initiating endothelium-mediated vasodilation, and facilitating renal sodium and water excretion. The effect of long-term activation of the ET_BR on arterial pressure, however, never has been directly tested. In this study we evaluated cardiovascular responses to chronic (5-day) activation of ET_BR in male rats using continuous intravenous infusion of the selective agonist sarafotoxin 6c. Surprisingly, we found that sarafotoxin 6c caused a sustained increase in arterial pressure that rapidly reversed on termination of infusion. The hypertension was associated with increased renal excretion of sodium and water and decreased plasma volume. Alterations in daily sodium intake did not affect the magnitude of the hypertension. Hemodynamic studies revealed a decreased cardiac output and increased total peripheral resistance during sarafotoxin 6c infusion. Infusion of sarafotoxin 6c caused a small increase in plasma ET levels. Nevertheless, the hypertension was not affected by coadministration of a selective ET_A receptor antagonist (atrasentan) but was completely prevented by treatment with a combined ET_A receptor and ET_BR antagonist (A186280). These experiments reveal for the first time that chronic activation of ET_BR in rats causes sustained hypertension.