ENDOTHELIN-A RECEPTOR ANTAGONISM ATTENUATES THE HYPERTENSION AND RENAL INJURY IN DAHL SALT-SENSITIVE RATS

The aim of this study was to examine the role of endothelin-A (ETA) re ceptors in mediating the hypertension and renal injury associated with high salt intake in Dahl salt-sensitive (DS) rats. To achieve this go al, we examined the effects of chronic selective ETA antagonist (A-127 722) treatment at a dose of 10 mg/kg/d on arterial pressure, renal fun ction, and morphology in DS and Dahl salt-resistant (DR) rats placed o n a high sodium (8% NaCl) diet (HSD) for 3 weeks. Placement of DS rats (n=13) on HSD for 3 weeks caused a progressive increase in systolic p ressure (from 118+/-3 to 186+/-15 mm Hg). The increase in systolic pre ssure was significantly attenuated (from 125+/-4 to 167+/-12 mm Hg) in DS rats treated with A-127722 (n=13). Mean arterial pressure (MAP) me asured directly at the end of the study was also significantly lower b y 18 mm Hg (P<.02) in the DS rats treated with A-127722. The slope of the chronic pressure-natriuresis curve was shifted to the right in DS rats and to the left by chronic ETA receptor blockade in DS rats. The hypertension in DS rats was associated with marked proteinuria (from 4 .1+/-1.1 to 74.3+/-5.3 mg/24 h/100 g body weight) that was significant ly attenuated (from 5.7+/-1.2 to 55.2+/-6.5 mg/24 h/100 g body weight) in DS rats treated with A-127722. The percentage of glomeruli display ing fibrosis, hypercellularity, and hyalinization was also significant ly reduced after treatment with A-127722 in DS rats. Arterial pressure , protein excretion, renal hemodynamics, and morphologic structure wer e not significantly changed in response to ETA receptor blockade in DR rats placed on HSD. These data indicate that endothelin-A receptor ac tivation may play a role in the exacerbation of hypertension and devel opment of renal injury in DS rats.