Antihypertensive and renoprotective effects of ABT‐627 and chlorthalidone treatment in Dahl S rats on a high salt high fat diet.

Abstract

Over the last two decades, it has become increasingly evident that endothelin‐1 (ET‐1) is important in blood pressure regulation and may be a good target for the treatment and prevention of hypertension; however, the use of ETA receptor antagonists can produce fluid retention and may be better suited for use in combination with other antihypertensive medications, especially diuretics. Therefore, we determined the antihypertensive and renoprotective effects of an ETA receptor antagonist (ABT‐627, 5 mg/kg/day), a thiazide diuretic (chlorthalidone, 5 mg/kg/day), and combination of both in high fat (59% fat)/high salt (4% NaCl) fed Dahl S rats, a rodent model of salt sensitive hypertension. First, we found that after 4 weeks of treatment, mean arterial pressure (MAP; telemetry) was significantly reduced by both ABT‐627 and chlorthalidone (CH), an effect that was significantly enhanced by combination treatment (vehicle: 176±8, ABT‐627: 146±3, CH: 135±2, ABT‐627+CH: 115±6 mmHg; p<0.05). Associated with the reduction in blood pressure, ABT‐627 and CH alone both reduced proteinuria while the combination treatment significantly reduced proteinuria further (vehicle: 578±145, ABT‐627: 297+29, CH: 138+10, ABT‐627+CH: 95+13 mg/day; p<0.05). Finally, we found that urinary nephrin excretion, a marker of glomerular damage, was significantly decreased in CH and ABT‐627+CH (vehicle: 1072+218, CH: 423+45, ABT‐627+CH: 315+54 μg/day; p<0.05). These results indicate that simultaneous blockade of ETA receptors and diuretic treatment provides greater antihypertensive and renoprotective effects than either drug alone in Dahl salt sensitive rats maintained on a Western diet.