Role of endothelin ET(A) receptors in the hypertension produced by 4-day L-nitroarginine methyl ester and cyclosporine treatment.

Studies were designed to examine the influence of endothelin type A receptor (ETA) blockade on the hypertensive and renal response to 4 day treatment with the nitric oxide (NO) synthase inhibitor, L-nitroarginine methyl ester (L-NAME), and cyclosporine. In the first series of experiments, male Sprague-Dawley rats maintained in metabolic cages were given the L-NAME at 50 mg/100 ml in the drinking water with or without the ETA receptor antagonist, A-127722 (2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[[(dibutyl amino)carbonyl]methyl]-pyrrolidine-3-carboxylic acid; 10 mg kg(-1) day(-1)), in either food or water. After 4 days, tail cuff estimates of systolic arterial pressure and a blood sample were obtained. A-127722 prevented the rise in tail cuff pressure produced by L-NAME. In the second series of experiments, rats were given cyclosporine at 20 mg kg(-1) day(-1) (i.p.) or cyclosporine plus L-NAME. Control groups were given olive oil (1 ml/kg i.p.). Treatment with cyclosporine alone had no effect on tail cuff pressure or plasma creatinine, but significantly attenuated the normal increase in body weight over the 4-day period. The combination of cyclosporine plus L-NAME significantly increased both tail cuff pressure and plasma creatinine and completely prevented any gain in body weight. L-NAME plus olive oil produced a significant increase in tail cuff pressure but changed no other variable. To determine the role of ETA receptors in this setting, a final series of rats were treated with cyclosporine and L-NAME along with A-127722 in the drinking water. ETA receptor blockade had no effect on the increase in tail cuff pressure, plasma creatinine or the attenuated weight gain. These results indicate that subchronic (4-day) L-NAME hypertension is maintained, at least in part, by activation of ETA receptors although the hypertensive and renal response to combined L-NAME and cyclosporine treatment does not involve ETA receptor activation. These results support the hypothesis that endothelial dysfunction predisposes the kidney to functional derangements associated with cyclosporine.