ETA-RECEPTOR BLOCKADE ATTENUATES THE HYPERTENSION BUT NOT RENAL DYSFUNCTION IN DOCA-SALT RATS

Endothelin (ET)-1 has potent renal and systemic vasoconstrictor proper ties, and thus we investigated whether ET-1 plays a role in increasing blood pressure and decreasing renal function in DOCA-salt hypertensio n. After a right nephrectomy, rats had DOCA or placebo pellets implant ed subcutaneously and were given saline or tap water to drink, respect ively. Additional groups of rats were given the ETA receptor antagonis t A-127722 in their water. Rats were maintained in metabolic cages for monitoring excretory function and food and water intake. Three weeks after surgery, mean arterial pressure (MAP) was recorded in the consci ous rats via a carotid artery catheter. As expected, DOCA-salt rats ha d significantly higher MAP compared with uninephrectomized controls (1 97 +/- 6 vs. 133 +/- 3 mmHg). Creatinine clearance, used as an estimat e of glomerular filtration rate, was significantly reduced in DOCA-sal t rats (2.9 +/- 0.4 vs. 6.8 +/- 0.3 dl . day(-1) . 100 g(-1) body wt i n controls). ETA receptor blockade with A-127722 significantly reduced MAP (156 +/- 8 mmHg) but had no effect on creatinine clearance of DOC A-salt-treated rats (2.8 +/- 0.3 dl . day(-1) . 100 g(-1) body wt). Pl asma ET-1 levels were significantly raised after DOCA-salt treatment ( 1.4 +/- 0.5 pg/ml vs. 0.4 +/- 0.1 pg/ml in controls). A-127722 treatme nt increased circulating ET-1 levels in both placebo (2.3 +/- 0.5 pg/m l) and DOCA-salt (5.6 +/- 0.7 pg/ml) rats. However, ET-1 mRNA expressi on in renal cortical and medullary tissue was not affected by either A -127722 or DOCA-salt treatments. Thus ETA receptors appear to play a r ole in the maintenance and development of DOCA-salt hypertension but n ot in the accompanying reduction of renal function.