ETA receptor blockade attenuates the hypertension but not renal dysfunction in DOCA-salt rats.
Endothelin (ET)-1 has potent renal and systemic vasoconstrictor properties, and thus we investigated whether ET-1 plays a role in increasing blood pressure and decreasing renal function in DOCA-salt hypertension. After a right nephrectomy, rats had DOCA or placebo pellets implanted subcutaneously and were given saline or tap water to drink, respectively. Additional groups of rats were given the ETA receptor antagonist 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 conscious rats via a carotid artery catheter. As expected, DOCA-salt rats had significantly higher MAP compared with uninephrectomized controls (197 +/- 6 vs. 133 +/- 3 mmHg). Creatinine clearance, used as an estimate of glomerular filtration rate, was significantly reduced in DOCA-salt rats (2.9 +/- 0.4 vs. 6. 8 +/- 0.3 dl . day-1 . 100 g-1 body wt in controls). ETA receptor blockade with A-127722 significantly reduced MAP (156 +/- 8 mmHg) but had no effect on creatinine clearance of DOCA-salt-treated rats (2.8 +/- 0.3 dl . day-1 . 100 g-1 body wt). Plasma 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 treatment increased circulating ET-1 levels in both placebo (2.3 +/- 0.5 pg/ml) and DOCA-salt (5.6 +/- 0.7 pg/ml) rats. However, ET-1 mRNA expression in renal cortical and medullary tissue was not affected by either A-127722 or DOCA-salt treatments. Thus ETA receptors appear to play a role in the maintenance and development of DOCA-salt hypertension but not in the accompanying reduction of renal function.
Vascular Biology Center, Medical College of Georgia, Augusta, Georgia 30912-2500, USA.
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Allcock
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Venema
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Pollock
D000818:Animals; D000077868:Atrasentan; D001794:Blood Pressure / Q000187:drug effects*; D003404:Creatinine / Q000378:metabolism; D003900:Desoxycorticosterone; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000096:biosynthesis / Q000097:blood; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism; D007679:Kidney Medulla / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009392:Nephrectomy; D011759:Pyrrolidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D012982:Sodium, Dietary; D013237:Stereoisomerism; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014882:Water-Electrolyte Balance / Q000187:drug effects / Q000502:physiology*
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D012982:Sodium, Dietary; D003900:Desoxycorticosterone; D003404:Creatinine; D000077868:Atrasentan