DO ET(A) RECEPTORS PARTICIPATE IN THE HEMODYNAMIC AND RENAL EFFECTS OF CHRONIC NITRIC-OXIDE BLOCKADE

Chronic nitric oxide (NO) blockade promotes progressive hypertension, marked renal vasoconstriction, and glomerular and renal interstitial i njury. Inhibition of the renin/angiotensin system prevents only partia lly the functional and structural abnormalities associated with this m odel. Because endothelin (ET) is a powerful endogenous vasoconstrictor and promitogen, we examined the hypothesis that it might also mediate the hemodynamic and renal structural effects of chronic NO blockade. Four groups of 16 adult male Munich-Wistar rats were studied. Group C received daily i.p. saline injections and no drug treatment. Group C FR received daily i.p. injections of the ET(A) inhibitor FR139317, 32 mg/kg. Group NAME received the NO inhibitor N-omega-nitro-L-arginine methyl ester (L-NAME), 65 mg/kg/day in the drinking water, and group N AME + FR received both L-NAME and FR139317. At 2 weeks of treatment, r enal and systemic hemodynamic parameters assessed under anesthesia wer e similar in Groups C and C + FR. Rats of Group NAME exhibited systemi c hypertension and renal vaso-constriction characteristic of this mode l. FR139317 was ineffective in preventing these abnormalities in Group NAME + FR. In eight additional rats of each group observed at 30 days , FR139317 treatment was equally inactive in the prevention of glomeru lar collapse and interstitial expansion, the two chief modalities of r enal injury in this model. These results suggest that ET does not part icipate, at least via the ET(A) receptor, in the pathogenesis of hyper tension, renal dysfunction, or renal injury associated with the chroni c NO inhibition model.