Do ETA 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 injury. Inhibition of the renin/angiotensin system prevents only partially the functional and structural abnormalities associated with this model. 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 ETA 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 NAME+FR received both L-NAME and FR139317. At 2 weeks of treatment, renal and systemic hemodynamic parameters assessed under anesthesia were similar in Groups C and C+FR. Rats of Group NAME exhibited systemic hypertension and renal vasoconstriction characteristic of this model. 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 glomerular collapse and interstitial expansion, the two chief modalities of renal injury in this model. These results suggest that ET does not participate, at least via the ETA receptor, in the pathogenesis of hypertension, renal dysfunction, or renal injury associated with the chronic NO inhibition model.
Fujihara
C K
CK
Department of Clinical Medicine, University of São Paulo Medical School, Brazil.
De Nucci
G
G
Zatz
R
R
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001381:Azepines / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects*; D007211:Indoles / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000502:physiology*
D001381:Azepines; D007211:Indoles; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; C079574:FR 139317; D009569:Nitric Oxide; D001120:Arginine; D019331:NG-Nitroarginine Methyl Ester