EFFECTS OF PROSTAGLANDINS AND NITRIC-OXIDE ON THE RENAL EFFECTS OF ANGIOTENSIN-II IN THE ANESTHETIZED RAT

The potential influences of nitric oxide (NO) and prostaglandins on th e renal effects of angiotensin II (Ang II) have been investigated in t he captopril-treated anaesthetized rat by examining the effect of indo methacin or the NO synthase inhibitor, N-omega-nitro-L-arginine methyl ester (L-NAME), on the renal responses obtained during infusion of An g II directly into the renal circulation. 2 Intrarenal artery (i.r.a.) infusion of Ang II (1-30 ng kg(-1) min(-1)) elicited a dose-dependent decrease in renal vascular conductance (RVC; -38+/-3% at 30 ng kg(-1) min(-1); P < 0.01) and increase in filtration fraction (FF; +49+/- 8% ; P < 0.05) in the absence of any change in carotid mean arterial bloo d pressure (MBP). Urine output (Uv), absolute (UNaV) and fractional so dium excretion (FENa), and glomerular filtration rate (GFR) were uncha nged during infusion of Ang II 1-30 ng kg(-1) min(-1) (+6+17%. + 11 +/ - 17%, + 22 +/- 23%, and -5 +/- 9%, respectively, at 30 ng kg(-1) min( -1)). At higher doses, Ang II (100 and 300 ng kg(-1) min(-1)) induced further decreases in RVC, but with associated increases in MBP, Uv and UNaV. 3 Pretreatment with indomethacin (10 mg kg(-1) i.v.) had no sig nificant effect on basal renal function, or on the Ang II-induced redu ction in RVC (-25+/-7% vs -38+/-3% at Ang II 30 ng kg(-1) min(-1)). In the presence of indomethacin, Ang II tended to cause a dose-dependent decrease in GFR (-38+/-10% at 30 ng kg(-1) min(-1)); however, this ef fect was not statistically significant (P = 0.078) when evaluated over the dose range of 1-30 ng kg(-1) min(-1), and was not accompanied by any significant changes in Uv, UNaV or FENa (-21+/-12%, -18+/-16% and +36+/-38%, respectively). 4 Pretreatment with L-NAME (10 mu g kg(-1) m in(-1) i.v.) tended to reduce basal RVC (control -11.8+/-1.4, +L-NAME -7.9+/-1.8 ml min(-1) mmHg(-1) x 10(-2)), and significantly increased basal FF (control +15.9+/-0.8, +L-NAME + 31.0+/-3.7%). In the presence of L-NAME, renal vasoconstrictor responses to Ang II were not signifi cantly modified (- 38+/-3% vs -35+/-13% at 30 ng kg(-1) min(-1)), but Ang II now induced dose-dependent decreases in GFR, Uv and UNaV (-51+/ -11%, -41+/-14% and -31+/-17%, respectively, at an infusion rate of An g II, 30 ng kg(-1) min(-1)). When evaluated over the range of 1-30 ng kg(-1) min(-1), the effect of Ang II on GFR and Uv were statistically significant (P < 0.05), but on UNaV did not quite achieve statistical significance (P=0.066). However, there was no associated change in FEN a observed, suggesting a non-tubular site of interaction between Ang I I and NO. 5 In contrast to its effects after pretreatment with L-NAME alone, Ang II (1-30 ng kg(-1) min(-1)) failed to reduce renal vascular conductance in rats pretreated with the combination of L-NAME and the selective angiotensin AT(1) receptor antagonist, GR117289 (1 mg kg(-1 ) i.v.). This suggests that the renal vascular effects of Ang II are m ediated through AT(1) receptors. Over the same dose range, Ang II also failed to significantly reduce GFR or Uv. 6 In conclusion, the renal haemodynamic effects of Ang II in the rat kidney appear to be modulate d by cyclooxygenase-derived prostaglandins and NO. The precise site(s) of such an interaction cannot be determined from the present data, bu t the data suggest complex interactions at the level of the glomerulus .