Nitric oxide synthesis influences the renal vascular response to heme oxygenase inhibition.

We studied the effects of the heme oxygenase (HO) inhibitor stannous mesoporphyrin (SnMP; 40 micromol/kg i.v.) on renal hemodynamics in anesthetized rats with and without 48-h pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthesis. SnMP decreased renal blood flow (RBF) and increased renal vascular resistance (RVR) in both groups. The SnMP-induced reduction of RBF in L-NAME-pretreated rats was more prominent than in rats without pretreatment (43 +/- 7 vs. 13 +/- 3%) as was the SnMP-induced elevation of RVR (87 +/- 31 vs. 14 +/- 5%). The renal vasoconstrictor effect of SnMP is linked, in part, to amplification of prevailing neurohormonal constrictor mechanisms, since in L-NAME-pretreated rats it was prevented by concurrent administration of prazosin or losartan. However, SnMP (15 micromol/l) also elicits vasoconstriction in isolated, pressurized renal interlobular arteries and the response is more intense in vessels obtained from L-NAME-pretreated rats than from rats without pretreatment. These data indicate that the status of NO synthesis conditions the vascular response to HO inhibition in the rat kidney.

Angiotensin II induces carbon monoxide production in the perfused kidney: relationship to protein kinase C activation.

Heme oxygenase (HO)-derived carbon monoxide (CO) attenuates vascular reactivity to constrictor stimuli. ANG II produces vasoconstriction and induces HO-1 isoform expression. However, direct evidence that ANG II promotes HO product generation is lacking. Therefore, we examined the effects of ANG II on CO release and HO isoform expression in isolated rat kidneys. Kidneys were perfused with oxygenated Krebs buffer. ANG II (1 micromol/l) increased (P < 0.05) perfusion pressure from 97 +/- 9 to 150 +/- 14 mmHg; it also increased (P < 0.05) the concentration of CO in the venous effluent (from 27.1 +/- 11.9 to 45.6 +/- 11.7, 62.5 +/- 16.7, 94.8 +/- 20.7, and 101.9 +/- 13.1 nmol/l after 30, 60, 90, and 120 min, respectively). The pressor effect of ANG II was blunted (P < 0.05) in kidneys perfused with buffer containing losartan (10 micromol/l) or PKC inhibitors staurosporine (0.1 micromol/l) or calphostin C (1 micromol/l). Kidneys perfused with buffer containing ANG II for 120 min also displayed increased (P < 0.05) HO-1 expression. Stannous mesoporphyrin (30 micromol/l) decreased CO release (P < 0.05) in preparations perfused with and without ANG II; the HO inhibitor also increased (P < 0.05) perfusion pressure, more so in kidneys perfused with that without ANG II. We conclude that ANG II stimulates CO production and release in isolated, perfused rat kidneys. This action of ANG II is linked to the activation of AT(1) receptors and involves PKC activation and upregulation of renal HO-1 but not of HO-2 protein expression. The study suggests upregulation of renal HO-1 and CO release are protagonic events in a counterregulatory mechanism that attenuates ANG II-induced renal vasoconstriction.