Contribution of renal oxygenases to glycerol-induced acute renal failure in the rat

Administration of glycerol produces acute renal failure (ARF) accompanied by profound vasoconstriction. It was hypothesized that impaired arachidonic acid metabolism may contribute to the vasoconstriction through alteration of renal eicosanoids or endothelin-1 or angiotensin II stimulation of renal oxygenases. Arachidonic acid (5, 10, 25 microg) in the control kidney produced increases in perfusion pressure of 15 +/- 9, 18 +/- 8, and 43 +/- 18 mm Hg, respectively. These responses were increased 1.5-fold in glycerol-induced renal failure (p < 0.01). Indomethacin (10 microM), the cyclooxygenase inhibitor, converted arachidonic acid vasoconstriction to epoxide-mediated vasodilator responses, which were unchanged in ARF. In ARF, 5,8,11,14-eicosatetraynoic acid (10 microM), the all-purpose inhibitor of arachidonic acid metabolism; indomethacin (10 microM), a cyclooxygenase inhibitor; 5,8,11-eicosatriyenoic acid (2.5 microM), the 5- and 12-lipoxygenase inhibitor; or aminobenzotriazole (50 mM), the cytochrome P-450 monooxygenase inhibitor, markedly attenuated arachidonic acid-induced vasoconstriction by 73 +/- 11% (p < 0.01), 89 +/- 1% (p < 0.01), 62 +/- 11% (p < 0.01), and 82 +/- 2% (p < 0.01), respectively. In ARF, angiotensin II-induced vasoconstriction was amplified by 67% (p < 0.01). Eicosatetraynoic acid, eicosatriyenoic acid, and aminobenzotriazole reduced these responses by 33 +/- 6% (p < 0.05), 53 +/- 6% (p < 0.01), and 52 +/- 11% (p < 0.05), respectively. Vasoconstriction by endothelin-1 was unchanged in ARF (24 +/- 17%). However, indomethacin attenuated endothelin-1 vasoconstriction by 41 +/- 11% (p < 0.05), whereas eicosatriyenoic acid and aminobenzotriazole were without effect. These data suggest that the increased renal vascular reactivity in ARF in response to arachidonic acid involves a relatively greater production of cyclooxygenase metabolites than monoxygenase- or lipoxygenase-derived eicosanoid metabolites. Furthermore, increased angiotensin II vasoconstriction is predominantly through lipoxygenase and monoxygenase metabolic pathways, whereas for endothelin-1, increased cyclooxygenase-derived vasoconstrictor metabolites play a significant role in its amplified vasoconstrictor effect in glycerol-induced ARF.