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Nitric oxide-epoxygenase interactions and arachidonate-induced dilation of rat renal microvessels

Center for Cardiovascular Diseases, College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas 77004; and ²Department of Pharmacology, New York Medical College, Valhalla, New York 10595

Submitted 27 January 2003 ; accepted in final form 15 July 2003

Nitric oxide (NO) is an inhibitor of hemoproteins including cytochrome P-450 enzymes. This study tested the hypothesis that NO inhibits cytochrome P-450 epoxygenase-dependent vascular responses in kidneys. In rat renal pressurized microvessels, arachidonic acid (AA, 0.03–1 µM) or bradykinin (BK, 0.1–3 µM) elicited NO- and prostanoid-independent vasodilation. Miconazole (1.5 µM) or 6-(2-propargyloxyphenyl)hexanoic acid (30 µM), both of which are inhibitors of epoxygenase enzymes, or the fixing of epoxide levels with 11,12-epoxyeicosatrienoic acid (11,12-EET; 1 and 3 µM) inhibited these responses. Apamin (1 µM), which is a large-conductance Ca²⁺-activated K⁺ (BK_Ca) channel inhibitor, or 18-glycyrrhetinic acid (30 µM), which is an inhibitor of myoendothelial gap junctional electromechanical coupling, also inhibited these responses. NO donors spermine NONOate (1 and 3 µM) or sodium nitroprusside (0.3 and 3 µM) but not 8-bromo-cGMP (100 µM), which is an analog of cGMP (the second messenger of NO), blunted the dilation produced by AA or BK in a reversible manner without affecting that produced by hydralazine. However, the non-NO donor hydralazine did not affect the dilatory effect of AA or BK. Spermine NONOate did not affect the dilation produced by 11,12-EET, NS-1619 (a BK_Ca channel opener), or cromakalim (an ATP-sensitive K⁺ channel opener). AA and BK stimulated EET production, whereas hydralazine had no effect. On the other hand, spermine NONOate (3 µM) attenuated basal (19 ± 7%; P < 0.05) and AA stimulation (1 µM, 29 ± 9%; P < 0.05) of renal preglomerular vascular production of all regioisomeric EETs: 5,6-; 8,9-; 11,12-; and 14,15-EET. These results suggest that NO directly and reversibly inhibits epoxygenase-dependent dilation of rat renal microvessels without affecting the actions of epoxides on K⁺ channels.

epoxides; cytochrome P-450; vasodilation

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