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

Abstract

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 microM) or bradykinin (BK, 0.1-3 microM) elicited NO- and prostanoid-independent vasodilation. Miconazole (1.5 microM) or 6-(2-propargyloxyphenyl)hexanoic acid (30 microM), 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 microM) inhibited these responses. Apamin (1 microM), which is a large-conductance Ca2+-activated K+ (BKCa) channel inhibitor, or 18alpha-glycyrrhetinic acid (30 microM), which is an inhibitor of myoendothelial gap junctional electromechanical coupling, also inhibited these responses. NO donors spermine NONOate (1 and 3 microM) or sodium nitroprusside (0.3 and 3 microM) but not 8-bromo-cGMP (100 microM), 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 BKCa 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 microM) attenuated basal (19 +/- 7%; P < 0.05) and AA stimulation (1 microM, 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.

In vivo regulation of endothelium-dependent vasodilation in the rat renal circulation and the effect of streptozotocin-induced diabetes

“…In support of this, results of a number of previous studies show that NO inhibits cytochrome P-450 enzymes (41), including the epoxygenases responsible for production of epoxyeicosatrienoic acids, a putative EDHF (37). There is also strong evidence from in vitro studies of vascular reactivity that NO can inhibit EDHF activity (1,37).…”

Glial Cells Dilate and Constrict Blood Vessels: A Mechanism of Neurovascular Coupling

“…However, NO could also favor vasoconstriction. NO could inhibit cytochrome P450 epoxygenase, the enzyme that metabolizes arachidonic acid to vasodilating EETs (Udosen et al, 2003). By reducing EET production, NO would promote vasoconstriction.…”

Contribution of endothelium-derived hyperpolarizing factor to exercise-induced vasodilation in health and hypercholesterolemia

“…This was unexpected based on experimental studies, demonstrating that the contribution of EDHF is only evidenced after NO blockade. 16,[46][47][48] Even after inhibition of NO with l-NMMA, K + Ca channel activation continued to contribute to exercise-induced microvascular dilation. Similarly, after the initial inhibition of K + Ca channels with TEA, further inhibition of exercise-vasodilation with l-NNMA was observed, with an additional 13.6% reduction in mean exercise flow, suggesting an independent and additive effect of dual blockade.…”