Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 285, Issue 5, Pages H2054-H2063Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00075.2003
Keywords
epoxides; cytochrome P-450; vasodilation
Funding
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [P01HL034300, R01HL059884] Funding Source: NIH RePORTER
- NHLBI NIH HHS [HL 59884, HL 03674, P01 HL034300] Funding Source: Medline
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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 muM) or bradykinin (BK, 0.1-3 muM) elicited NO- and prostanoid-independent vasodilation. Miconazole (1.5 muM) or 6-(2-propargyloxyphenyl)hexanoic acid (30 muM), 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 muM) inhibited these responses. Apamin (1 muM), which is a large-conductance Ca2+-activated K+ (BKCa) channel inhibitor, or 18alpha-glycyrrhetinic acid (30 muM), which is an inhibitor of myoendothelial gap junctional electromechanical coupling, also inhibited these responses. NO donors spermine NONOate (1 and 3 muM) or sodium nitroprusside (0.3 and 3 muM) but not 8-bromo-cGMP (100 muM), 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 muM) attenuated basal (19 +/- 7%; P < 0.05) and AA stimulation (1 mu M, 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 epoxy-genase-dependent dilation of rat renal microvessels without affecting the actions of epoxides on K+ channels.
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