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Metabolites of Cytochrome P450 2C9 are not Essential for the Regulation of Coronary Vasomotor Tone in Swine

Epoxyeicosatrienoic acids (EETs) are produced from arachidonic acid by cytochrome P450 (CYP450) epoxygenase enzymes. EETs are thought to be involved in the regulation of coronary vasomotor tone through activation of the BKCa channel on vascular smooth muscle, resulting in hyperpolarization and vasodilation. We have recently found that blockade of the BKCa channel results in coronary vasoconstriction at rest that increases progressively with increasing exercise intensity. We therefore hypothesized that EETs are involved in coronary vasodilation during exercise through activation of the BKCa channel. To test this hypothesis, swine (n=5) were studied at rest and while running on a treadmill at 1‐4 km/h. Inhibition of CYP450 2C9 with sulfaphenazole (5 mg/kg iv) did not affect coronary vasomotor tone at rest or during exercise, either under control conditions or in the presence of combined NO synthase (nitro‐L‐arginine, 20 mg/kg iv) and cyclooxygenase (indomethacin, 10 mg/kg iv) blockade. In contrast, blockade of BKCa channels with tetraethylammonium (20 mg/kg) resulted in coronary vasoconstriction at rest that increased progressively with increasing exercise intensity. The effect of tetraehylammonium was not influenced by pretreatment with sulfaphenazole.