Display of the characteristics of endothelium‐derived hyperpolarizing factor by a cytochrome P450‐derived arachidonic acid metabolite in the coronary microcirculation

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Abstract
1 In addition to nitric oxide (NO) and prostacyclin (PGI2) an endothelium-derived factor, which hyperpolarizes vascular smooth muscle cells via activation of K+ channels, contributes to the dilator effect of bradykinin in different vascular beds. Since this so-called endothelium-derived hyperpolarizing factor (EDHF) also seems to play an important role in the coronary circulation, we investigated its nature and mechanism of action in the rat isolated perfused heart (Langendorff preparation). 2 Bolus injections of bradykinin (1, 10, and 100 pmol) elicited a transient dose-dependent dilator response (e.g., 12 ± 2% decrease in coronary perfusion pressure (CPP) at 10 pmol bradykinin, n = 41). Administration of the cyclo-oxygenase inhibitor, diclofenac (1 μm), augmented the bradykinin-induced dilation approximately twofold (n = 9 P < 0.01). Combined treatment with the NO synthase inhibitor, NG-nitro-L-arginine (30 μm) and diclofenac (1 μm) significantly reduced the duration, but increased the amplitude of the dilator response to bradykinin (27 ± 2% decrease in CPP, n = 24, P < 0.01). 3 The abolition of this NG-nitro-L-arginine/diclofenac-insensitive dilator response to bradykinin by tetrabutylammonium (0.3 μm), an inhibitor of Ca2+-dependent K+ channels (4 ± 1% decrease in CPP, n = 6, P < 0.01), supports the view that the dilator compound released in the coronary microcirculation is EDHF. 4 This EDHF-type dilation was reversibly inhibited by the phospholipase A2 inhibitor, quinacrine (3 μm, 9 ± 3% decrease in CPP, n = 6, P < 0.01) and by the cytochrome P450 inhibitor SKF525a (3 μm, 6 ± 1% decrease in CPP, n = 6, P < 0.01). 5 Tetrabutylammonium, quinacrine or SKF 525a did not affect the endothelium-independent dilator response to sodium nitroprusside (1 nmol), indicating that these compounds did not affect smooth muscle relaxation in a non-specific manner. 6 These findings suggest that in the coronary microcirculation bradykinin stimulates the release of a cytochrome P450-derived arachidonic acid metabolite, which exhibits the characteristic features of EDHF.