17-ODYA - CAS 34450-18-5

Flow-induced vasodilation in hamster cremasteric arterioles was investigated with special reference to the roles of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). Arterioles (approximately 60 microm resting diameter) were cannulated, and suffused with MOPS solution at 37 degrees C (mean intraluminal pressure: 80 cm H(2)O). Step increases in the perfusate flow elicited a dose-dependent vasodilation, which was almost proportional to the increases in calculated wall shear stress (WSS). N(omega)-nitro L-arginine methyl ester (L-NAME, 100 microM) reduced the flow-induced vasodilation by approximately 50%, whereas indomethacin (10 microM) produced no significant effect. In the presence of L-NAME, the residual vasodilation was eliminated by treatment with the cytochrome P-450 monooxygenase inhibitor 17-octadecynoic acid (17-ODYA, 50 microM), sulfaphenazol (10 microM), tetraethylammonium (TEA, 3 mM; a nonselective Ca(2+)-activated K(+) channel inhibitor), or charybdotoxin (ChTX, 0.1 microM; intermediate or large conductance Ca(2+)-activated K(+) channel inhibitor). In the absence of L-NAME, the dilation was also reduced by approximately 50% by treatment with 17-ODYA, TEA, or ChTX.

In several blood vessels, endothelium-dependent vasorelaxation is in part mediated by an endothelium-derived hyperpolarizing factor (EDHF), the nature of which is as yet unknown. However, some evidence suggests that EDHF might be a cytochrome P-450-dependent monooxygenase metabolite of arachidonic acid. By using isometric tension measurements on rat main mesenteric arteries, the influence of four structurally and mechanistically different cytochrome P-450 inhibitors (proadifen, miconazole, 1-amino-benzotriazole, and 17-octadecynoic acid) was investigated on relaxations elicited by EDHF, assessed as the nitro-L-arginine-resistant component of acetylcholine-induced relaxation, and on relaxations provoked by the endothelium-independent potassium channel opener cromakalim. Proadifen (30 microM) inhibited the EDHF- as well as the cromakalim-induced relaxation, but not that elicited by nitroprusside. Also miconazole (30 microM) inhibited both the EDHF and the cromakalim-induced relaxation. On the other hand, 17-octadecynoic acid (5 microM) had no influence, and 1-aminobenzotriazole (1 mM) even potentiated EDHF- and cromakalim-induced relaxations. We conclude that the EDHF, released from the rat mesenteric artery by acetylcholine, is unlikely to be a cytochrome P-450-dependent monooxygenase metabolite of arachidonic acid and that proadifen and miconazole interfere with the action of cromakalim.

The present study examined the effects of 20-hydroxyeicosatetraenoic acid (20-HETE) and 17-octadecynoic acid (17-ODYA), an inhibitor of the metabolism of arachidonic acid by P-450, on K(+)-channel activity in vascular smooth muscle cells (VSM) isolated from renal arterioles of the rat. Two types of K+ channels were characterized using inside-out excised membrane patches. One channel exhibited a large conductance (250.3 +/- 5 pS), was activated by membrane depolarization and elevations in cytoplasmic Ca2+ concentration, and was blocked by low concentrations (< 1 mM) of tetraethylammonium (TEA). The other K+ channel exhibited an intermediate conductance (46.3 +/- pS), was activated by membrane depolarization but not by changes in intracellular Ca2+ concentration, and was blocked by 4-aminopyridine (5 mM). Addition of 20-HETE to the bath (1-100 nM), reduced the frequency of opening of the large-conductance Ca(2+)-activated K+ channel recorded using cell-attached patches on VSM. It had no effect on the intermediate-conductance K+ channel: 17-ODYA (1 microM) increased the activity of the large-conductance Ca(2+)-activated K+ channel, and this effect was reversed by 20-HETE (10 nM). 20-HETE (1-1000 nM) reduced the diameter of isolated perfused small renal arteries of the rat by approximately 15% TEA (1 mM) blocked the vasoconstrictor response to 20-HETE (100 nM).