Effects of inhibitors of arachidonic acid metabolism and calcium entry on responses to acetylcholine, potassium and norepinephrine in the isolated canine saphenous vein

Abstract

The present study was designed to determine whether interference with the metabolism of arachidonic acid or the entry of extracellular calcium affects the responses of the canine saphenous vein to acetylcholine, potassium or norepinephrine. Rings of canine saphenous vein, with or without endothelium, were suspended in organ chambers filled with physiological salt solution and set at their optimal length for isometric tension recording. Removal of the endothelium, confirmed by the absence of the characteristic relaxation induced by thrombin in intact rings, did not affect concentration-response curves to acetylcholine or norepinephrine. The cyclooxygenase inhibitor, indomethacin, augmented the response to acetylcholine. This effect was comparable in rings with and without endothelium and in rings pretreated with phentolamine. Indomethacin did not alter the response to norepinephrine but augmented that to potassium. Similar results were obtained with the cyclooxygenase inhibitors, acetylsalicylic acid and meclofenamate. The antioxidant and lipoxygenase inhibitor nordihydroguaiaretic acid and the cyclooxygenase/lipoxygenase inhibitor phenidone blocked the ability of indomethacin to augment acetylcholine- and potassium-induced contractions. Arachidonic acid-induced contractions were not blocked by indomethacin but were inhibited by nordihydroguaiaretic acid, phenidone and the calcium entry blockers diltiazem and nimodipine. Diltiazem and nimodipine inhibited responses to potassium and acetylcholine without affecting those to norepinephrine. The augmentation by indomethacin of potassium- and acetylcholine-evoked contractions with inhibited by diltiazem and nimodipine. In rings of femoral artery denuded of endothelium, indomethacin had no effect on the responses to acetylcholine, norepinephrine or potassium. These results suggest that, in the canine saphenous vein but not in the femoral artery, activation of the lipoxygenase pathway for the metabolism of arachidonic acid augments preferentially contractions which depend upon the entry of extracellular calcium.