Abstract

Oxidatively modified low-density lipoprotein(LDL) may be involved in the vasomotor disturbances associated with hypercholesterolemia and atherosclerosis, but effects of this lipoprotein on agonist-induced coronary vasoconstriction have not been reported. This study determined the effects of oxidized LDL on contraction of isolated porcine coronary arteries to several contractile agonists and investigated the mechanism of these effects. Oxidized LDL (10-100 microgram/ml) enhanced 5-hydroxytryptamine (5-HT)-induced contraction in a concentration-dependent manner, whereas native LDL (100 microgram/ml) had no effect. Enhancement of 5-HT-induced contraction was dependent on the presence of endothelium and blocked by L-NG-monomethyl-arginine (100 microM). Oxidized LDL (100 microgram/ml) similarly inhibited endothelium- and nitric oxide-dependent relaxation induced by 5-HT, but had no effect of relaxation induced by sodium nitroprusside. Furthermore, contraction to U46619 and acetylcholine, agonists that did not mediate endothelium-dependent relaxation, was unaffected by oxidized LDL (100 microgram/ml). Lysophosphatidylcholine (10-30 mumol/liter) also enhanced 5-HT-induced contraction and inhibited 5-HT-induced, endothelium-dependent relaxation. Endothelium-dependent relaxation to bradykinin was unaffected by lysophosphatidylcholine (20 muM). Thus, oxidized LDL enhanced 5_HT-induced coronary vasoconstriction in an endothelium dependent manner, actions that were mimicked by relevant concentrations of lysophosphatidylcholine. These in vitro effects of oxidized LDL mimicked effects of hypercholesterolemia and atherosclerosis on 5-HT vasoactivity in human coronary arteries in vivo, suggesting that oxidized LDL may play an important role in the development of vasomotor disturbances in these pathologies.