Endothelium-dependent vasodilation by melittin: are lipoxygenase products involved?
Vascular relaxation in response to acetylcholine and other vasodilator compounds has been shown to depend on intact endothelial cells. These dilator compounds obviously induce the formation of an unstable endothelium-derived relaxing factor or factors (EDRF) from the intima which relax the subjacent smooth muscle cells. The chemical identity of this factor (these factors) is still unclear. In the present study we demonstrate that endothelium-dependent relaxation of rabbit aorta was induced by melittin, a polypeptide toxin that activates phospholipase A2 to liberate polyunsaturated fatty acids (especially arachidonic acid) from membrane phospholipids. The relaxation induced by melittin had several properties similar to the acetylcholine relaxation. It was inhibited by potential inhibitors of phospholipase (mepacrine and p-bromophenacylbromide), by inhibitors of lipoxygenase (nordi-hydroguaiaretic acid, compound BW 755C, and 5,8,11,14-eicosatetraynoic acid) but not by the cyclooxygenase inhibitor indomethacin. An exogenous preparation of phospholipase C also induced endothelium-dependent relaxations. These findings support the hypothesis that oxidized metabolites of polyunsaturated fatty acids (e.g., arachidonic acid) may be involved directly (as mediators) or indirectly in the process of endothelium-dependent relaxation. On the other hand, exogenous arachidonic acid was a comparatively weak endothelium-dependent relaxant. However, this does not exclude an important role of endogenous arachidonic acid since the exogenous acid may not sufficiently reach its site of metabolism.
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D015117:5,8,11,14-Eicosatetraynoic Acid / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D001514:Bee Venoms / Q000494:pharmacology*; D002396:Catechols / Q000494:pharmacology; D004727:Endothelium / Q000378:metabolism / Q000502:physiology; D005260:Female; D008084:Lipoxygenase / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors; D008297:Male; D009637:Masoprocol; D008555:Melitten / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D009569:Nitric Oxide; D010740:Phospholipases / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000494:pharmacology; D011817:Rabbits; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000378:metabolism
D000975:Antioxidants; D001095:Arachidonic Acids; D001514:Bee Venoms; D002396:Catechols; D016859:Lipoxygenase Inhibitors; D011720:Pyrazoles; D014665:Vasodilator Agents; D015117:5,8,11,14-Eicosatetraynoic Acid; D008555:Melitten; D016718:Arachidonic Acid; D009569:Nitric Oxide; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D009637:Masoprocol; D008084:Lipoxygenase; D010740:Phospholipases; D000109:Acetylcholine