The inhibition of release of endothelium-derived relaxant factor by manoalide, a potent inhibitor of phospholipase A2.
1 The inhibitory action of manoalide on vascular relaxation was characterized. Manoalide was a potent inhibitor of endothelium-dependent relaxations in the isolated aorta of the rabbit. Responses to acetylcholine (ACh), A23187 and substance P were reduced by manoalide in a dose-dependent manner whilst those to nitroglycerin were unaffected. 2 Repeated washing of manoalide-treated tissues did not restore the relaxant response to ACh, indicating an irreversible action of manoalide. Scanning electron microscopic studies revealed that the endothelium remained intact on manoalide-treated tissues. 3 Rabbit aortae from which the endothelium had been removed relaxed in response to perfusion with ACh when delivered via an upstream endothelium-bearing tissue, indicating release of an endothelium-derived relaxant factor (EDRF). Incubation of the tissue without endothelium with manoalide (100 nM; 30 min) or inclusion of manoalide in the superfusate at a point just distal to the endothelium bearing tissue did not reduce the relaxant potency of EDRF. 4 Contractile responses of the guinea-pig isolated ileum to ACh were not affected by manoalide and, furthermore, binding of [3H]-quinuclidinyl benzilate to striatal membranes was not reduced by manoalide except at very high concentrations. 5 Manoalide therefore appears to inhibit vascular relaxation with a selectivity directed towards that mediated by EDRF. A direct antagonism of neither cholinoceptors nor EDRF receptors occurs and it is suggested that manoalide acts at a site within the endothelium to inhibit the synthesis and/or release of EDRF. Based upon these and previous data the possibility that EDRF is lipid-like or controlled by an arachidonic acid metabolite must continue to be considered.
Long
C J
CJ
Department of Pharmacology, Smith Kline and French Laboratories, Philadelphia, PA 19479.
Sarau
H M
HM
Berkowitz
B A
BA
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001688:Biological Products / Q000378:metabolism*; D005260:Female; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide; D010740:Phospholipases / Q000037:antagonists & inhibitors*; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D011813:Quinuclidinyl Benzilate; D051381:Rats; D011956:Receptors, Cell Surface / Q000187:drug effects; D013729:Terpenes / Q000494:pharmacology*
D001688:Biological Products; D011956:Receptors, Cell Surface; D013729:Terpenes; D009569:Nitric Oxide; D011813:Quinuclidinyl Benzilate; C045673:manoalide; D010740:Phospholipases; D010741:Phospholipases A; D054467:Phospholipases A2