The inhibition of release of endothelium‐derived relaxant factor by manoalide, a potent inhibitor of phospholipase A₂

Abstract

1 The inhibitory action of manoalide on vascular relaxation was characterized. Manoalide was a potent inhibitor ofendothelium-dependent relaxations in the isolated aorta of the rabbit. Responses to acetylcholine (ACh), A23 187 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 endotheliumderived 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.

Role of arachidonic acid lipoxygenase metabolites in the regulation of vascular tone

“…All of these studies used pharmacological inhibitors to determine the contribution of AA metabolites. A large number of structurally different LO inhibitors, including nordihydroguaiaretic acid (NDGA), phenidone, BW755c, caffeic acid, diethylcarbamazine, AA861, TKM777, cinnanyl-dihydroxy-cyanocinnamate, ebselen, and others (21,33,45,47,50,94,116,146), as well as inhibitors of phospholipases A 2 and C (21,33,46,85,146,153), inhibited relaxations to ACh. Interestingly, inhibitors of CPY also inhibited the endothelium-dependent relaxations to ACh (21,45,116,147).…”

Endothelium-dependent relaxation of human basilar arteries.

“…7 Moreover, the peptidoleukotrienes LTC 4 and LTD 4 possess the capacity to relax some arterial rings in an endothelium-dependent manner. 8 ' 9 It has also been demonstrated that the decrease in tone in response to ACh and arachidonic acid is attenuated in the presence of SKF525A, an inhibitor of cytochrome P450-dependent monooxygenase.…”