Effects of Nonsteroidal Phospholipase Inhibitors and Glucocorticoids on Endothelium-Dependent Relaxations of Rabbit Aorta Induced by Different Agents

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Abstract
The present study investigates the effect of described nonsteroidal phospholipase inhibitors [mepacrine, papaverine, trifluoperazine (TFP), p-bromophenacyl bromide (pBPB), compound CB 874] and of glucocorticoids on endothelium-dependent and -independent relaxations of rabbit aorta. Endothelium-dependent relaxations were elicited by acetylcholine, Ca2+ ionophore A23187, melittin, and thimerosal. These four agents also stimulated vascular prostacyclin formation. Prostacyclin does not relax rabbit aorta; it was measured as an indicator of phospholipid hydrolysis. All putative nonsteroidal phospholipase inhibitors blocked acetylcholine-induced relaxations. Since papaverine did not inhibit prostacyclin production, it cannot be considered a phospholipase inhibitor in this tissue. Relaxations in response to A23187 were blocked only by pBPB and CB 874, which can interact with phospholipases directly. Melittin-induced relaxations were suppressed by mepacrine, TFP, pBPB, and CB 874. Relaxations elicited by thimerosal were not affected by mepacrine, but were abolished by the other three inhibitors. All inhibitors were ineffective against endothelium-independent relaxations induced by glyceryl trinitrate. Effective blockade of endothelial relaxations correlated with inhibition of prostacyclin formation. In the presence of glucocorticoids, no inhibition of endothelium-mediated relaxations and no inhibition of prostacyclin formation occurred, indicating unimpaired phospholipase activity. These findings suggest that cleavage of phospholipids may be important in the triggering of the production of endothelium-derived relaxing factor.

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