Stimulation of vascular prostacyclin by SKF 525-A (proadifen) and related compounds.

SKF 525-A (proadifen), a well-known inhibitor of drug metabolism and cytochrome P-450 activity, stimulated the release of prostacyclin (PGI2) from the rabbit aorta in vitro. The threshold concentration producing a detectable effect was 20 microM; the time course of SKF 525-A action exhibited particular features--progressive onset, long duration and slow reversibility--distinct from those of other stimuli (ADP, ionophore A23187 f.i.). The PGI2-stimulating activity of SKF 525-A was characterized by specific structural requirements: activity was abolished by the deletion of the terminal propyl group and increased by its elongation into an isobutyl group; chlorination of the phenyl groups increased the potency. SKF 525-A increased the production of PGI2 by cultured endothelial cells from bovine aorta and human umbilical vein, but had no effect on cultured smooth muscle from the bovine aortic media. Stimulation of PGI2 release could be explained by an increased availability of free arachidonic acid, which was probably independent from cytochrome P-450 inhibition. In human platelets, SKF 525-A inhibited prostaglandin and thromboxane production induced by A23187, thrombin and ADP. Simultaneous stimulation of endothelial PGI2 and inhibition of platelet TxA2 represents an original pharmacological profile: SKF 525-A might thus constitute the prototype of a new class of antiplatelet drugs.