Inhibition Of Prostacyclin Release From Cultured Endothelial-Cells By Nitrovasodilator Drugs

Pretreatment (18 h) of the bovine aortic endothelial cell line AG4762 to 500 mu M sodium nitroprusside (SNP), glyceryl trinitrate (GTN) or 3-morpholino-sydnonimine (SIN-1) significantly inhibited 100 nM bradykinin-stimulated prostacyclin (PGI(2)) release. SIN-1 produced the greatest reduction (67 +/- 6%), followed by SNP (47 +/- 12%) and GTN (45 +/- 9%). Only SIN-1 and GTN inhibited basal PGI(2) release where again the effect of SIN-1 (66 +/- 6%) was greater than that of GTN (31 +/- 15%). There was no effect of SNP on basal PGI(2) release.We have demonstrated this inhibition of bradykinin-stimulated PGI(2) release is not the result of cell death. In addition, 8-bromo-cyclic GMP, whilst having no effect on basal PGI(2) release, demonstrated a small but significant inhibition (15 +/- 6%) of the enhanced response to 100 nM bradykinin.These studies may reflect a mechanism by which the release of vasodilators from endothelial cells is altered during therapy with nitrovasodilators and thus may contribute to the development of tolerance to these drugs.