Abstract
The salidiuretic furosemide increases renal blood flow (RBF) and inhibits platelet aggregation. The increase in RBF is inhibited by indomethacin and thus may be attributable to the modification of renal prostaglandin (PG) metabolism by furosemide. The suppression of platelet function is also ascribed to the influence of furosemide on platelet PG metabolism. Piretanide is a new salidiuretic similar to furosemide in its pharmacological profile. In the present study, we examined the effect of piretanide on platelet function with special referenci to effects on platelet PG metabolism.
At the concentration of 5 x10-4M, piretanide inhibited platelet aggregation and ATP secretion induced by ADP, collagen, epinephrine and PGH2. The primary aggregation induced by ADP, however, was sustained in the presence of piretanide. The inhibitory effect of piretanide on ATP secretion was more prominent than that on platelet aggregation. For arachidonic acid-induced aggregation, complete inhibition was observed after the addition of piretanide if a low concentration (0.6mM) of arachidonic acid was employed. However, complete aggregation was transiently noted followed by disaggregation if a high concentration (3.6mM) of arachidonic acid was employed. 14C-serotonin release from platelets after the addition of ADP or collagen was almost completely abolished by 5x10-4M piretanide. Piretanide at the concentration of 5x10-4M also suppressed partially malondialdehyde formation induced by A23187 or thrombin. When platelets were incubated with 14 C-arachidonic acid in the presence of piretanide, the production of thromboxane B2 measured by thin-layer chromatography was decreased whereas the production of PGF2α and PGE2 was increased. Analysis of thromboxane B2 and PGD2 by gas chromatographymass spectrometry also demonstrated the decreased production of thromboxane B2 and the increased production of PGD2. The slight increase in cAMP levels of platelets was observed after the addition of arachidonic acid. Piretanide enhanced this increase remarkably, but aspirin cancelled the enhancing effect of piretanide. Piretanide did not influence either adenylate cyclase activity or cAMP phosphodiesterase activity of platelets.
These results indicate that piretanide causes a partial inhibition of platelet thromboxane synthetase followed by reorientation of cyclic endoperoxide metabolism, that is, the decrease in thromboxane A2 production and the increase in PGD2 production which stimulates platelet adenylate cyclase. The inhibitory effect of piretanide on platelet function would result not only from reduced formation of thromboxane A2 but also from increased production of PGD2.
