ANTIVASOCONSTRICTOR AND ANTIAGGREGATORY ACTIVITIES OF PICOTAMIDE UNRELATED TO THROMBOXANE A(2) ANTAGONISM

Picotamide is a dual thromboxane (Tx) A(2) receptor antagonist/Tx synt hase inhibitor although some observations suggest an anti-vasoconstric tor effect independent of TxA(2) inhibition/antagonism. The aim of our study was to assess whether picotamide antagonises vascular contracti ons induced by different vasoactive substances in vitro. Picotamide in hibited competitively the contraction of rabbit aortic rings induced b y the TxA(2) mimetic U46619 (pA(2) = 3.59) but also the contractions i nduced by phenylephrine (pA(2) = 3.93) and serotonin (5-HT) (pA(2) = 5 .81) although in a not competitive way. Picotamide did not inhibit pot assium-induced contractions, thus excluding aspecific effects on vascu lar smooth muscle. Picotamide inhibited 5-HT-induced platelet aggregat ion in vitro with an IC50 (212 mu M) similar to that found when other aggregating stimuli are used, but it did not affect shape change (IC50 > 1 mM) suggesting that the effects of picotamide can not be ascribed to 5-HT2-receptor antagonism; in the same experimental conditions nei ther a Tx-receptor antagonist (BM13.177) nor a dual Tx-receptor antago nist/synthase inhibitor (ridogrel) affected 5-HT-induced platelet resp onses. Our studies demonstrate that picotamide exerts antivasoconstric tor and platelet inhibitory effects unrelated to TxA, antagonism. This activity may contribute to the anti-thrombotic/anti-ischaemic effects of the drug in vivo.