Antivasoconstrictor and Antiaggregatory Activities of Picotamide Unrelated to Thromboxane A2 Antagonism

Abstract

SummaryPicotamide is a dual thromboxane (Tx) A2 receptor antagonist/Tx synthase inhibitor although some observations suggest an anti-vasoconstrictor effect independent of TxA2 inhibition/antagonism. The aim of our study was to assess whether picotamide antagonises vascular contractions induced by different vasoactive substances in vitro. Picotamide inhibited competitively the contraction of rabbit aortic rings induced by the TxA2 mimetic U46619 (pA2 = 3.59) but also the contractions induced by phenylephrine (pA2 = 3.93) and serotonin (5-HT) (pA2 = 5.81) although in a not competitive way. Picotamide did not inhibit potassium-induced contractions, thus excluding aspecific effects on vascular smooth muscle. Picotamide inhibited 5-HT-induced platelet aggregation in vitro with an IC50 (212 μM) 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 neither a Tx-receptor antagonist (BM13.177) nor a dual Tx-receptor antagonist/synthase inhibitor (ridogrel) affected 5-HT-induced platelet responses.Our studies demonstrate that picotamide exerts antivasoconstrictor and platelet inhibitory effects unrelated to TxA2 antagonism. This activity may contribute to the anti-thrombotic/anti-ischaemic effects of the drug in vivo.

The receptor antagonist picotamide inhibits adrenergic and thromboxane-induced contraction of hyperplastic human prostate smooth muscle

“…In our organ bath experiments, the effects of endogenous TXA2 produced by TXS may not be relevant, as a defined basal tension was adjusted before tissues were challenged with exogenous agonists or by EFS. Inhibition of phenylephrine-induced smooth muscle contraction has been previously reported from rabbit aortic rings, in addition to 5-HT-and TXA2-mediated vasocontraction (33). While picotamide, seratrodast, and L-665,240 competitively antagonize the TXA2-R, antagonism of ␣ 1 -adrenoceptors and serotonin receptors by picotamide is noncompetitive (33).…”

“…However, some observations suggest an antivasoconstrictor effect independent of TXA2 inhibition/antagonism. Thus picotamide was shown to inhibit vascular contractions induced by phenylephrine and serotonin (5-HT) in a noncompetitive way (33).…”

Inhibitors of platelet signal transduction as anti-aggregatory drugs

“…Antivasoconstrictory effects of picotamide could be observed in rabbit aortic rings. However, the competitive inhibition of vasoconstriction was not limited to thromboxane A 2 evoked, but also to phenylephrine and serotonin-induced contraction [191]. These results indicate an antithrombotic and anti-ischaemic activity of picotamide unrelated to thromboxanemediated pathways.…”

Picotamide inhibits a wide spectrum of agonist‐induced smooth muscle contractions in porcine renal interlobar and coronary arteries

“…As picotamide has been originally described as a thromboxane A 2 receptor antagonist, a corresponding inhibition pattern should be expected, including right shifts of concentration response curves and increases of EC 50 values for U46619, as described for rabbit aortic rings. 13 On the other hand, inhibition of U46619-induced contractions without patterns of competitive agonists has been reported from human trigone tissues, and partially from human prostate tissues. 11,12 requires extended experimental settings and is not possible on the basis of our data.…”

“…Thus, besides platelet aggregation, picotamide inhibited vascular, prostate, and trigone smooth muscle contractions in vitro. [11][12][13] In addition to an expectable, competitive inhibition of thromboxane A 2 receptor-induced contractions, inhibition of α 1 -adrenoceptorand serotonin-induced contractions with non-competitve features was observed in rabbit aortic rings. 13 In rat aortic rings, picotamide inhibited acetylcholine-induced contractions.…”