Download PDF
Thromb Haemost 1997; 78(05): 1385-1391
DOI: 10.1055/s-0038-1665416
Review Article
Schattauer GmbH Stuttgart

Antivasoconstrictor and Antiaggregatory Activities of Picotamide Unrelated to Thromboxane A2 Antagonism

Roberta Vezza
The Institute of Internal and Vascular Medicine, University of Perugia, Perugia, Italy;
,
Domenico Spina
1   The Sackler Institute of Pulmonary Pharmacology, Department of Respiratory Medicine, King's College School of Medicine and Dentistry, London, UK;
,
Ronald J Tallarida
2   Department of Pharmacology, Temple University, Philadelphia, USA
,
Malevika Nathan
The Institute of Internal and Vascular Medicine, University of Perugia, Perugia, Italy;
,
Clive P Page
1   The Sackler Institute of Pulmonary Pharmacology, Department of Respiratory Medicine, King's College School of Medicine and Dentistry, London, UK;
,
Paolo Gresele
The Institute of Internal and Vascular Medicine, University of Perugia, Perugia, Italy;
› Author Affiliations
Further Information

Publication History

Received 16 1996

Accepted after resubmission 09 July 1997

Publication Date:
12 July 2018 (online)

  PDF Download  Permissions and Reprints

Summary

Picotamide 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.

 

  • References

  • 1 Moncada S, Vane JR. Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2, and prostaglandin I2 . Pharmacol Rev 1979; 30: 293-331
    PubMedGoogle Scholar
  • 2 FitzGerald GA. Mechanisms of platelet activation: thromboxane A2 as an amplifying signal for other agonists. Am J Cardiol 1991; 68: 11-5B
    CrossrefPubMedGoogle Scholar
  • 3 Ellis EF, Oelz O, Roberts LJ, Payne NA, Sweetman BJ, Nies AS, Oates JA. Coronary arterial smooth muscle contraction by a substance released from platelets: evidence that it is thromboxane A2 . Science 1976; 193: 461-470
    PubMedGoogle Scholar
  • 4 Halushka PV, Allan CJ, Davis-Bruno KL. Thromboxane A2 receptors. J Lipid Mediators Cell Signalling 1995; 12: 361-378
    CrossrefPubMedGoogle Scholar
  • 5 Dorn II GW. Distinct platelet thromboxane A2/prostaglandin H2 receptor subtypes. A radioligand binding study of human platelets. J Clin Invest 1989; 84: 1883-1891
    CrossrefPubMedGoogle Scholar
  • 6 Dorn II GW, De Jesus A. Human platelet aggregation and shape change are coupled to separate thromboxane A2/prostaglandin H2 receptors. Am J Physiol 1991; 260: H327-H334
    CrossrefPubMedGoogle Scholar
  • 7 Lukasiewicz H, Peng ML, Morinelli TA, Eckardt A, Kirby EP, Niewiarowski S. Separation of different receptor-mediated effects of prostaglandin H2 analogue (U46619) on human platelets by means of human granulocytic elastase and chymotrypsin. Biochem Pharmacol 1989; 38: 3213-3217
    CrossrefPubMedGoogle Scholar
  • 8 Takahara K, Murray R, FitzGerald GA, Fitzgerald DJ. The response of thromboxane A2 analogues in human platelets. Discrimination of two binding sites linked to distinct effector systems. J Biol Chem 1990; 265: 6836-6844
    PubMedGoogle Scholar
  • 9 Dorn II GW. Tissue- and species-specific differences in ligand binding to thromboxane A2 receptors. Am J Physiol 1991; 261: R145-R153
    PubMedGoogle Scholar
  • 10 Furci L, Fitzgerald DJ, FitzGerald GA. Heterogeneity of prostaglandin H2/thromboxane A2 receptors: distinct subtypes mediate vascular smooth muscle contraction and platelet aggregation. J Pharmacol Exp Ther 1991; 258: 74-81
    PubMedGoogle Scholar
  • 11 Dorn II GW, Becker MW. Thromboxane A2 stimulated signal transduction in vascular smooth muscle. J Pharmacol Exp Ther 1993; 265: 447-456
    PubMedGoogle Scholar
  • 12 Gresele P, Deckmyn H, Nenci GG, Vermylen J. Thromboxane synthase inhibitors, thromboxane receptor antagonists and dual blockers in thrombotic disorders. Trends Pharmacol Sci 1991; 12: 158-163
    CrossrefPubMedGoogle Scholar
  • 13 Watts JS, Wharhon KA, White BP, Lumley P. Thromboxane (Tx)A2 receptor blockade and TxA2 synthase inhibition alone and in combination: comparison of anti-aggregatory efficacy in human platelets. Br J Pharmacol 1991; 102: 497-505
    CrossrefPubMedGoogle Scholar
  • 14 Salvati P, Dho L, Ukmar G, Vorga L, Rimoldi O, Patrono C. A comparative evaluation of thromboxane receptor blockade, thromboxane synthase inhibition and both in animal models of arterial thrombosis. J Pharmacol Exp Ther 1994; 269: 238-245
    PubMedGoogle Scholar
  • 15 Masuda A, Mais DE, Oatis JE, Halushka PV. Platelet and vascular thromboxane A2/prostaglandin H2 receptors. Evidence for difference subclasses in the rat. Biochem Pharmacol 1991; 42: 537-544
    CrossrefPubMedGoogle Scholar
  • 16 Gresele P, Deckmyn H, Amout J, Nenci GG, Vermylen J. Characterization of N N’, bis (3-picolyl)-4 -methoxy -isophtalamide (picotamide) as a dual thromboxane synthase inhibitor/thromboxane receptor antagonist in human platelets. Thomb Haemost 1989; 61: 479-484
    PubMedGoogle Scholar
  • 17 Modesti PA, Cecioni I, Colella A, Costoli A, Paniccia R, Neri Semeri GG. Binding kinetics and antiplatelet activities of picotamide, a thromboxane A2 receptor antagonist. Br J Pharmacol 1994; 112: 81-86
    CrossrefPubMedGoogle Scholar
  • 18 Gresele P, Corona C, Alberti P, Nenci GG. Picotamide protects mice from death in a pulmonary embolism model by a mechanism independent from thromboxane suppression. Thromb Haemost 1990; 64: 80-86
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Janssens WJ, Deckmyn H, Gresele P, Vermylen J. BM13.177 selectively inhibits endoperoxide analogue induced vascular contractions. Arch Int Pharmacodyn Ther 1985; 276: 28-34
    PubMedGoogle Scholar
  • 20 Spina D, Harrison S, Page CP. Regulation by phosphodiesterase isoenzymes of non-adrenergic non-cholinergic contraction in guinea pig isolated main bronchus. Br J Pharmacol 1995; 116: 2334-2340
    CrossrefPubMedGoogle Scholar
  • 21 Vezza R, Roberti R, Nenci GG, Gresele P. Prostaglandin E2 potentiates platelet aggregation by priming protein kinase C. Blood 1993; 73: 2006-2013
    PubMedGoogle Scholar
  • 22 De Clerk F, David JL, Janssen PAJ. Inhibition of 5-hydroxytryptamine induced and amplified human platelet aggregation by ketanserin (R41468), a selective 5-HT2-receptor antagonist. Agents Action 1982; 12: 388-397
    CrossrefPubMedGoogle Scholar
  • 23 Arunlakshana O, Schild HO. Some quantitative uses of drug antagonists. Br J Pharmacol 1959; 14: 48-58
    PubMedGoogle Scholar
  • 24 Tallarida RJ, Murray RB. Manual of pharmacologic calculation with computer programs. 2nd. ed Springer-Verlag; New York: 1987
    Google Scholar
  • 25 Chou TC. Derivation and properties of Michaelis-Menten type and Hill type equations for reference ligands. J Theor Biol 1976; 39: 253-276
    PubMedGoogle Scholar
  • 26 Armstrong RA, Jones RL, Peesapati V, Will SG, Wilson NH. Competitive antagonism at thromboxane receptors in human platelets. Br J Pharmacol 1985; 84: 595-607
    CrossrefPubMedGoogle Scholar
  • 27 Keith RA, Solama AI. Individual variation of prostanoid agonist responses in rabbit aorta: evidence for the independent regulation of prostanoid receptor subtypes. Br J Pharmacol 1987; 92: 133-148
    CrossrefPubMedGoogle Scholar
  • 28 Fernandez del PozoB, Perez-Vizcaino F, Villamore E, Zaragoza F, Tamargo J. Stereoselective effects of the enantiomers, quinidine and quinine, on depolarization- and agonist-mediated responses in rat isolated aorta. BrJ Pharmacol 1996; 117: 105-110
    CrossrefPubMedGoogle Scholar
  • 29 Jones RL, Wilson NH, Lawrence RA. EP171: a high affinity thromboxane A2-mimetic, the actions of which are slowly reversed by receptor blockade. Br J Pharmacol 1989; 96: 875-887
    CrossrefPubMedGoogle Scholar
  • 30 Jones RL, Peesapati V, Wilson NH. Antagonism of the thromboxane sensitive contractile system of the rabbit aorta, dog saphenous vein and guinea pig trachea. Br J Pharmacol 1982; 76: 423-438
    CrossrefPubMedGoogle Scholar
  • 31 Patscheke H, Stegmeier K, Muller-Beckman B, Sponer G, Staiger C, Neu-gebauer G. Inhibitory effect of selective thromboxane receptor antagonist BM13.177 on platelet aggregation, vasoconstriction and sudden death. Biomed Biochim Acta 1984; 43: 5312-5318
    PubMedGoogle Scholar
  • 32 Kosakai K, Wakabayashi S, Sato T, Mochizuki S, Tomiyama A, Zhou Q, Satake N, Shibata S. Pharmacologic properties of KTZ-962 (6-isopropyl-3-[4-(p-chlorobenzene sulphonyl phenylamino)-butyl]-azulene-1-sulfonic acid sodium salt: a new TxA2/prostaglandin endoperoxide receptor antagonist. J Cardiovasc Pharmacol 1993; 21: 441-447
    CrossrefPubMedGoogle Scholar
  • 33 Modesti PA, Colella A, Abbate R, Gensini GF, Neri Semeri GG. Competitive inhibition of platelet thromboxane A2 receptor binding by picotamide. Eur J Pharmacol 1989; 169: 85-93
    CrossrefPubMedGoogle Scholar
  • 34 Janssens WJ, Cools FJS, Hoskens LAM, Nueten JM. Effect of ridogrel on vascular contractions caused by vasoactive substances released during platelet activation. Thromb Haemost 1990; 64: 91-96
    Article in Thieme ConnectPubMedGoogle Scholar
  • 35 Robertson RM, Robertson D. Drugs used for the treatment of myocardial ischemia. In: The Pharmacological Basis of Therapeutics. Hardman LE, Limbird LE, Molinoff PB, Ruddon RW, Gilman AG. eds McGraw Hill; New York, NY: 1996. pp 759-779
    Google Scholar
  • 36 Fossati T, Parisi S, Abbiati G, Castiglioni C. Determination of picotamide in human plasma and urine by high performance liquid chromatography. J Chromatogr 1992; 577: 382-386
    CrossrefPubMedGoogle Scholar
  • 37 Modesti PA, Abbate R, Gensini GF, Colella A, Neri-Semeri GG. Kinetic analysis of the TxA2 receptor antagonist. Evidence for the existence of an uptake system. Eicosanoids 1990; 03: 139-143
    PubMedGoogle Scholar
  • 38 Feniunk W, Humprey PPA, Perren MJ, Watts AD. A comparison of 5-hydroxytryptamine receptors mediating contraction in rabbit aorta and dog saphenous vein: evidence for different receptor types obtained by use of selective agonists and antagonists. Br J Pharmacol 1985; 86: 697-704
    CrossrefPubMedGoogle Scholar
  • 39 Gresele P, Vezza R, Nenci GG. Inhibition of cytoplasmic calcium movements in stimulated platelets by picotamide. Thromb Haemost 1989; 62: A552
    PubMedGoogle Scholar
  • 40 Pulcinelli FM, Pignatelli P, Riondino S, Parisi S, Castiglioni C, Gazzaniga P. Effect of picotamide on the calcium mobilization and phospholipase C activation in human platelets. Thromb Res 1994; 74: 453-461
    CrossrefPubMedGoogle Scholar
  • 41 Collins P, Henderson AH, Lang D, Lewis MJ. Endothelium-derived relaxing factor and nitroprusside compared in noradrenaline- and K+-contracted rabbit and rat aortae. J Physiol 1988; 400: 395-404
    CrossrefPubMedGoogle Scholar
  • 42 Christie MI, Lewis MJ. Vascular smooth muscle sensitivity to endothelium-derived relaxing factor is different in different arteries. Br J Pharmacol 1988; 95: 630-636
    CrossrefPubMedGoogle Scholar
  • 43 Feldhoff CM, Gresele P, Pieters G, Vermylen J. Acetylsalicylic acid, BM13.177 and picotamide improve the survival of endotoxin-infused rabbit. Thromb Res 1988; 52: 487-492
    CrossrefPubMedGoogle Scholar
  • 44 Balsano F, Violi F. Effect of picotamide on the clinical progression of peripheral vascular disease. A double blind placebo-controlled study. The ADEP group Circulation 1993; 87: 1563-1569
    CrossrefPubMedGoogle Scholar
  • 45 De Clerck F, Janssen PAJ. 5-hydroxytryptamine and thromboxane A2 in ischaemic heart disease. Blood Coag Fibrinol 1990; 01: 201-220
    PubMedGoogle Scholar
  • 46 Neri Semeri GG, Gensini GF, Poggesi L, Modesti PA, Rostagno C, Boddi M, Gori AM, Martini F, Ieri A, Margheri M, Abbate R. The role of extraplatelet thromboxane A2 in unstable angina investigated with a dual thromboxane A2 inhibitor: importance of activated monocytes. Coron Artery Dis 1994; 05: 137-145
    CrossrefPubMedGoogle Scholar