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Thromb Haemost 1994; 72(02): 309-312
DOI: 10.1055/s-0038-1648858
Original Article
Schattauer GmbH Stuttgart

The Calcium Modulator Nifedipine Exerts Its Antiaggregatory Property via a Nitric Oxide Mediated Process

R Berkels
The Institut für Pharmakologie, Universität zu Köln Germany
,
W Klaus
The Institut für Pharmakologie, Universität zu Köln Germany
,
M Boiler
The Institut für Pharmakologie, Universität zu Köln Germany
,
R Rösen
The Institut für Pharmakologie, Universität zu Köln Germany
› Author Affiliations
Further Information

Publication History

Received 02 19 1993

Accepted after resubmission 25 April 1994

Publication Date:
24 July 2018 (online)

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Summary

The in vitro effect of nifedipine, a calcium channel blocker of the dihydropyridine (DHP) type, on platelet aggregation was reinvestigated considering especially the capability of platelets to form endogenous nitric oxide (NO). We studied the dose-dependent antiaggregatory property of nifedipine in porcine platelet rich plasma. Aggregation was stimulated by collagen (7.5 ¼g/ml). Nifedipine inhibited collagen-induced platelet aggregation with an IC50 of 380 nmol/1. The antiaggregatory effect of nifedipine could be significantly diminished by N-nitro-L-arginine (NNA) in a concentration dependent manner, whereas oxy haemoglobin (4 ¼M), a NO scavenger, totally abolished the effect of nifedipine. L-Arginine, the precursor of NO, dose-dependently inhibited the collagen-induced platelet aggregation but did not potentiate the effects of nifedipine. Therefore, we propose that in platelet rich plasma the nifedipine induced inhibition of platelet aggregation is mediated by NO, a potent endogenous inhibitor of aggregation. We could confirm this hypothesis by measuring NO directly with a specific electrode.

 

  • References

  • 1 Kroll M, Schafer A. Biochemical mechanisms of platelet activation. Blood 1989; 74: 1185-1195
    PubMedGoogle Scholar
  • 2 Massini P, Luscher E. On the significance of the influx of calcium ions into stimulated human blood platelets. Biochim Biophys Acta 1976; 436 (03) 652-663
    CrossrefPubMedGoogle Scholar
  • 3 Johnson H. Effects by nifedipine (Adalat®) on platelet function in vitro and in vivo. Thromb Res 1981; 21: 523-528
    CrossrefPubMedGoogle Scholar
  • 4 Rostagno C, Abbate R, Gensini G, Coppo M, Prisco D, Boddi M. In vitro effects of two novel calcium antagonists (Nitrendipine and Nisoldipine) on intraplatelet calcium redistribution, platelet aggregation and thromboxane A2 formation Comparison with Diltiazem, Nifedipine and Verapamil. Thromb Res 1991; 63: 457-462
    CrossrefPubMedGoogle Scholar
  • 5 Takahara K, Kuroiwa A, Matsushima T. Effects of nifedipine on platelet function. Am Heart J 1985; 109 (01) 4-8
    CrossrefPubMedGoogle Scholar
  • 6 Catterall W, Striessnig J. Receptor sites for Ca2+ channel antagonists. TIPS 1992; 13: 256-262
    PubMedGoogle Scholar
  • 7 Ware J, Johnson P, Smith M, Salzman E. Inhibition of human platelet aggregation and cytoplasmatic calcium response by calcium agonists: studies with aequorin and quin 2. Circ Res 1986; 59: 39-42
    CrossrefPubMedGoogle Scholar
  • 8 Doyle M, Riiegg T. Lack of evidence for voltage dependent calcium channels on platelets. Biochem Biophys Res Com 1985; 127: 161-167
    CrossrefPubMedGoogle Scholar
  • 9 Pannochia A, Praloran N, Arduino C, Della DoraN, Bazzan M, Shinco P, Buraglio M, Piled A, Tamponi G. Absence of (-) [3H] desmethoxyverapamil binding sites on human platelets and lack of evidence for voltage-dependent calcium channels. ti J Pharmacol 1987; 142: 83-91
    PubMedGoogle Scholar
  • 10 Motulsky H, Snavely M, Hughes R, Insel P. Interaction of verapamil and other calcium channel blockers with α1, andα2 adrenergic receptors. Circ Res 1983; 52: 226-231
    CrossrefPubMedGoogle Scholar
  • 11 Normann J, Ansell J, Phillips M. Dihydropyridine Ca2+ entry blockers selectively inhibit peak I cAMP phosphodiesterase. Eur J Pharmacol 1983; 93: 107-112
    CrossrefPubMedGoogle Scholar
  • 12 Geiger J, Nolte C, Butt E, Sage S, Walter U. Role of cGMP and cGMP-dependent protein kinase in nitrovasodilator inhibition of agonist evoked calcium elevation in human platelets. Proc Natl Acad Sci USA 1992; 89: 1031-1035
    CrossrefPubMedGoogle Scholar
  • 13 Latta G, Verheggen R, Rücker W, SchrÖr K. Inhibition of human platelet aggregation and thromboxane formation by calcium antagonists. Naunyn-Schmiedeberg,s Arch Pharmacol 1983; 324: R-49
    PubMedGoogle Scholar
  • 14 Atlas D, Adler M. Alpha adrenergic antagonists as possible calcium channel inhibitors. Proc Natl Acad Sci USA 1981; 78: 1237-1241
    CrossrefPubMedGoogle Scholar
  • 15 Al-Mondhiry H, Ballard J, McGarvey V. Fibrinogen interaction with human platelets: Effect of other coagulation factors, prostaglandins and platelet inhibitors. Thromb Res 1983; 31: 415-426
    CrossrefPubMedGoogle Scholar
  • 16 Gunther J, Dhein S, Rosen R, Klaus W, Fricke U. Nitric oxide (EDRF) enhances the vasorelaxing effect of nitrendipine in various isolated arteries. Basic Res Cardiol 1992; 87: 452-460
    PubMedGoogle Scholar
  • 17 Vilaine JP, Biondi ML, Villeneuve N, Feletou M, Peglion JL, Vanhoutte PM. The calcium channel antagonist S 11568 causes endothelium dependent relaxation in canine arteries. Eur J Pharmacol 1991; 197 (01) 41-48
    CrossrefPubMedGoogle Scholar
  • 18 Adams D, Barakeh J, Laskey R, van BreemenC. Ion channels and regulation of intracellular calcium in vascular endothelial cells. FASEB J 1989; 3: 2389-2400
    CrossrefPubMedGoogle Scholar
  • 19 Ignarro LJ. Biosynthesis and metabolism of endothelium-derived nitric oxide. Annu Rev Pharmacol Toxicol 1990; 30: 535-560
    CrossrefPubMedGoogle Scholar
  • 20 Radomski M, Palmer R, Moncada S. An L-arginine/nitric oxide pathway in human platelets regulates aggregation. Procl Natl Acad Sci 1990; 87: 5193-5197
    PubMedGoogle Scholar
  • 21 Malinski T, Radomski M, Taha Z, Moncada S. Direct electrochemical measurement of nitric oxide released from human platelets. Biochem Biophys Res Com 1993; 194: 960-965
    CrossrefPubMedGoogle Scholar
  • 22 Pronai L, Ichimori K, Nozaki H, Nakazawa H, Okino H, Carmichael A. Investigation of the existence and biological role of L-arginine/nitric oxide pathway in human platelets by spin trapping/EPR studies Eur J Biochem 1991; 202: 923-930
    CrossrefPubMed
  • 23 Mellion B, Ignarro L, Meyers B, Ohlstein E, Ballot B, Hyman A, Kadowitz P. Inhibition of human platelet aggregation by S-nitrosothiols. Heme-dependent activation of soluble guanylate cyclase and stimulation of cyclic GMP accumulation. Mol Pharmacol 1983; 23: 653-664
    PubMedGoogle Scholar
  • 24 RÖsen R, Bernards W, Jumpertz K, Kreie K, Wiesmüller G, Klaus W. Interaktion zwischen Thrombozyten und Koronarsystem in Gegenwart von SIN 1 bzw. Nitroglycerin nach Endothelschädigung. Z Kardiol 1991; 80: 23-27
    PubMedGoogle Scholar
  • 25 Bom R. Quantitative investigations into the aggregation of blood platelets. J Physiol London 1962; 167: 67P-68P
    PubMedGoogle Scholar
  • 26 Tsukahara H, Gordienko DV, Goligorsky MS. Continuous monitoring of nitric oxide release from human umbilical vein endothelial cells. Biochem Biophys Res Com 1993; 193 (02) 722-729
    CrossrefPubMedGoogle Scholar
  • 27 Costa J, Murphy D. Unique specialisations for the subcellular compartimentation of amines in pig and human platelets. In: Cellular response mechanisms and their biological significance Rotman A, Meyer FA, Gitler C, Silberg A. (eds) John Wiley & Sons Ltd; 1980: 233-249
  • 28 Smith R, Palmer R, Bucknall C, Moncada S. Role of nitric oxide synthesis in the regulation of coronary vascular tone in the isolated perfused rabbit heart. Cardiovascular Res 1992; 26: 508-512
    CrossrefPubMedGoogle Scholar
  • 29 Glass R, Goode A, Houghton B, Rowell L. Plasma arginine in cancer of the gastrointestinal tract: effect of surgical treatment. Gut 1986; 27: 844-848
    CrossrefPubMedGoogle Scholar
  • 30 Kirchmeier CM, Altorjay I, Bellinger O, Breddin HK. EinfluB von SIN 1 auf Wech-selwirkungen von Endothelzellen und Thrombozyten. Z Kardiol 1991; 80 (Suppl. 05) 13-16
    PubMedGoogle Scholar