Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1996 Jan;117(1):105–110. doi: 10.1111/j.1476-5381.1996.tb15161.x

Stereoselective effects of the enantiomers, quinidine and quinine, on depolarization- and agonist-mediated responses in rat isolated aorta.

B F del Pozo 1, F Pérez-Vizcaíno 1, E Villamor 1, F Zaragozá 1, J Tamargo 1
PMCID: PMC1909366  PMID: 8825350

Abstract

1. The effects of the two enantiomers, quinidine and quinine, were studied on depolarization- and agonist-induced isometric contractions in rat isolated thoracic aortic rings. 2. Quinidine or quinine (10(-6)M-3 x 10(-4)M) produced a concentration-dependent relaxation of 80 mM KCl-contracted rings, the pD2 values being 4.89 and 4.23, respectively. Thus, quinidine was about 4-5 times more potent than quinine. 3. The voltage-dependence of quinidine- and quinine-induced inhibition was studied in rings that had been incubated in 5 or 40 mM KCl Ca(2+)-free solution and then contracted by changing the bath solution to 100 mM KCl and 2 mM Ca2+. The inhibitory effects of quinidine were significantly enhanced when the rings were preincubated in 40 mM KCl (depolarizing conditions), when compared to normally polarized rings. In contrast, the effects of quinine were similar in 5 or 40 mM KCl solution. 4. The antagonism of noradrenaline (NA)-induced contractions by low concentrations of quinidine (< 10(-4)M) and quinine (< 3 x 10(-4)M) was competitive, as demonstrated by the concentration-dependent parallel rightward shift of the NA concentration-response curves (pA2 values 6.20 and 5.68, respectively, P < 0.05). 5. At low concentrations (< or = 3 x 10(-5)M), quinidine and quinine did not shift the concentration-response curve to 5-hydroxytryptamine (5-HT) or endothelin-1, whereas at higher concentrations they produced a downward shift of these curves. Quinidine and quinine (> 10(-4)M) inhibited to a similar extent both the phasic (induced in Ca(2+)-free media) and tonic responses (after restoring extracellular Ca2+) induced by 5-HT. 6. In conclusion, quinidine and quinine produced a stereoselective inhibition of depolarization and NA-induced contractions, quinidine being more potent than quinine. The inhibition of KCl-induced contractions could be attributed to inhibition of Ca2+ entry. Both drugs also behaved as competitive antagonists of alpha 1D-adrenoceptors. At high concentrations, quinidine and quinine also decreased the contractions induced by endothelin-1 and 5-HT in a non-stereoselective manner.

Full text

PDF
105

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bateman D. N., Dyson E. H. Quinine toxicity. Adverse Drug React Acute Poisoning Rev. 1986 Winter;5(4):215–233. [PubMed] [Google Scholar]
  2. Bayer R., Kalusche D., Kaufmann R., Mannhold R. Inotropic and electrophysiological actions of verapamil and D 600 in mammalian myocardium. III. Effects of the optical isomers on transmembrane action potentials. Naunyn Schmiedebergs Arch Pharmacol. 1975;290(1):81–97. doi: 10.1007/BF00499991. [DOI] [PubMed] [Google Scholar]
  3. Bean B. P., Sturek M., Puga A., Hermsmeyer K. Calcium channels in muscle cells isolated from rat mesenteric arteries: modulation by dihydropyridine drugs. Circ Res. 1986 Aug;59(2):229–235. doi: 10.1161/01.res.59.2.229. [DOI] [PubMed] [Google Scholar]
  4. Bolton T. B. Mechanisms of action of transmitters and other substances on smooth muscle. Physiol Rev. 1979 Jul;59(3):606–718. doi: 10.1152/physrev.1979.59.3.606. [DOI] [PubMed] [Google Scholar]
  5. Burges R. A., Gardiner D. G., Gwilt M., Higgins A. J., Blackburn K. J., Campbell S. F., Cross P. E., Stubbs J. K. Calcium channel blocking properties of amlodipine in vascular smooth muscle and cardiac muscle in vitro: evidence for voltage modulation of vascular dihydropyridine receptors. J Cardiovasc Pharmacol. 1987 Jan;9(1):110–119. [PubMed] [Google Scholar]
  6. Caldwell R. W., Elam J. T., Mecca T. E., Nash C. B. Vascular alpha-adrenergic blocking properties of quinidine. Eur J Pharmacol. 1983 Oct 28;94(3-4):185–192. doi: 10.1016/0014-2999(83)90407-7. [DOI] [PubMed] [Google Scholar]
  7. Carrón R., Pérez-Vizcaino F., Delpón E., Tamargo J. Effects of propafenone on 45Ca movements and contractile responses in vascular smooth muscle. Br J Pharmacol. 1991 Jun;103(2):1453–1457. doi: 10.1111/j.1476-5381.1991.tb09810.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Colatsky T. J. Mechanisms of action of lidocaine and quinidine on action potential duration in rabbit cardiac Purkinje fibers. An effect on steady state sodium currents? Circ Res. 1982 Jan;50(1):17–27. doi: 10.1161/01.res.50.1.17. [DOI] [PubMed] [Google Scholar]
  9. Dohi Y., Kojima M., Sato K. Vasorelaxant effect of mexiletine in mesenteric resistance arteries of rats. Br J Pharmacol. 1994 Mar;111(3):673–680. doi: 10.1111/j.1476-5381.1994.tb14790.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. HIATT E. P. Sympatholytic effects of quinine and quinidine. Am J Physiol. 1950 Jan;160(1):212–216. doi: 10.1152/ajplegacy.1949.160.1.212. [DOI] [PubMed] [Google Scholar]
  11. Hondeghem L. M., Katzung B. G. Antiarrhythmic agents: the modulated receptor mechanism of action of sodium and calcium channel-blocking drugs. Annu Rev Pharmacol Toxicol. 1984;24:387–423. doi: 10.1146/annurev.pa.24.040184.002131. [DOI] [PubMed] [Google Scholar]
  12. Hondeghem L. M., Matsubara T. Quinidine blocks cardiac sodium channels during opening and slow inactivation in guinea-pig papillary muscle. Br J Pharmacol. 1988 Feb;93(2):311–318. doi: 10.1111/j.1476-5381.1988.tb11436.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Mariano D. J., Schomer S. J., Rea R. F. Effects of quinidine on vascular resistance and sympathetic nerve activity in humans. J Am Coll Cardiol. 1992 Nov 15;20(6):1411–1416. doi: 10.1016/0735-1097(92)90256-m. [DOI] [PubMed] [Google Scholar]
  14. McDonald T. F., Pelzer S., Trautwein W., Pelzer D. J. Regulation and modulation of calcium channels in cardiac, skeletal, and smooth muscle cells. Physiol Rev. 1994 Apr;74(2):365–507. doi: 10.1152/physrev.1994.74.2.365. [DOI] [PubMed] [Google Scholar]
  15. Mecca T. E., Elam J. T., Nash C. B., Caldwell R. W. alpha-Adrenergic blocking properties of quinine HCl. Eur J Pharmacol. 1980 May 2;63(2-3):159–166. doi: 10.1016/0014-2999(80)90439-2. [DOI] [PubMed] [Google Scholar]
  16. Motulsky H. J., Maisel A. S., Snavely M. D., Insel P. A. Quinidine is a competitive antagonist at alpha 1- and alpha 2-adrenergic receptors. Circ Res. 1984 Sep;55(3):376–381. doi: 10.1161/01.res.55.3.376. [DOI] [PubMed] [Google Scholar]
  17. Nelson L. D., Schmid P. G., Holmsten D., Mark A. L., Heistad D. D., Abboud F. M. Effects of quinidine on venous responses to adrenergic and nonadrenergic constrictor stimuli: indirect evidence of two sites of action in vascular smooth muscle. Proc Soc Exp Biol Med. 1974 Jun;146(2):409–413. doi: 10.3181/00379727-146-38116. [DOI] [PubMed] [Google Scholar]
  18. Pérez-Vizcaino F., Duarte J., Tamargo J. Effects of flecainide on isolated vascular smooth muscles of rat. Br J Pharmacol. 1991 Nov;104(3):726–730. doi: 10.1111/j.1476-5381.1991.tb12495.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Pérez-Vizcaíno F., Fernández del Pozo B., Zaragozá F., Tamargo J. Voltage- and time-dependent inhibitory effects on rat aortic and porcine coronary artery contraction induced by propafenone and quinidine. Br J Pharmacol. 1994 Dec;113(4):1281–1288. doi: 10.1111/j.1476-5381.1994.tb17137.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Roden D. M., Bennett P. B., Snyders D. J., Balser J. R., Hondeghem L. M. Quinidine delays IK activation in guinea pig ventricular myocytes. Circ Res. 1988 May;62(5):1055–1058. doi: 10.1161/01.res.62.5.1055. [DOI] [PubMed] [Google Scholar]
  21. Salata J. J., Wasserstrom J. A. Effects of quinidine on action potentials and ionic currents in isolated canine ventricular myocytes. Circ Res. 1988 Feb;62(2):324–337. doi: 10.1161/01.res.62.2.324. [DOI] [PubMed] [Google Scholar]
  22. Salomone S., Godfraind T. Radioligand and functional estimates of the interaction of the 1,4-dihydropyridines, isradipine and lacidipine, with calcium channels in smooth muscle. Br J Pharmacol. 1993 May;109(1):100–106. doi: 10.1111/j.1476-5381.1993.tb13537.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Scamps F., Undrovinas A., Vassort G. Inhibition of ICa in single frog cardiac cells by quinidine, flecainide, ethmozin, and ethacizin. Am J Physiol. 1989 Mar;256(3 Pt 1):C549–C559. doi: 10.1152/ajpcell.1989.256.3.C549. [DOI] [PubMed] [Google Scholar]
  24. Schmid P. G., Nelson L. D., Mark A. L., Heistad D. D., Abboud F. M. Inhibition of adrenergic vasoconstriction by quinidine. J Pharmacol Exp Ther. 1974 Jan;188(1):124–134. [PubMed] [Google Scholar]
  25. Tamargo J., Delpón E. Dihydropyridines and vascular diseases. Z Kardiol. 1991;80 (Suppl 7):106–111. [PubMed] [Google Scholar]
  26. Towart R., Wehinger E., Meyer H. Effects of unsymmetrical ester substituted 1,4-dihydropyridine derivatives and their optical isomers on contraction of smooth muscle. Naunyn Schmiedebergs Arch Pharmacol. 1981 Sep;317(2):183–185. doi: 10.1007/BF00500079. [DOI] [PubMed] [Google Scholar]
  27. WEIDMANN S. Effects of calcium ions and local anesthetics on electrical properties of Purkinje fibres. J Physiol. 1955 Sep 28;129(3):568–582. doi: 10.1113/jphysiol.1955.sp005379. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. White N. J. Drug treatment and prevention of malaria. Eur J Clin Pharmacol. 1988;34(1):1–14. doi: 10.1007/BF01061409. [DOI] [PubMed] [Google Scholar]
  29. Wibo M., DeRoth L., Godfraind T. Pharmacologic relevance of dihydropyridine binding sites in membranes from rat aorta: kinetic and equilibrium studies. Circ Res. 1988 Jan;62(1):91–96. doi: 10.1161/01.res.62.1.91. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES