Gender-related Differences in Drug-induced Prolongation of Cardiac Repolarization in Prepubertal Guinea Pigs

Abstract

Underlying mechanisms of drug-induced long QT syndrome are not fully understood. Our objective was to evaluate gender-related differences for block of the rapid (I_Kr ) or/and the slow (I_Ks) components of the delayed rectifier potassium current in prepubertal male and female guinea pigs (n = 120) treated with or without verapamil. Indapamide (I_Ks blocker) prolonged the monophasic action potential duration at 90% repolarisation (MAPD₉₀) in females more than in males (15.1 + 0.5 vs 9.7 + 1.3 msec; P < .05) in verapamil treated animals. In contrast, MAPD₉₀ prolongation induced by domperidone or dofetilide (I_Kr blockers) was not different between genders. Verapamil treatment augmented prolongation of MAPD₉₀ caused by dofetilide or domperidone (P < .01). In conclusion, 1) females exhibited greater prolongation of MAPD₉₀ when exposed to indapamide, 2) no gender-related differences were observed for I_Kr blockers, and 3) verapamil treatment did not uncover gender-related differences in I_Kr or I_Ks block, although it augmented prolongation of cardiac repolarization by I_Kr blockers.

Keywords

drug-induced long QT syndrome potassium channel blockers cardiac repolarization gender membrane transporters

References

Morissette P. , Hreiche R. , Turgeon J. Drug-induced long QT syndrome and torsade de pointes. Can J Cardiol. 2005;21:857-864.

Selzer A. , Wray HW Quinidine syncope. Paroxysmal ventricular fibrillation occurring during treatment of chronic atrial arrhythmias. Circulation. 1964;30:17-26.

Roden DM Drug-induced prolongation of the QT interval. N Engl J Med . 2004;350:1013-1022.

Makkar RR , Fromm BS , Steinman RT , Meissner MD , Lehmann MH Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA. 1993;270:2590-2597.

Bazett A. An analysis of the time relationship of electrocardiograms. Heart. 1920;7:353-370.

Rautaharju PM , Zhou SH , Wong S. , et al. Sex differences in the evolution of the electrocardiographic QT interval with age. Can J Cardiol . 1992;8:690-695.

Drici MD , Burklow TR , Haridasse V. , Glazer RI , Woosley RL Sex hormones prolong the QT interval and downregulate potassium channel expression in the rabbit heart. Circulation. 1996;94:1471-1474.

Rodriguez I. , Kilborn MJ , Liu XK , Pezzullo JC , Woosley RL Drug-induced QT prolongation in women during the menstrual cycle. JAMA. 2001;285: 1322-1326.

Hunt CM , Westerkam WR , Stave GM Effect of age and gender on the activity of human hepatic CYP3A. Biochem Pharmacol. 1992;44:275-283.

10.

Morris ME , Lee HJ , Predko LM Gender differences in the membrane transport of endogenous and exogenous compounds . Pharmacol Rev. 2003;55:229-240.

11.

Kleinman LI , Loewenstein MS , Goldstein L. Sex difference in the transport of p-aminohippurate by the rat kidney. Endocrinology. 1966;78:403-406.

12.

Orzes N. , Bellentani S. , Aldini R. , et al. Sex differences in the hepatic uptake of sulphobromophthalein in the rat. Clin Sci (Lond). 1985;69:587-593.

13.

Anton FM , Garcia Puig J. , Ramos T. , Gonzalez P. , Ordas J. Sex differences in uric acid metabolism in adults: evidence for a lack of influence of estradiol-17 beta (E2) on the renal handling of urate. Metabolism. 1986;35: 343-348.

14.

Schuetz EG , Furuya KN , Schuetz JD Interindividual variation in expression of P-glycoprotein in normal human liver and secondary hepatic neoplasms. J Pharmacol Exp Ther . 1995;275:1011-1018.

15.

Couture L. , Nash JA , Turgeon J. The ATP-binding cassette transporters and their implication in drug disposition: a special look at the heart. Pharmacol Rev. 2006;58: 244-258.

16.

Morissette P. , Hreiche R. , Turgeon J. Modulatory role of verapamil treatment on the cardiac electrophysiological effects of cisapride. Can J Physiol Pharmacol. 2007;84: 1285-1290.

17.

Drolet B. , Khalifa M. , Daleau P. , Hamelin BA , Turgeon J. Block of the rapid component of the delayed rectifier potassium current by the prokinetic agent cisapride underlies drug-related lengthening of the QT interval. Circulation. 1998;97:204-210.

18.

Zhang S. , Zhou Z. , Gong Q. , Makielski JC , January CT Mechanism of block and identification of the verapamil binding domain to HERG potassium channels. Circ Res. 1999;84:989-998.

19.

Rasmussen HS , Allen MJ , Blackburn KJ , Butrous GS , Dalrymple HW Dofetilide, a novel class III antiarrhythmic agent. J Cardiovasc Pharmacol. 1992;20(suppl 2): S96-S105.

20.

Drolet B. , Rousseau G. , Daleau P. , Cardinal R. , Turgeon J. Domperidone should not be considered a no-risk alternative to cisapride in the treatment of gastrointestinal motility disorders. Circulation . 2000;102: 1883-1885.

21.

El Ela AA , Hartter S. , Schmitt U. , Hiemke C. , Spahn-Langguth H. , Langguth P. Identification of P-glycoprotein substrates and inhibitors among psychoactive compounds-implications for pharmacokinetics of selected substrates. J Pharm Pharmacol . 2004;56:967-975.

22.

Schinkel AH , Wagenaar E. , Mol CA , van Deemter L. P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest. 1996;97:2517-2524.

23.

Yamreudeewong W. , DeBisschop M. , Martin LG , Lower DL Potentially significant drug interactions of class III antiarrhythmic drugs. Drug Saf. 2003;26:421-438.

24.

Turgeon J. , Daleau P. , Bennett PB , Wiggins SS , Selby L. , Roden DM Block of IKs, the slow component of the delayed rectifier K+ current, by the diuretic agent indapamide in guinea pig myocytes. Circ Res . 1994;75: 879-886.

25.

James AF , Arberry LA , Hancox JC Gender-related differences in ventricular myocyte repolarization in the guinea pig. Basic Res Cardiol. 2004;99:183-192.

26.

Brouillette J. , Lupien MA , St- Michel C. , Fiset C. Characterization of ventricular repolarization in male and female guinea pigs. J Mol Cell Cardiol. 2007;42: 357-366.

27.

Fiset C. , Drolet B. , Hamelin BA , Turgeon J. Block of IKs by the diuretic agent indapamide modulates cardiac electrophysiological effects of the class III antiarrhythmic drug dl-sotalol. J Pharmacol Exp Ther. 1997;283: 148-156.

28.

Varro A. , Lathrop DA , Hester SB , Nanasi PP , Papp JG Ionic currents and action potentials in rabbit, rat, and guinea pig ventricular myocytes. Basic Res Cardiol. 1993;88:93-102.

29.

Nerbonne JM Molecular basis of functional voltage-gated K+ channel diversity in the mammalian myocardium. J Physiol . 2000;525(pt 2):285-298.

30.

Grube M. , Kock K. , Oswald S. , et al. Organic anion transporting polypeptide 2B1 is a high-affinity transporter for atorvastatin and is expressed in the human heart. Clin Pharmacol Ther. 2006;80:607-620.

31.

Hagenbuch B. , Meier PJ The superfamily of organic anion transporting polypeptides. Biochim Biophys Acta. 2003;1609:1-18.

32.

Leu BL , Huang JD Inhibition of intestinal P-glycoprotein and effects on etoposide absorption . Cancer Chemother Pharmacol. 1995;35:432-436.

33.

Meerum Terwogt JM , Beijnen JH , ten Bokkel Huinink WW , Rosing H. , Schellens JH Co-administration of cyclosporin enables oral therapy with paclitaxel. Lancet . 1998; 352:285.

34.

Grube M. , Meyer zu Schwabedissen HE , Prager D. , et al. Uptake of cardiovascular drugs into the human heart: expression, regulation, and function of the carnitine transporter OCTN2 (SLC22A5). Circulation. 2006;113: 1114-1122.

35.

Letsas KP , Alexanian IP , Pappas LK , et al. QT interval prolongation and torsade de pointes associated with indapamide. Int J Cardiol. 2006;112:373-374.