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 (IKr ) or/and the slow (IKs) components of the delayed rectifier potassium current in prepubertal male and female guinea pigs (n = 120) treated with or without verapamil. Indapamide (IKs blocker) prolonged the monophasic action potential duration at 90% repolarisation (MAPD 90) 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 (IKr blockers) was not different between genders. Verapamil treatment augmented prolongation of MAPD 90 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 IKr or IKs block, although it augmented prolongation of cardiac repolarization by IKr blockers.
Morissette P. , Hreiche R., Turgeon J.Drug-induced long QT syndrome and torsade de pointes. Can J Cardiol. 2005;21:857-864.
2.
Selzer A., Wray HWQuinidine syncope. Paroxysmal ventricular fibrillation occurring during treatment of chronic atrial arrhythmias. Circulation. 1964;30:17-26.
3.
Roden DMDrug-induced prolongation of the QT interval. N Engl J Med . 2004;350:1013-1022.
4.
Makkar RR, Fromm BS, Steinman RT, Meissner MD, Lehmann MHFemale gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA. 1993;270:2590-2597.
5.
Bazett A.An analysis of the time relationship of electrocardiograms. Heart. 1920;7:353-370.
6.
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.
7.
Drici MD, Burklow TR, Haridasse V., Glazer RI, Woosley RLSex hormones prolong the QT interval and downregulate potassium channel expression in the rabbit heart. Circulation. 1996;94:1471-1474.
8.
Rodriguez I. , Kilborn MJ, Liu XK, Pezzullo JC, Woosley RLDrug-induced QT prolongation in women during the menstrual cycle. JAMA. 2001;285: 1322-1326.
9.
Hunt CM, Westerkam WR, Stave GMEffect of age and gender on the activity of human hepatic CYP3A. Biochem Pharmacol. 1992;44:275-283.
10.
Morris ME, Lee HJ, Predko LMGender 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 JDInterindividual 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 CTMechanism 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 HWDofetilide, 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 DLPotentially 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 DMBlock 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 JCGender-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 JGIonic currents and action potentials in rabbit, rat, and guinea pig ventricular myocytes. Basic Res Cardiol. 1993;88:93-102.
29.
Nerbonne JMMolecular 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 PJThe superfamily of organic anion transporting polypeptides. Biochim Biophys Acta. 2003;1609:1-18.
32.
Leu BL, Huang JDInhibition 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 JHCo-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.
