Gender Difference in the Cycle Length-Dependent QT and Potassium Currents in Rabbits 1 XIAO-KE LIU, ALEXANDER KATCHMAN, MILOU-DANIEL DRICI, STEVEN N. EBERT, IVAN DUCIC, MARTIN MORAD and RAYMOND L. WOOSLEY Department of Pharmacology, Georgetown University Medical Center, Washington, DC Accepted for publication January 30, 1998 This paper is available online at http://www.jpet.org ABSTRACT Women are known to have a longer electrocardiographic Q-T than men, which may contribute to their being at greater risk of developing drug-induced polymorphic ventricular arrhythmias. However, little is known about the underlying mechanisms. In the present study, we evaluated potential gender differences in Q-T interval in isolated perfused rabbit hearts using the Lang- endorff technique and evaluated the density of outward potas- sium currents in single ventricular myocytes using the whole- cell patch-clamp technique. We found that female hearts demonstrated a greater Q-T lengthening (Q-T%) upon an increase in cycle length (CL), resulting in a significantly longer Q-T (301  4.8 ms, CL = 2.3 s) at a long CL in female hearts compared with male hearts (267  4.0 ms, P  .01). Ventricular myocytes isolated from female hearts showed a smaller I Ktail and peak I Kl outward current density. A 50% reduction in ex- tracellular K + and Mg ++ shifted the I-V relationship of I Kl and I to and reduced their amplitude. However, neither the I-V relation- ship of I Kr nor the gender difference in the Q-T–CL relationship was significantly altered. We conclude that 1) female rabbit ventricular myocytes have significantly lower I Kr and I Kl outward current densities than do male cells, which may contribute to the gender difference in Q-T, and 2) a lower base-line I Kr density may contribute to the steeper Q-T–CL relationship in female hearts. Women are known to have a longer, CL-dependent electro- cardiographic Q-T interval than men (Stramba-Badiale et al., 1997). However, little is known about the mechanism respon- sible for this gender difference. Prolongation of the Q-T in- terval on the electrocardiogram has clinical importance be- cause it is a common feature associated with a complex form of ventricular arrhythmia known as TdP (Dessertenne, 1966). An acquired long Q-T syndrome secondary to drug administration has been associated with TdP and sudden death in patients treated with antiarrhythmic drugs (Ben- David and Zipes, 1993; Carlsson et al., 1990; Roden et al., 1986). A gender difference in Q-T duration may therefore result in a gender difference in the incidence of TdP. Indeed, recent clinical observations have indicated that the occur- rence of TdP displays a gender difference with a higher-than- expected occurrence in females (Kawasaki et al., 1995; Leh- mann et al., 1996; Makkar et al., 1993). Crucial to generation of TdP is prolongation of the Q-T interval and APD that permits EADs to occur (Zeng and Rudy, 1995). Because potassium currents are major determi- nants of cardiac repolarization, and because shortening of the action potential suppresses EADs in isolated myocytes (Bouchard et al., 1995), the activity of one or more potassium channels may be critical in modulating EADs. In fact, most drugs that are associated with TdP clinically have also been shown to block cardiac potassium channels, especially the rapid component of I K ,I Kr (Ben-David and Zipes, 1993; Carlsson et al., 1990; Roden et al., 1986; Lehmann et al., 1996). Furthermore, overexpression of HERG, the gene cod- ing for I Kr , has been shown to shorten APD and suppress EAD in rabbit ventricular myocytes (Nuss et al., 1997). In the present study, we examined the gender differences in the CL-dependent Q-T in isolated perfused rabbit hearts. In addition, we measured the density of outward potassium currents that may contribute to such a difference in single rabbit ventricular myocytes. Materials and Methods Langendorff preparation. Hearts from 35 New Zealand White male and female rabbits (3– 4 months old, weight 3–3.5 kg; HRP Inc., Denver, Pennsylvania) were studied using the nonrecirculating Lan- gendorff technique as described previously (Zabel et al., 1995). The hearts were perfused with an oxygenated Tyrode’s solution (95% O 2 , 5% CO 2 ), pH 7.4, containing (mmol/l) NaCl 115, KCl 4.7, CaCl 2 2, Received for publication November 22, 1996. 1 This work was supported in part by a grant from the National Institutes of Health (Grant #RO1 HL54590 to R.L.W.). ABBREVIATIONS: TdP, torsades de pointes; APD, action potential duration; I Kr and I Ks , rapid and slow components, respectively, of the delayed rectifier; I Kl , inward rectifier; I to , transient outward current; CL, cycle length; EAD, early afterdepolarization; HERG, human ether-a-go-go-related gene. 0022-3565/98/2852-0672$03.00/0 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 285, No. 2 Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A. JPET 285:672–679, 1998 672 at ASPET Journals on July 26, 2016 jpet.aspetjournals.org Downloaded from