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 (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, MAPD(90) prolongation induced by domperidone or dofetilide (I(Kr) 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 MAPD(90) 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.

Field and action potential recordings in heart slices: correlation with established in vitro and in vivo models

“…Another important point of discussion concerns a potential bias introduced by sex‐specific differences in ventricular repolarization (for review, see Cheng, 2006). Females are more sensitive towards APD prolongation than males, particularly at extremely low stimulation rates, as demonstrated in rabbit Purkinje fibre (Lu et al ., 2000) and Langendorff heart (Liu et al ., 1998), and in human patients and volunteers (Lehmann et al ., 1999; Somberg et al ., 2011), whereas this issue remains controversial in guinea pig ventricle (Brouillette et al ., 2007; Hreiche et al ., 2009) and in canine ventricle (Xiao et al ., 2006). Also, inward currents vary with sex and cardiac region as shown for the L‐type calcium current (Sims et al ., 2008).…”

Sex Differences in Drug Disposition

“…For example, drug-induced long QT syndrome has a higher rate of incidence in females, particularly during the ovulatory phase of the menstrual cycle compared to the luteal phase [100]. It has been established that there exists a basal sex hormonal regulatory impact on cardiac potassium channels and that in drug-induced QT prolongation, drug-hormone interactions seen at particular doses cause a blockade in these channels [101–103]. Heightened sensitivity to opioids in females has been consistently observed.…”

Arrhythmias in Female Patients: Incidence, Presentation and Management

“…Other studies, however, have shown IKs blockers but not IKr blockers lead to greater action potential duration prolongation in female than male guinea pigs. 17 Androgens have the opposite effect, with testosterone decreasing action potential duration in a dose-dependent manner, and enhancing IKs and Ica channels, effects blocked by a testosterone blocker. 18…”