Are there sex-specific differences in ventricular repolarization or in drug-induced early afterdepolarizations in isolated rabbit purkinje fibers?
Women are known to have a longer QT interval than men and a greater propensity toward drug-induced "torsades de pointes" (TdPs). However, little is known about these sex differences in isolated cardiac tissues. We evaluated potential sex differences in repolarization in isolated rabbit Purkinje fibers using a microelectrode technique. Isolated male or female Purkinje fibers were perfused in a Tyrode's solution with solvent, dofetilide (1 x 10(-8) M) or quinidine (1 x 10(-5) M), and stimulated at 1 or 0.2 Hz. Female Purkinje fibers with solvent (n = 11) tended to have a longer duration of the action potential at 90% repolarization (APD90) than male fibers with solvent (n = 10): 331 (median) vs. 272 ms at 1 Hz (p > 0.05); 473 vs. 367 ms at 0.2 Hz (p < 0.05). Dofetilide (1 x 10(-8) M) significantly increased APD90 more in female Purkinje fibers (n = 11) than in male fibers (n = 10): 670 vs. 385 ms at 1 Hz, at 20 min after the infusion (p < 0.05), and 1,000 vs. 937 ms at 0.2 Hz at the end of the 25-min infusion (p < 0.05), respectively. Quinidine (1 x 10(-5) M) tended to increase APD90 more in female Purkinje fibers (n = 11) than in male fibers (n = 10): 705 vs. 500 ms at 1 Hz, at 20 min after the infusion (p > 0.05). Furthermore, dofetilide (1 x 10(-8) M) and quinidine (1 x 10(-5) M) elicited a higher incidence of early afterdepolarizations in female Purkinje fibers than in male fibers at 0.2 Hz (100 vs. 60%, p < 0.05; and 91 vs. 50%, p > 0.05). Our data indicate that female Purkinje fibers tend to have longer ventricular repolarization and are at higher risk of drug-induced early afterdepolarizations at a slow stimulation rate than male fibers. This may contribute to a sex difference in QT interval and to a greater tendency on the part of women to the development of drug-induced TdPs.
Lu
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HR
Department of Cardiovascular Safety Pharmacology, Janssen Research Foundation, Beerse, Belgium. hlu@janbe.jnj.com
Mariën
R
R
Saels
A
A
De Clerck
F
F
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects; D004558:Electric Stimulation; D005260:Female; D007552:Isotonic Solutions / Q000494:pharmacology; D008133:Long QT Syndrome / Q000139:chemically induced; D008297:Male; D011690:Purkinje Fibers / Q000187:drug effects / Q000502:physiology*; D011802:Quinidine / Q000009:adverse effects; D011817:Rabbits; D012737:Sex Factors; D012997:Solvents / Q000494:pharmacology; D013268:Stimulation, Chemical; D016276:Ventricular Function / Q000187:drug effects / Q000502:physiology*
D000889:Anti-Arrhythmia Agents; D007552:Isotonic Solutions; D012997:Solvents; C037692:Tyrode's solution; D011802:Quinidine