Synergistic effects of ketoconazole and pimozide on QT interval in isolated rabbit hearts: Influence of gender and pacing rate

W. X. Wang, D. Flockhart, M. D. Drici, R. L. Woosley

Research output: Contribution to journalArticle

Abstract

Pimozide (PIM), a drug to treat Tourette's disease, is known to cause torsades de pointes (TdP). Because female sex and bradycardia are risk factors for this arrhythmia, we evaluated the effects of gender and pacing rate on QT response to PIM in isolated perfused rabbit hearts pretreated with vehicle or ketoconazole (Keto). Male and female NZ rabbits were perfused using the Langendorff technique. After baseline measurements of QT, Keto (5 μM) or vehicle was perfused for 40 min followed by addition of PIM (0.5 μM, 40 min). Hearts were paced at 0.4 sec and 1.0 sec cycle lengths. Results: PIM increased QT more with Keto than with vehicle(14.6% ± 2.6 vs 6.5% ± 1.4, p<0.005). The increased QT by PIM after Keto was greater in females (8.3% ± 2.4 vs 20.8 ± 3.0, p<0.002) and a larger increase in QT at slower pacing rate (reverse use dependence) was seen in females (p<0.005). Keto alone increased QT only 3±1% in males and females. Conclusion: Keto enhanced PIM actions in female hearts more than male This may be relevant to the greater risk of TdP in women.

Original languageEnglish (US)
Number of pages1
JournalClinical Pharmacology and Therapeutics
Volume61
Issue number2
StatePublished - Dec 1 1997

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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