Negative inotropic effect of diazepam in isolated guinea pig heart

• Published in: Journal of Veterinary Medical Science Vol. 63; no. 2; pp. 135 - 143
• Main Authors: Hara, Y. (Kitasato Univ., Tokyo (Japan)), Kobayashi, H, Ooshiro, S, Futamura, K, Nishino, T, Chugun, A, Temma, K, Kondo, H
• Format: Journal Article
• Language: English
• Published: Japan JAPANESE SOCIETY OF VETERINARY SCIENCE 01.02.2001; Japan Science and Technology Agency
• Subjects: Adjuvants, Anesthesia - pharmacology; Animals; Anti-Arrhythmia Agents - pharmacology; CALCIUM; Calcium Channels - drug effects; calcium current; Depression, Chemical; diazepam; Diazepam - pharmacology; Dose-Response Relationship, Drug; Female; Flumazenil - pharmacology; GABA Modulators - pharmacology; GUINEA PIGS; Guinea Pigs - physiology; HEART; Heart - drug effects; Heart - physiology; IN VITRO EXPERIMENTATION; In Vitro Techniques; Isoquinolines - pharmacology; Male; Membrane Potentials - drug effects; Myocardial Contraction - drug effects; Myocardial Contraction - physiology; negative inotropic effect; NEUROLEPTICS; patch clamp method; Patch-Clamp Techniques; Verapamil - pharmacology
• ISSN: 0916-7250; 1347-7439
• DOI: 10.1292/jvms.63.135

The inotropic effect of diazepam, a benzodiazepine derivative, and its mechanism of action were examined using guinea pig heart and single ventricular cell preparations. In Langendorff hearts and right ventricular free-wall preparations, diazepam (10 to 100 μM) produced a monophasic negative inotropic effect in a concentration dependent manner. Neither a central type (flumazenil 1 μM) nor a peripheral type (PK11195 10 μM) of benzodiazepine receptor antagonist antagonized the monophasic negative inotropic effects of diazepam. Diazepam (10 to 100 μM) shortened action potential duration of papillary muscle in a concentration dependent manner. In isolated single ventricular cells, diazepam (30 and 100 μM) inhibited the calcium current (ICa) in a concentration dependent manner. Diazepam produced a significant decrease in ICa elicited by first depolarizing pulses, however, the decrease of ICa was not augmented during a train of depolarizing pulses. Thus, diazepam appears to produce a tonic block of cardiac calcium channels and the mode of inhibition is clearly different from the use-dependent block of verapamil. From these results, it was concluded that diazepam produces a monophasic negative inotropic effect that is independent of the benzodiazepine receptor, and is probably mediated through an inhibition of ICa in guinea pig heart preparations.