Negative inotropic effect of diazepam in isolated guinea pig heart.
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 microM) produced a monophasic negative inotropic effect in a concentration dependent manner. Neither a central type (flumazenil 1 microM) nor a peripheral type (PK11195 10 microM) of benzodiazepine receptor antagonist antagonized the monophasic negative inotropic effects of diazepam. Diazepam (10 to 100 microM) shortened action potential duration of papillary muscle in a concentration dependent manner. In isolated single ventricular cells, diazepam (30 and 100 microM) inhibited the calcium current (I(Ca)) in a concentration dependent manner. Diazepam produced a significant decrease in I(Ca) elicited by first depolarizing pulses, however, the decrease of I(Ca) 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 I(Ca) in guinea pig heart preparations.
Department of Veterinary Pharmacology, School of Veterinary Medicine and Animal Sciences, Kitasato University, Aomori, Japan.
Y
Y
Hara
H
H
Kobayashi
S
S
Ooshiro
K
K
Futamura
T
T
Nishino
A
A
Chugun
K
K
Temma
H
H
Kondo
D000759:Adjuvants, Anesthesia / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects; D003864:Depression, Chemical; D003975:Diazepam / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005442:Flumazenil / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D006168:Guinea Pigs / Q000502:physiology*; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D014700:Verapamil / Q000494:pharmacology
D000759:Adjuvants, Anesthesia; D000889:Anti-Arrhythmia Agents; D015220:Calcium Channels; D018757:GABA Modulators; D007546:Isoquinolines; D005442:Flumazenil; D014700:Verapamil; D003975:Diazepam; C037850:PK 11195