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.
Hara
Y
Y
Department of Veterinary Pharmacology, School of Veterinary Medicine and Animal Sciences, Kitasato University, Aomori, Japan.
Kobayashi
H
H
Ooshiro
S
S
Futamura
K
K
Nishino
T
T
Chugun
A
A
Temma
K
K
Kondo
H
H
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