PK 11195 antagonizes the positive inotropic response of the isolated rat heart to diazepam but not the negative inotropic response

Abstract

The influence of the ligand PK 11195 (1-(2-chlorophenyl)- N-methyl- N-(1-methylpropyl)-3-isoquinolinecarboxamide), antagonist of the peripheral-type benzodiazepine receptor, on the inotropic response of the perfused rat heart to diazepam (7-chloro-5-phenyl-methyl-1,3-dihydro-2 H-1,4-benzodiazepin-2-one) was studied. Diazepam induced a positive inotropic response which was preceded by a transient negative inotropic response. Concentrations of 10 −7 M PK 11195 were ineffective, whereas concentrations of 10 −6 and 10 −5 M PK 11195 reduced the positive inotropic response significantly. At 5 · 10 −5 M PK 11195 the response was completely abolished. The negative inotropic response was not changed by either concentration of PK 11195 used. It is concluded that the positive inotropic response of the isolated rat heart to diazepam may well be mediated through peripheral-type benzodiazepine receptors; the negative inotropic response must be related to other (more complex) mechanisms.