title: Modification of cardiac actions of RO 05-4864 by PK 11195 and flumazenil in the perfused rat heart.
abstract: The benzodiazepine analogue Ro 05-4864 [chlorodiazepam] (2.10[-5] to 4.10[-4] M) induced a concentration-dependent increase of coronary flow rate (Emax 82.4% [+/- 2.2 SEM]) and an increase of contraction force (Emax 68.3% [+/- 4.7 SEM]) of the retrograde perfused, isolated Langendorff rat heart. The influence of PK 11195, antagonist of the peripheral type benzodiazepine receptor, and flumazenil (Anexate), antagonist of the central type benzodiazepine receptor, on these responses to Ro 5-4864 was studied. In concentrations of 10(-7) to 5.10(-5) M, PK 11195 significantly reduced both the increase of coronary flow rate and of contraction force, without affecting these functions by itself; the positive inotropic response produced by Ro 05-4864 was even abolished in the presence of 5.10(-5) M PK 11195. The Emax values of Ro 05-4864 on both coronary flow and inotropy were reduced significantly by PK 11195. In the presence of flumazenil, 10(-7) to 10(-5) M, both the vasodilatory and the positive inotropic response induced by Ro 05-4864 were significantly counteracted as well. The Emax values of Ro 05-4864 were reduced significantly. In conclusion, the results support earlier suggestions that it is tempting to involve peripheral type benzodiazepine receptors in cardiac actions of benzodiazepines. The finding that the centrally acting benzodiazepine antagonist flumazenil reduced the cardiac actions of Ro 05-4864 is as yet difficult to explain. On the other hand concentrations of both agonist and antagonist employed are so-much high that interference of other receptors than benzodiazepine receptors must be considered as well.
authors.affiliation: Department of Pharmacology, University of Amsterdam, Academic Medical Centre, The Netherlands. R.S.Leeuwin@AMC.UVA.NL
authors.forename: R S
authors.initials: RS
authors.lastname: Leeuwin
authors.forename: A
authors.initials: A
authors.lastname: Zeegers
authors.forename: J
authors.initials: J
authors.lastname: van Hamme
authors.forename: H
authors.initials: H
authors.lastname: van Wilgenburg
mesh_terms: D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D005442:Flumazenil / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D007546:Isoquinolines / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects
chemical_list: D001570:Benzodiazepinones; D007546:Isoquinolines; C028513:4'-chlorodiazepam; D005442:Flumazenil; C037850:PK 11195