MODIFICATION OF CARDIAC ACTIONS OF RO-05-4864 BY PK-11195 AND FLUMAZENIL IN THE PERFUSED RAT-HEART

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 Langen dorff rat heart. The influence of PK 11195, antagonist of the peripher al 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 1119 5 significantly reduced both the increase of coronary flow rate and of contraction force, without affecting these functions by itself; the p ositive inotropic response produced by Ro 05-4864 was even abolished i n the presence of 5.10(-5) M PK 11195. The Emax values of Ro 05-4864 o n both coronary flow and inotropy were reduced significantly by PK 111 95. In the presence of flumazenil, 10(-7) to 10(-5) M, both the vasodi latory 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 sug gestions 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 car diac actions of Ro 05-4864 is as yet difficult to explain. On the othe r hand concentrations of both agonist and antagonist employed are so-m uch high that interference of other receptors than benzodiazepine rece ptors must be considered as well.