Actions of benzodiazepines on the inotropy of the perfused rat heart

The inotropic responses of four benzodiazepines (diazepam, midazolam and the more recently developed adinazolam and alprazolam) have been studied in a Langendorff heart preparation of the rat. Added to the perfusate in increasing concentrations (2 x 10-5 to 6 x 10-4 M), diazepam induced a concentration-dependent biphasic effect on the contractile force (n = 12), and, in low concentrations (2 x 10-5 to 1 x 10-4 M), a significant enhancement which diminished after concentrations higher than 1 x 10-4 M were applied. The increase in contractile force was preceded by a transient short-lasting concentration-dependent inhibition. Midazolam (2 x 10-5 to 6 x 10-4 M) produced a significant concentration-dependent increase in heart contractile force which diminished at the highest concentrations. The maximum increase was only half that caused by diazepam (60 and 140 %, respectively). Adinazolam and alprazolam, in the range of 2 x 10-8 to 2 x 10-7 M and 6 x 10-7 to 1 x 10-5 M, respectively, produced a marked concentration- dependent and short-lasting increase in inotropy (maximum response = 290 and 180%, respectively). Propranolol (10-7 M) antagonized the inotropic effects of both diazepam and midazolam, whereas the positive inotropic response to alprazolam remained unchanged. This study shows that benzodiazepines may elicit both positive and negative concentration-dependent inotropic responses in the isolated rat heart. Differences between the drugs tested are both qualitative and quantitative. The newer benzodiazepines adinazolam and alprazolam are more powerful in increasing contractile force, as judged from the maximum response, even at relatively low concentrations. The underlying mechanism(s) of these actions is (are) unknown as yet and the subject of investigation.