ACTIONS OF BENZODIAZEPINES ON THE INOTROPY OF THE PERFUSED RAT-HEART

The inotropic responses of four benzodiazepines (diazepam, midazolam a nd the more recently developed adinazolam and alprazolam) have been st udied in a Langendorff heart preparation of the rat. Added to the perf usate in increasing concentrations (2 x 10(-5) to 6 x 10(-4) M), diaze pam induced a concentration-dependent biphasic effect on the contracti le 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 for ce was preceded by a transient short-lasting concentration-dependent i nhibition. Midazolam (2 x 10(-5) to 6 x 10(-4) M) produced a significa nt concentration-dependent increase in heart contractile force which d iminished 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-de pendent and short-lasting increase in inotropy (maximum response = 290 and 180 %, respectively). Propranolol (10(-7) M) antagonized the inot ropic effects of both diazepam and midazolam, whereas the positive ino tropic response to alprazolam remained unchanged. This study shows tha t benzodiazepines may elicit both positive and negative concentration- dependent inotropic responses in the isolated rat heart. Differences b etween the drugs tested are both qualitative and quantitative. The new er benzodiazepines adinazolam and alprazolam are more powerful in incr easing contractile force, as judged from the maximum response, even at relatively low concentrations. The underlying mechanism(s) of these a ctions is (are) unknown as yet and the subject of investigation.