Ro 5-4864 and PK 11195, but not diazepam, depress cardiac function in an isolated working rat heart model

The present study was designed to investigate the effects of diazepam, a benzodiazepine (BZ) with high affinity to central BZ receptors and moderate affinity to mitochondrial BZ receptors, and of Ro 5-4864 and PK 11195, ligands specific for mitochondrial BZ receptors, on cardiac function in the isolated working rat heart model. Five concentrations of these drugs (10(-9)-10(-5) mol/l) were used, and the chronotropic (heart rate) and inotropic [maximum elastance of the left ventricle at end systole (Emax), maximal first derivative of left ventricular (LV) pressure (dP/dtmax), LV pressure at dP/dtmax (pressure at dP/dtmax), aortic flow, stroke work, and total pressure-volume area] cardiac parameters were measured. Diazepam, Ro 5-4864, and PK 11195 showed no significant chronotropic activity up to 10(-5) mol/l. Diazepam did not alter the inotropic properties of the heart. Ro 5-4864 at 10(-5) mol/l significantly decreased the indices of contractility, namely, Emax, dP/dtmax, and pressure at dP/dtmax. Aortic flow, stroke work, and total pressure-volume area were significantly depressed at the same concentration. The negative inotropism of PK 11195 appeared to be identical, by most indices, to that of Ro 5-4864, both qualitatively (same pattern) and quantitatively (similar maximal variations); however, for some indices a depressant effect was also found at 10(-7) mol/l. These results show that at high concentrations Ro 5-4864 and PK 11195, but not diazepam, have a depressant effect on mechanical function.