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.
Rappaport Family Institute for Research, Medical Sciences, Haifa, Israel.
Y
Y
Edoute
J
J
Giris
S A
SA
Ben-Haim
A
A
Lochner
A
A
Weizman
G
G
Hayam
Y
Y
Katz
M
M
Gavish
D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects
D001570:Benzodiazepinones; D007546:Isoquinolines; D011963:Receptors, GABA-A; C028513:4'-chlorodiazepam; D003975:Diazepam; C037850:PK 11195