TY - JOUR
T1 - Ro 5-4864 and PK11195, but not diazepam, depress cardiac function in an isolated working rat heart model
AU - Edoute, Yeouda
AU - Giris, Jacob
AU - Ben-Haim, Shlomo A.
AU - Lochner, Amanda
AU - Weizman, Abraham
AU - Hayam, Gal
AU - Katz, Yeshavahu
AU - Gavish, Moshe
PY - 1993
Y1 - 1993
N2 - 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 mitochondiral 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 inotropismof 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.
AB - 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 mitochondiral 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 inotropismof 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.
KW - Benzodiazepine receptors (mitochondrial type)
KW - Diazepam
KW - Heart
KW - PK 11195
KW - Ro 5-4864
UR - http://www.scopus.com/inward/record.url?scp=0027477402&partnerID=8YFLogxK
U2 - 10.1159/000139049
DO - 10.1159/000139049
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AN - SCOPUS:0027477402
SN - 0031-7012
VL - 46
SP - 224
EP - 230
JO - Pharmacology
JF - Pharmacology
IS - 4
ER -