title: Possible mechanism of benzodiazepine-induced relaxation of vascular smooth muscle.
abstract: This study investigated the mechanism of benzodiazepine-induced relaxation of vascular smooth muscle. The ability of several benzodiazepine and isoquinolinecarboxamide compounds, including a pair of enantiomers, to inhibit [3H]Ro5-4864 binding to the peripheral-type benzodiazepine binding site in rat aortic smooth muscle was compared with their relative ability to induce relaxation of rat aortic rings. The binding was performed in a membrane fraction obtained from a pellet centrifuged at 11,400 g and enriched with high-affinity [3H]Ro5-4864 binding. The rank order of potency (Ki) for inhibition of [3H]Ro5-4864 binding to isolated membranes was: (-)PK 14067 (6.4 +/- 0.7 nM) = PK 11195 (6.6 +/- 0.8 nM) greater than Ro5-4864 (17.6 +/- 2.1 nM) greater than diazepam (600 +/- 180 nM) = (+)PK 14068 (530 +/- 70 nM) greater than clonazepam (14,300 +/- 2,100 nM). However, micromolar concentrations of these agents were required to induce relaxation of rat aortic rings contracted with KCl and/or norepinephrine (NE). Moreover, the relaxations induced by these agents were not stereoselective. The rank order of potency (IC50) for relaxation of KCl-induced contracted muscle was: Ro5-4864 (6.6 +/- 0.3 microM) = PK 11195 (6.7 +/- 0.9 microM) = (-)PK 14067 (11.6 +/- 0.7 microM) = (+)PK 14068 (7.6 +/- 1.1 microM) greater than diazepam (47.4 +/- 5.3 microM) = clonazepam (47.5 +/- 5.7 microM). Further investigation of the mechanism of benzodiazepine-induced relaxation showed that (-)PK 14067 and (+)PK 14068 inhibited CaCl2-induced contractions. The benzodiazepines relaxed muscle contracted with KCl to a greater magnitude than those contracted with NE or prostaglandin F2 alpha (PGF2 alpha).(ABSTRACT TRUNCATED AT 250 WORDS)
authors: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, OH 45267-0575.
authors: J F
authors: JF
authors: French
authors: R M
authors: RM
authors: Rapoport
authors: M A
authors: MA
authors: Matlib
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000378:metabolism; D001667:Binding, Competitive / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002122:Calcium Chloride / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009638:Norepinephrine / Q000037:antagonists & inhibitors; D011189:Potassium Chloride / Q000037:antagonists & inhibitors; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism
chemical_list: D014151:Anti-Anxiety Agents; D001570:Benzodiazepinones; D002121:Calcium Channel Blockers; D011963:Receptors, GABA-A; C028513:4'-chlorodiazepam; D011189:Potassium Chloride; D002122:Calcium Chloride; D009638:Norepinephrine