Key result
Benzodiazepine and isoquinolinecarboxamide compounds required micromolar concentrations to induce non-stereoselective relaxation of rat aortic rings, despite nanomolar binding affinities.
Benzodiazepine-induced relaxation of vascular smooth muscle occurs at micromolar concentrations and lacks stereoselectivity, suggesting mechanisms beyond high-affinity peripheral benzodiazepine receptor binding.
Challenges peripheral benzodiazepine receptor mediation of vascular relaxation; leaves open in vivo relevance and alternative mechanisms.
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)
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French et al. (1989) studied this question. Benzodiazepine and isoquinolinecarboxamide compounds was evaluated on Inhibition of [3H]Ro5-4864 binding and relaxation of rat aortic rings. Benzodiazepine and isoquinolinecarboxamide compounds required micromolar concentrations to induce non-stereoselective relaxation of rat aortic rings, despite nanomolar binding affinities.
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