Archives internationales de pharmacodynamie et de thérapie
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Arch Int Pharmacodyn Ther · Mar 1996
Comparative StudySome pharmacological properties of a newly synthesized 3-acetoxy-6 beta-acetylthio-10-oxo-N-cyclopropylmethyl-dihydronormorphine (KT-95).
The pharmacological properties of a newly synthesized 3-acetoxy-6 beta-acetylthio-10-oxo-N-cyclopropylmethyl-dihydronormorphine (KT-95) were examined. This compound, as well as (-)-3-acetyl-6 beta-acetylthio-N-cyclopropylmethylnormorphine (KT-90) and morphine, inhibited the twitch response to electrical stimulation of the guinea-pig ileal preparation that contains mu- and kappa-receptors. The inhibitory effect of KT-95 was about 17 times more potent than morphine, and about 4 times more potent than KT-90. ⋯ In the pressure test, KT-95 was 20.17 times more potent than morphine. The analgesic action, induced by KT-95 (2.05 mumol/kg, s.c.), was also in this test abolished by simultaneous administration of norbinaltorphimine (0.14 mumol/rat, s.c.), suggesting that this action of KT-95 is mediated through the kappa-opioid receptor. These results indicate that KT-95 behaves as a kappa-agonist with mu- and delta-antagonistic activities, and suggest that analgesia, induced by KT-95, is mainly mediated through kappa-receptors.
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The antagonism of depolarizing blockers, principally succinylcholine and decamethonium, by tetraethyl- and tetrabutylammonium ions in an in vivo neuromuscular preparation in anesthetized cats is described; possible mechanisms for these effects are discussed. Tetraethyl- (50-100 mg/kg, i.v.) and tetrabutylammonium (1-5 mg/kg, i.v.) produced sharp reversals of 95-99% succinylcholine and decamethonium blocks. These reversals were effective and sustained at any point during the course of the blockades. ⋯ The present studies support this in showing the prevention of succinylcholine and decamethonium block by the prior administration of tetraethylammonium, which also interacts with acetylcholine receptors. It is proposed that a possible mechanism for tetraethylammonium reversals of succinylcholine and decamethonium blocks may be attributable to the tetraethylammonium reversal of a K+ current block by quaternary ammonium ions such as succinylcholine and decamethonium. Tetraethyl- and tetrabutylammonium ions proved to be effective antagonists of succinylcholine block following inactivation of plasma cholinesterases by hexafluorenium.
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Arch Int Pharmacodyn Ther · Mar 1995
Comparative StudyEnhancement of defecation and distal colonic motor activity by KW-5092, a novel gastroprokinetic agent, in rats.
KW-5092 ([1-[2-[[[5-(piperidinomethyl)-2-furanyl]- methyl]amino]ethyl]-2-imidazolidinylidene]propanedinitrile fumarate) is a novel gastroprokinetic agent with acetylcholinesterase inhibitory and acetylcholine release facilitatory activity. The present study examined the effects of KW-5092 on the defecation and colonic motor activity in rats. KW-5092, at 1 to 30 mg/kg, p.o., dose-dependently increased the fecal pellet output. ⋯ In the in vivo study, KW-5092, at 1 to 10 mg/kg, p.o., induced an increase in the distal colonic motor index, which was dose-dependently inhibited by atropine (0.1 to 1 mg/kg, i.v.). The present results suggest that KW-5092 induces the defecation in rats by enhancing the distal colonic motor activity via its acetylcholinesterase inhibitory activity and/or acetylcholine release facilitatory activity. KW-5092 may be a useful drug in the treatment of constipation.
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Arch Int Pharmacodyn Ther · Nov 1993
Comparative StudyEffects of hemorrhage on regional cerebral blood flow in awake and in isoflurane-anesthetized rats.
During hemorrhage, redistribution of cerebral blood flow may occur. We compared the effects of hemorrhage on regional cerebral blood flow in awake rats and in rats anesthetized with 1% or 2% isoflurane. In half of each group, regional cerebral blood flow was measured without hemorrhage. ⋯ However, the absolute value of the cortical flow was higher in the awake animals than in the isoflurane groups. Our experiment demonstrated that hemorrhage decreased the regional cerebral blood flow. However, it did not alter the redistribution of the cerebral blood flow in awake animals nor in the animals anesthetized with isoflurane.
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Arch Int Pharmacodyn Ther · Nov 1992
Influence of the endothelium on the responses to endogenous agonists in human internal mammary and gastroepiploic arteries.
The higher patency rate of internal mammary artery grafts compared to venous grafts has been ascribed to its endothelial function, namely a greater capacity to release endothelium-derived relaxing factor and to inhibit serotonin-induced contractions. Gastroepiploic and mammary arteries were obtained intraoperatively from 27 patients and suspended in organ chambers to record isometric tension. The relaxations to acetylcholine were similar in both vessels. ⋯ However, the capacity to contract, expressed in tension developed, was higher in the gastroepiploic artery: the KCl (90 mM)-induced contraction was 2.6 +/- 0.3 g in the internal mammary vs 7.9 +/- 0.9 g in the gastroepiploic artery (p < 0.001). Histologically, similar wall thickness and paucity of atherosclerotic lesions were observed, but the medium was mainly elastic in the internal mammary and muscular in the gastroepiploic artery. Thus, despite a similar endothelial function and greater responsiveness of the mammary artery to endogenous vasoconstrictors when compared to a receptor-independent vasoconstrictor, the higher contractile capacity of the gastroepiploic artery might be a disadvantage in terms of graft function and patency.