Japanese journal of pharmacology
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Antiarrhythmic effects of bisaramil were examined by using new in vivo triggered arrhythmia models, and they were compared with those of other antiarrhythmic drugs. Bisaramil (3-10 micrograms, i.c.) suppressed triggered ventricular arrhythmias that were produced during pauses between trains of rapid ventricular stimulation (cycle length: 250 msec, train number: 15) in anesthetized open-chest dog hearts administered with subtoxic doses of digitalis or adrenaline to the anterior descending coronary artery. ⋯ Bisaramil was the most effective among the antiarrhythmic drugs used in the present experiment. Since bisaramil has been reported to be effective in suppressing other canine automatic ventricular arrhythmias, and the triggered ventricular arrhythmias occur in clinical situations, bisaramil may become a useful drug for the treatment of clinical arrhythmias.
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The antinociceptive effect of a selective kappa-opioid receptor agonist R-84760, (3R)-3-(1-pyrrolidinylmethyl)-4-[(1S)-5,6-dichloro-1-indancarbo nyl]- tetrahydro-1,4-thiazine hydrochloride, in the second phase of the formalin test, a model of tonic pain, was examined in mice. R-84760 had a 2700 times more potent antinociceptive effect than morphine. The effect of R-84760 was antagonized by subcutaneously administered nor-binaltorphimine, a kappa-selective opioid receptor antagonist. ⋯ Intrathecally administered (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), an N-methyl-D-aspartate (NMDA)-receptor antagonist, reduced and threo-beta-hydroxyaspartate, a reuptake inhibitor of glutamate, augmented the second phase nociceptive response. However, R-84760 did not influence the intrathecally injected NMDA-induced nociceptive response. These results suggest the following: R-84760 produces an extremely potent antinociceptive effect against tonic pain through the kappa-opioid receptors; the sites of action of subcutaneously administered R-84760 are the supraspinal and spinal loci in the central nervous system; and a part of the mechanism of the antinociceptive effect of R-84760 is activation of the descending noradrenergic pathway.