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.
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Pharmacological characteristics of the canine isolated splenic artery were investigated by the cannula insertion method for observing vascular responses to vasoactive agents and periarterial nerve stimulation. Four alpha-adrenoceptor agonists and tyramine induced vasoconstrictions in a dose-dependent manner, and the order of potency was noradrenaline (NA) > phenylephrine > clonidine > methoxamine > tyramine. Xylazine (a selective alpha 2-adrenoceptor agonist) did not elicit any vasoconstriction. ⋯ The parameters of electrical stimulation to elicit a clear and constant vasoconstriction were 0.2 msec of pulse duration, 6 V and 0.1 Hz. The vasoconstrictive responses to electrical stimulation at 6-12 V, 0.1-10 Hz and 0.2-1 msec of pulse duration were completely inhibited by tetrodotoxin (TTX) and strongly inhibited by guanethidine. The results in this study suggest that: 1) in contrast with other regional arteries, the canine splenic artery has an alpha 1-adrenoceptor-related and clonidine-sensitive vasoconstrictive response, 2) this artery has no functional postsynaptic alpha 2-adrenoceptors, 3) it may be easier to observe the vascular responses to vasoactive agents in the isolated and perfused arterial segments, and 4) the isolated and perfused canine splenic artery is useful as a preparation to study the sympathetic nerve transmission.
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Comparative Study
Effects of lidocaine, disopyramide and verapamil on the in vivo triggered ventricular arrhythmia in digitalized canine heart.
Triggered activity due to delayed after depolarization has been postulated to be one of the generation mechanisms of some arrhythmias, especially that due to digitalis toxicity. The present experiment demonstrates an in vivo canine model of ventricular arrhythmias that were triggered by ventricular stimulation during administration of low doses of ouabain. Ventricular ectopic beats could be induced by stimulation before the occurrence of spontaneous ventricular arrhythmia, and the coupling interval of the first ectopic beat was shortened as the stimulation rate increased. Verapamil (0.2 mg/kg, i.v.) was ineffective in suppressing the occurrence of the triggered ventricular ectopic beats, but lidocaine (1 and 3 mg/kg, i.v.) and disopyramide (0.3 and 1 mg/kg, i.v.) were effective in suppressing these digitalis-induced triggered ventricular ectopic beats in a dose-dependent fashion.
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A novel transient middle cerebral artery (MCA) occlusion model in the rat was used to evaluate the effect of nimodipine on brain edema and mortality. Nimodipine (30 micrograms/kg) administered immediately after 3 hr of transient unilateral MCA occlusion attenuated significantly the post-ischemic increase of tissue water content and partly attenuated 45Ca accumulation in the parieto-temporal cortex ipsilateral to the left MCA occlusion 3 hr after reperfusion. Nimodipine decreased the mortality rate at 6 and 9 hr after recirculation, although the survival rate at 24 hr after recirculation was not different from the control group. These results suggest that nimodipine has beneficial effects in the early phase of the reperfusion period.