We concluded that compound 48/80 (1) penetrates into the central nervous system to produce a central effect; (2) acts as pro-convulsive, and (3) paradoxically augments the anticonvulsive action of morphine, likely caused by the ability of the compound to increase the permeability of blood-brain barrier for morphine or by the release of histamine from mast cells in the brain, acting as anticonvulsant through the stimulation of H1 receptors or both. The precise mechanism of the increased death rate by C48/80 or morphine in intact and in mast-cell-depleted mice appears to involve pro-convulsive effects, cardiovascular impairment, and respiratory depression. The nullification of morphine-induced lethal toxicity by C48/80 could be due to the antagonistic interaction of the drug with opiate receptors in the brain.
We studied the role of the resting period (1, 2, 4, 8, 16 min; n = 6-7), external Ca2+ (0.2, 0.4, 0.6 g/l; n + 5-6), stimulation frequency (1, 2, 3 Hz; n = 6), 4-aminopyridine (4-AP, 2 mM; n = 5); theophylline (1 mM; n = 6), ouabain (5 microM; n = 6), and verapamil (1 microM; n = 6) on post-rest adaptation in the isolated left atria of rats driven electrically by a 2x threshold intensity for 2 ms. Resting periods resulted in three-phasic adaptive changes in contractility during the post-rest stimulation before normalization: P1, hypercontractile phase, an initial twitch potentiation; P2, post-rest hypocontractile decay reached after 8 to 12 single twitches; and P3, a late reactive hypercontractile phase marked less than that of P1 and gradually declining to the pre-resting level. P1 and P2 were augmented along with increasing the resting period from 1 min to 16 min, whereas t1 (time between P1 and P2) shortened and P2 and t2 (time between P2 and P3) were not affected. P1 and P3 to become more apparent after shifting the stimulation frequency from 1 Hz to 3 Hz, accompanied by a shortening of t1 and t2 (p < 0.05) and an insignificant reversal of P2. An increase in Ca2+ concentration by 2- or 3-fold at 2 Hz reduced P1 was and antagonized P2, while leaving other parameters almost unaffected. The reduction of P1 by Ca2+ became more prominent at 3 Hz. Exposure to 4-AP depressed P1 and P3 at 1 Hz, which was reversed by increasing the stimulation frequency--P3 tended to diminish, whereas t1 and t2 were shortened. Theophylline reduced P1 antagonized P2, and shortened t1 and t2 significantly, and a combination of theophylline and 4-AP augmented the effects. Ouabain increased P1 and P2 in a frequency-dependent manner; prolonged t2 at 1 Hz, but shortened t2 at higher frequencies. Verapamil inhibition of Ca2+ channels augmented P1 and t1 and reduced P2 and P3, and the effects on all three parameters were augmented by combined 4-AP/verapamil. We concluded that the post-rest adaptive changes in contractility are a consequence of phasic changes in sarcoplasmic Ca2+ concentration and that such changes reflect an imbalance between the release from and uptake into the sarcoplasmic reticulum of Ca2+ and transsarcolemmal Ca2+ loss.
The likely effect of oral and subcutaneous meperidine on maximal electroshock seizure (MES) in mice was studied. Convulsive current fifty (CC50) was assessed to be 46m A, an electrical pulse causing seizure in 50% of test animals. Doses of 15, 30, 60, or 120 mg/kg meperidine given orally or subcutaneously increased the convulsion threshold of MES as evidenced by a significant dose-dependent reduction of MES below control value (p < .05). An initial hyperactivity reaction that was worsened by noisy and tactile stimuli and tail erection followed by sedation was observed after s.c. injection of 60 or 120 mg/kg meperidine. No significant difference was found between meperidine-induced reductions of control MES values obtained one and two hours after oral doses; the depressed MES values obtained one hour after oral administration of meperidine were significantly different and more powerful than those obtained two hours after s.c. drug administrations (p < .05). Combining previous literature information with the present results, we conclude that such an effect of meperidine can be attributed to cerebellar stimulation.
We studied the renovascular action of adenosine on isolated perfused rat 10 min after drug injections. Adenosine was applied intraarterially as a single bolus injection in logarithmically increasing doses (0.3-30 microg). Adenosine treatment induced a biphasic vascular-response, namely, an initial vasoconstriction followed by a long-lasting vasodilation. Pretreatment with 0.1. 0.3, or 1.0 mM theophylline or quinidine (2 microg/ml) significantly depressed both components of the adenosine response. The vasoconstrictor response to adenosine was not affected by either 0.5 or 1.0 microg/ml dihydroergocristine. whereas the vasodilatory response was dose-dependently reduced. The biphasic response to adenosine was markedly depressed by 10 microg/ml indomethacin and was augmented by combining this agent with quinidine. We studied the possible roles of the platelet activating factor (PAF) and nitric oxide-cGMP systems in the renovascular actions of adenosine. Tebokan (a PAF antagonist) antagonized both components of the response, but methylene blue (MM) reduced only the pressory part Electron-microscopic examination of kidneys exposed for 15 min to MM showed some acute degenerative alterations and constriction in the glomeruli. From these findings, we conclude that the P1/A1, and P2x purinoceptors, the prostaglandins, PAF, and the NO-cGMP systems have a share in the renovascular actions of adenosine.
Induction of cardiac contractures by 4-AP in Ca 2+ -free medium implied the involvement of SR and PLC-IP 3 cascade. Thus, the role of PLC-IP 3 cascade against contractile actions of 4-AP in electrically-driven rat atrial and diaphragmatic strips were studied both in the presence, and absence of Ca 2+ using neomycin, a PLC inhibitor, and heparin, an IP 3 -R antagonist. 4-AP was applied cumulatively in logarithmically increasing concentrations in the range of 1-16µg/ml, and the preparations were treated with neomycin (400µM) or heparin (400µg/ml) for 3min prior to 4-AP injection. Post-rest potentiation in atrial strips was obtained by interruption of stimulation for 30min. 4-AP caused biphasic alteration in twitch amplitudes, as initially increased up to 16mM and then depressed due to contracture development, which were not affected significantly by neomycin and heparin. Both atrial and denervated diaphragmatic strips challenged to 4-AP in the presence and absence of Ca 2+ developed dose dependent contractures which were significantly antagonized both by neomycin and heparin (p<0.05). Post-rest first contractions in controls were found to be reduced by 2min exposure to 4mM 4-AP and augmented by 3min exposure to heparin alone. 4-AP responses in the presence of neomycin and heparin were significantly higher than with those only treated with 4-AP alone and lesser than controls. Because of the fact that 4-AP inducing contracture in Ca 2+ -free medium, Ca 2+ causing contracture should be of SR in origin. Depending on these results, it was concluded that activation of PLC-IP 3 cascade by 4-AP is involved in the mediation of contracture and contractile actions of this molecule.
We studied the interaction of ondansetron with positive inotropic agents, including serotonin (5-hydroxytryptophane, 5-HT), noradrenaline, 4-aminopyridine (4-AP), calcium chloride, or with reserpine in isolated electrically driven rat atria. Concentrations of 5-HT ranging from 1 to 64 microg/ml increased atrial contractions in a dose-dependent manner. The inotropic effect of 5-HT in the right atria appeared to be weaker than that in the left atria. Ondansetron (30 microg/ml) depressed the positive inotropic effect of lower 5-HT concentrations . This effect was thought to be due to the local anesthetic action of ondansetron or its agonistic interaction with inhibitory imidazoline receptors on the sympathetic nerve endings that reduce noradrenaline release. The positive inotropic effect of 5-HT was abolished almost completely by cyproheptadine (2 microg/ml) and was reversed only partially by pretreatment with reserpine (1 or 3 mg/kg). This result was considered as evidence for the participation of pre- and post-junctional 5-HT2A receptors and the involvement of the sympathetic nervous system in the positive inotropic action of 5-HT in rat atria. Experiments with atropine (1 microg/ml) in atria from reserpine-pretreated rats revealed that the parasympathetic component of the autonomic nervous system is not involved in the inotropic action of 5-HT. Ondansetron (30 microg/ml) tended to increase the positive inotropic effects of noradrenaline, 4-AP, and calcium chloride, which were partially significant at certain concentrations. This result might be due to the activation of both pre- and post-junctional 5-HT2A receptors or due to the inhibition of noradrenaline reuptake into the sympathetic nerve endings through the activation of imidazoline receptors. From these findings, we conclude that the positive inotropic effect of 5-HT in the electrically driven rat atria seems to be mediated primarily by its interaction with 5-HT2A receptors, which are likely to be found on the pre- and post-junctional structures. Other mechanisms that might be involved in this relation are also discussed.
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