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A tonic inhibitory mechanism on heat production was studied by microinjecting procaine into various regions of the brain while recording temperature changes of the interscapular brown adipose tissue (IBAT) and rectum in urethane-anesthetized rats at room temperature of 23-25 degrees C. Procaine microinjected bilaterally (10%, 1.0 mu l/site, 1.5 mm to midline) into the midbrain and the upper- to mid-pontine area of the reticular formation increased temperatures of the IBAT and rectum. The highest temperature rise (1.02 +/- 0.11 degrees C for IBAT, 0.64 +/- 0.06 degrees C for rectum) with the shortest onset latency (1.5 +/- 0.3 min for IBAT, 4.6 +/- 1.1 min for rectum) was observed when procaine was injected into the lower midbrain (the area between 6 and 7 mm posterior to the bregma, and 6.5 to 8.5 mm deep from the cortical surface). These regions include the retrorubral field, pedunculopontine tegmental nucleus, and rubrospinal tract. Procaine-induced IBAT and rectal temperature increases were dose-dependent, and reproduced reliably from the same injection site of the same animal. Intravenous indomethacin, a prostaglandin H synthase inhibitor, did not affect procaine-induced temperature rise, and propranolol, a beta-blocker, completely blocked it. These results suggest that microinjected procaine exerts its local anesthetic effect and release a tonic inhibition resulting in a disinhibition-induced temperature increase through the enhanced central sympathetic outflow. They support the hypothesis that a bilateral tonic inhibitory mechanism on heat production exists in the lower midbrain.

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The effects of adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), and adenosine on compound action potentials were investigated in de-sheathed frog-sciatic nerve preparations. ATP and ADP but not adenosine antagonized the inhibitory action of tetrodotoxin (TTX) on nerve conduction. AMP had little or no antagonistic effect on TTX-induced axonal block. ATP was more effective than ADP. The effects of the nucleotides were related to the degree of the TTX-induced inhibition and were more evident where the blockade was more intense. ATP and ADP but not adenosine antagonized the procaine-induced axonal blockade which, in some experiments, was completely reversed by these nucleotides. ATP and ADP were of similar potency. The axonal blockade induced by pentobarbitone was not antagonized by ATP, ADP, AMP or adenosine. The possibility that ATP stimulates a TTX-sensitive sodium channel is discussed.

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The anticonvulsant profile of N-[beta-[4-(beta-phenylethyl)phenyl]-beta-hydroxyethyl]imidazole hydrochloride (denzimol, Rec 15-1533) has been evaluated in mice, rats and rabbits in comparison with some standard antiepileptic drugs. Denzimol suppressed electrically and chemically induced tonic seizures but did not prevent the clonic ones. In mice and rabbits the anticonvulsant activity of denzimol against maximal electroshock seizures was almost equal to that of phenytoin and phenobarbital with more rapid onset of action, whereas in rats the compound resulted in being the most potent and the less toxic one showing a longer duration of anticonvulsant activity than phenytoin. In the maximal pentetrazol seizures test in rats denzimol showed a profile similar to that of phenytoin and carbamazepine, but different from that of barbiturates and benzodiazepines so that it is suggested that its clinical application would be that of "grand mal" and psychomotor type seizures therapy.

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The effect of the adenine nucleotides on procaine-induced conduction block in rats was investigated in vivo and in vitro. Both adenine and cyclic nucleotides significantly shortened the duration of sciatic nerve blocks in rats without affecting the frequency, degree of block or time of onset. Adenosine 5'-triphosphate (ATP) and N6, O2' dibutyryl 3':5'-monophosphate (db-cyclic AMP) were most effective. In isolated sciatic nerve preparations, the adenine nucleotides (ATP, adenosine 5'diphosphate (ADP), adenosine 5'monophosphate (AMP)) rapidly reversed procaine-induced depression of the action potential. These results suggest that local anesthetic effects may be mediated through interference with the physiological functions of the nucleotides.

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The twitch-response enhancing potencies of (the agonists) substance P, bethanechol, 4-aminopyridine and of potassium chloride were compared in the field-stimulated guinea-pig vas deferens. The agonists were tested after the twitching activity of the isolated organ had been reduced to an equal extent by (the antagonists) tetrodotoxin, procaine, magnesium chloride, and by decreased stimulation frequency. Further experiments were performed in the functionally denervated organ. The potencies differed with the type of antagonism of the twitch-response. This pointed at different modes of action and/or sites of mechanism of the response-enhancing compounds. The pharmacological nature of agonists and antagonists as well as the results in the denervated organ indirectly suggested a predominantly neuronal point of mechanism of the agonists. This was most obvious for substance P.

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Anticonvulsant properties of two new derivatives, of phenylsuccinimide, N-morpholinomethyl-3-bromophenyl-succinimide(IL-7) and N-amino-3-bromophenylsuccinimide (IL-16), were studied. It was stated that both compounds have similar acute toxicity and act longer than phensuximide. They are especially active in maximal electroshock seizure (MES) test. Their effectiveness against convulsions produced by pentetrazole is less than that of phensuximide. Their effectiveness against procaine and strychnine is similar, only one of tested compounds has very high potency against strychnine. This compound, IL-16, has also a different pattern of effect-time which is probably due to its different pharmacokinetic behaviour.

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Extracellular and intracellular microelectrode studies were conducted to test the actions and interactions of opiate agonists, antagonists, and procaine on action potentials in frog sartorius muscles. Extracellular studies showed that morphine, methadone, propoxyphene, and procaine all depressed action potential production. Low concentrations of naloxone or naltrexone antagonized the excitability depression produced by the three opiate agonists but not the depression produced by procaine. Intracellular studies revealed that certain concentrations of the opiate agonists produced a biphasic decline in the stimulus-induced increase in sodium conductance (gNa). Naloxone or naltrexone antagonized only the second phase of this decline. These results show that part of the excitability depression produced by opiate agonists is due to an action on opiate drug receptors.

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In experiments on guinea pigs it is shown that a preliminary intraperitoneal administration of monoamine oxidase inhibitors (MAOI) -- transamine (10 mg/kg) or malic acid benzyldihydrazide (50 mg/kg) antagonizes the local anesthetic action of celnovocaine (CC) and novocaine (NC). An analogous effect is also observed following instillation of transamine (a 0.1% solution) and malic acid benzyldihydrazide (a 0.23% solution) into the eye 10 minutes before administration of the anesthetic. Instillation of a 0.1% serotonin creatinine sulphate solution also antagonizes anesthesia produced by CC and NC, while MAOI potentiates the effect of serotonin.

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1. (45)Ca efflux from single barnacle muscle fibres loaded with radio-calcium by microinjection was studied.2. The (45)Ca washout curve consisted of three exponential phases with half-times of 4.8, 12.6 and 111.1 min.3. Removal of external Ca(2+) reduced (45)Ca efflux by 65%. The (45)Ca efflux recovered upon restoring external Ca(2+), the magnitude of the recovery being dependent upon the external Ca(2+) concentration. 10 mM procaine was found to reduce the magnitude of the recovery.4. Removal of external Mg(2+) resulted in a 38% increase in (45)Ca efflux.5. External application of procaine at pH 7.8 caused a dose-dependent inhibition of (45)Ca efflux. The magnitude of the inhibition was reduced in the presence of low external Ca(2+) concentrations. 10 mM procaine at pH 9.3 caused a biphasic effect: inhibition was followed by stimulation.6. Microinjection of 0.5 M procaine caused only inhibition of (45)Ca efflux, whereas microinjection of 1.5 M procaine caused stimulation followed by inhibition. These effects were observed at an external pH of 7.8 and 9.3.7. Injection of 100 mM-EGTA abolished the stimulatory but not the inhibitory effect produced by procaine injection.8. These results are interpreted as indicating that a major fraction of the (45)Ca efflux involves Ca-Ca exchange which is inhibited by the charged form of procaine in a non-competitive manner at the external surface of the muscle fibre. The stimulatory action is attributed to release by procaine of Ca(2+) from internal binding sites.

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