Changes of 36Cl- flux and 35S-TBPS binding induced by stress and gabaergic drugs.
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Animals↗
Biomedical subjects
M Serra
Publications and source records attributed to M Serra.
Inhibition of rat fetal methionine synthase by nitrous oxide. An in vitro study.
The effect of in vitro exposure to nitrous oxide on rat fetal and maternal methionine synthase activity was investigated. Enzyme solutions were prepared from livers of fetuses and mothers on day 19 of gestation and exposed to air, 50% oxygen or 50% nitrous oxide in oxygen for periods up to 24 h. Normal activity of methionine synthase in the fetus was about 65% of that in the mother. Activity decreased by about 25% over 24 h when the enzyme was incubated at 37 degrees C in the presence of either air or 50% oxygen. Nitrous oxide produced a time-dependent decrease in activity which generally was similar for both fetal and maternal enzyme. After 24 h exposure to nitrous oxide, activity has decreased to 14 and 17% of fetal and maternal control values, respectively.
5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
Halothane metabolism in cirrhotic rats.
A rat model was used to determine whether the metabolism of halothane is changed in the presence of cirrhosis and whether exacerbation of liver dysfunction is correlated with such a change. Cirrhosis was produced by gavaging enzyme-induced male Wistar rats with carbon tetrachloride in corn oil once weekly for 12 weeks. Control rats received corn oil only. After a 3-week period without treatment, blood and urine were collected from each rat for determination of background levels of inorganic fluoride, bromide, and trifluoroacetic acid (halothane metabolites) and for assessment of liver function. Rats were then anesthetized with 1.05% halothane in 50% oxygen for 3 h. Following anesthesia, serial blood and urine samples were taken to monitor halothane metabolism and liver function. No differences were observed between cirrhotic and non-cirrhotic rats in serum levels and urinary excretion of halothane metabolites. However, serum levels of SGOT and SGPT were significantly increased about 1.5-fold in the noncirrhotic group and about 2.5-fold in the cirrhotic group after anesthesia. The increased levels observed in the cirrhotic group were significantly greater than in the noncirrhotic group. The results imply that the exacerbation of liver dysfunction after halothane anesthesia is most likely related to an indirect effect, such as change in liver blood flow, rather than to toxic metabolites.
Animals↗
N-terminal cyclization of a nonsulfated CCK analogue exhibits opioid antagonist activity in vitro.
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Animals↗
Synthesis and biological evaluation of N alpha-hydroxysulfonyl-[Nle28,31]-CCK26-33.
Two analogues of [Nle28,31]-CCK26-33 containing an N-terminal acetyl or N-terminal hydroxysulfonyl moiety were prepared and characterized. Both analogues were equipotent to native CCK26-33 in four bioassays, demonstrating that N-terminal sulfation of CCK26-33 analogues is compatible with full biological activity.
Amylases↗
Phorbol esters alter muscarinic receptor binding and inhibit polyphosphoinositide breakdown in human neuroblastoma (SH-SY5Y) cells.
Many recent reports have indicated that the effect of the phorbol ester tumor promoters is mediated through the Ca2+/phospholipid dependent protein kinase C. We have investigated the effect of two biologically active phorbol esters, 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA) and 4 beta-phorbol 12 beta,13 alpha-didecanoate (beta PDD) on muscarinic agonist binding and receptor-stimulated phosphoinositide breakdown in cultured human neuroblastoma (SH-SY5Y) cells. Preincubation of these cells with phorbol esters significantly reduced the carbachol-stimulated breakdown of inositol phospholipids and caused a decrease of agonist affinity for [3H](-)methyl quinuclidinyl benzilate ([3H](-)MQNB) binding without affecting the affinity of antagonist to the muscarinic receptor. The nontumor promoting 4 alpha-phorbol 12 beta,12 alpha-didecanoate (alpha PDD) was ineffective in our studies. These results suggest that the activation of protein kinase C may play an important role in regulating the muscarinic receptor system.
Atropine↗
Role of cholinergic neurons in the cardiovascular responses evoked by central injection of bradykinin or angiotensin II in conscious rats.
Intracerebroventricular (i.c.v.) injection of bradykinin (0.1-10 micrograms) or angiotensin II (0.01-10 micrograms) in conscious, freely moving rats evoked dose-related increases in arterial pressure. The pressor response to bradykinin (BK) was accompanied by an increase in heart rate while angiotensin II (ANG II) decreased heart rate. Pretreatment with hemicholinium-3 to deplete brain acetylcholine levels produced a choline-reversible blockade of the cardiovascular response to BK. In contrast, the pressor response to ANG II was only weakly inhibited by hemicholinium-3 and the bradycardia was unaffected. Central pretreatment with the nicotinic antagonist, hexamethonium (50 micrograms) was more effective than the muscarinic antagonist atropine (20 micrograms) at blocking the cardiovascular responses to i.c.v. injection of BK. Both blocking agents produced a weaker inhibitory effect on the pressor response to ANG II although no anticholinergic pretreatment significantly inhibited the fall in heart rate. These results are consistent with the possibility of a peptidergic-cholinergic interaction in the central cardiovascular actions of BK and perhaps for a component of the pressor response to ANG II.
Angiotensin II↗
Sedation and sleep induced by high doses of apomorphine after blockade of D-1 receptors by SCH 23390.
The effect of SCH 23390, a selective blocker of D-1 receptors, on apomorphine-induced behavioural and EEG changes was studied in rats. In control rats, a low dose of apomorphine (50 micrograms/kg s.c.) produced sedation associated with EEG synchronization. A high dose of apomorphine (1 mg/kg s.c.) produced stereotypy associated with EEG desynchronization. At the dose of 1 mg/kg i.p., SCH 23390 decreased motor activity but failed to alter the EEG pattern. The administration of either the low or high dose of apomorphine to SCH 23390-treated rats elicited a marked sedative response associated with EEG synchronization. The EEG synchronization produced by apomorphine (50 micrograms/kg) in SCH 23390-treated rats was prevented by (-)-sulpiride (25 mg/kg i.p.), a D-2 receptor blocker. It is concluded that by preventing the excitatory response to apomorphine SCH 23390 discloses the existence of a population of D-2 receptors mediating sedation and sleep.
Animals↗
Changes in the characteristics of low affinity GABA binding sites elicited by Ro15-1788.
3H-GABA binding was studied in cortical membranes from cerebral cortex of handling-habituated and naive rats after the in vitro addition of Ro15-1788. At low concentrations (10(-8), 10(-9) M) Ro15-1788 increased the total number of low affinity 3H-GABA binding sites in brain tissue from naive rats but failed to modify 3H-GABA binding in tissue from handling-habituated ones. On the contrary, Ro15-1788 at higher concentrations (10(-5), 10(-6)M) decreased the total number of low affinity 3H-GABA binding sites in tissue from handling-habituated rats but failed to modify 3H-GABA binding in tissue from naive animals. Ro15-1788 (10(-7)M) failed to modify significantly low affinity 3H-GABA binding in membranes from both naive and handling-habituated rats. However, this concentration abolished the effect of beta-carbolines and diazepam on 3H-GABA binding in membranes from naive and handling-habituated rats, respectively. The changes in the affinity of 3H-GABA binding were inversely related to the changes in the number. The results suggest that: a) the action "in vitro" of Ro15-1788 on low affinity 3H-GABA binding depends from its concentration at the benzodiazepine recognition sites; b) the benzodiazepine recognition site has a modulatory role in the control of the function of GABA-ergic receptor. Our data might explain the conflicting results obtained with this compound "in vivo".
Animals↗
Long term treatment with clonidine during the development of hypertension in spontaneously hypertensive rats.
Chronic administration of clonidine in the drinking water of spontaneously hypertensive (SH) rats from 11 through 17 weeks of age prevented the further development of hypertension in this model. A dosage adjustment (from about 0.1 to 0.5 mg/kg) was required to maintain a stable systolic pressure of about 200 mmHg. After six weeks of treatment clonidine was withheld for 48 hrs during which time blood pressure increased to a level similar to that of untreated controls.
Animals↗
Evidence for the presence of benzodiazepine receptor subclasses in different areas of the human brain.
The kinetic characteristics of [3H]flunitrazepam ([3H]FNT) and [3H]ethyl-beta-carboline-3-carboxylate ([3H]beta-CCE) were compared in three different areas of the human brain. As revealed by the Scatchard plot analysis the total number of binding sites labelled by [3H]beta-CCE was markedly lower than that labelled by [3H]FNT. In fact, only 50% of the binding sites for [3H]FNT were also available for [3H]beta-CCE. This finding indicates that in the cerebral cortex, hippocampus and cerebellum of the human brain at least 50% of the benzodiazepine recognition sites are that of Type II. This conclusion is further supported by the evidence that CL-218872 (5 X 10(-6) M), a specific ligand for Type I benzodiazepine recognition site, inhibited [3H]FNT binding by 50% in membranes from the above brain areas. The results suggest that two distinct types of benzodiazepines recognition sites are present in different areas of the human brain.
Adult↗
Stress and beta-carbolines decrease the density of low affinity GABA binding sites; an effect reversed by diazepam.
Cerebral cortex membranes from rats habituated to manipulations preceding decapitation (habituated rats) had 40% higher GABA binding than membranes from naive animals. Diazepam (5 X 10(-6) M), added to membranes from naive rats, increased GABA binding to the level of habituated rats, but failed to induce any further increase in membranes from the latter animals. Vice versa, beta-carbolines (FG 7142, beta-CCE, DMCM) added to membranes from habituated rats lowered GABA binding to the level of naive animals, but caused no further decrease in the membranes from this last group. Diazepam removed the effect of beta-carbolines in membranes from habituated rats. It is suggested that handling represents a stressful stimulus for naive animals and that stress lowers GABA binding by releasing an endogenous ligand for benzodiazepine receptors possessing similar properties to beta-carbolines. Finally, the results indicate that the emotional status of animals from which brain tissue is obtained should be considered when connections between GABA and benzodiazepine receptors are studied.
Animals↗
Evidence for an involvement of GABA receptors in the mediation of the proconvulsant action of ethyl-beta-carboline-3-carboxylate.
The kinetic characteristics of binding of [3H]-GABA and the pattern of isoniazid-induced convulsions were studied in rats treated with repeated intraventricular injections of ethyl-beta-carboline-3-carboxylate (beta-CCE) (10 micrograms/rat, twice daily for 8 days). Thirty-six hours after the last injection, the total number of binding sites for [3H]-GABA was decreased (25%) in the cerebral cortex and hippocampus. On the other hand, there was no significant difference in the dissociation constant (KD) between beta-CCE and solvent-treated rats. The decrease in binding sites for [3H]-GABA was paralleled by a strong potentiation of the convulsant pattern elicited by isoniazid. The results suggest that the proconvulsant effect elicited by beta-CCE is mediated by the decrease in the total number of binding sites for GABA, secondary to the interaction between beta-CCE and the benzodiazepine receptor coupled to the GABA receptor.
Animals↗
Inhibition of fetal methionine synthase by nitrous oxide.
The activity of the enzyme methionine synthase in fetal and maternal liver was investigated before and after exposure to nitrous oxide. Timed-pregnant rats on day 19 of gestation were exposed to either 10% or 50% nitrous oxide for various times up to 240 min. After exposure, fetal and maternal livers were removed and methionine synthase activity assayed. Normal methionine synthase activity in the fetus was about 50% of that in the mother. Both fetal and maternal methionine synthase activity decreased progressively with increasing time of exposure to nitrous oxide and recovered only slowly after the agent was discontinued.
5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
Foot shock-induced decrease of low affinity GABA receptors in the rat brain: antagonism by diazepam.
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Animals↗
Nitrous oxide inactivates methionine synthetase activity in rat testis.
Methionine synthetase (MS) activity in the brain and liver is decreased following nitrous oxide (N2O) exposure. Since MS is important for DNA synthesis, this interaction would be expected to have the most serious consequences on actively replicating tissue. The authors therefore measured MS activity in rat testes following 1 h exposure to either 10% or 50% N2O. Animals exposed to 10% N2O had a 29% reduction in MS activity, and exposure to 50% N2O caused a 63% reduction in enzyme activity. Testicular MS activity returned to normal by 24-48 h in the 10% exposure group and by 72 h in the 50% exposure group. This biochemical effect on testicular enzyme activity could be the basis for the reported deleterious effects of N2O on spermatogenesis.
5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
beta-Carbolines activate neurons in the substantia nigra pars reticulata: an effect reversed by diazepam and Ro15-1788.
Diazepam (0.5 mg/kg i.v.) was found to inhibit the firing rate of substantia nigra pars reticulata (SN-PR) cells by 50%. In contrast, beta-CCM, at the doses of 125 and 250 micrograms/kg i.v. increased the firing rate by 90 and 150%, respectively, while DMCM produced similar increases at doses of 250 and 500 micrograms/kg i.v. Both beta-carboline-induced excitation and diazepam-induced inhibition were reversed to baseline values by the specific antagonist of benzodiazepine recognition sites, Ro15-1788 (2.0 mg/kg i.v.). Moreover, the stimulant effect of beta-carbolines was also reversed by diazepam (1.0 mg/kg) to about 50% of baseline. The results indicate that beta-carbolines specifically influence the activity of SN-PR cells through a mechanism opposite to that of benzodiazepines themselves, acting on benzodiazepine recognition sites.
Animals↗
Increase of cyclic GMP in cerebellum by methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM).
The intraperitoneal administration of DMCM (0.5-3 mg/kg) produced a dose-related increase in the content of cyclic GMP in the rat cerebellar cortex. The effect of DMCM on cyclic GMP was abolished by pretreatment with benzodiazepine receptor ligands, diazepam and Ro15-1788 and by the GABA agonist muscimol. The results suggest that DMCM increases cerebellar cyclic GMP content through a direct action on benzodiazepine receptors located in the cerebellar cortex. The interaction between DMCM and the GABAergic system associated with benzodiazepine receptors is discussed. Cerebellar cyclic GMP content can be used as a biochemical index to differentiate agonists and antagonists for benzodiazepine receptors.
Animals↗