ABSTRACT
In the present study the response of the type I inhibitor activity to isoproterenol was used as an indirect index both of cAMP generation and beta-adrenergic receptor reactivity. Our results suggest that nifedipine, after prolonged treatment, produces subsensitivity in beta-adrenergic transmission without changes in the basal level of cAMP. Administration of isoproterenol produced a dose-dependent decrease of the type I inhibitor activity (an endogenous inhibitor of cAMP-dependent protein kinase, Walsh inhibitor) in the frontal cortex and hippocampus of rats. Prolonged treatment with nifedipine (5 mg kg-1 i.p., twice daily, 21 days) did not change the basal activity of the type I inhibitor, but markedly reduced the response of the type I inhibitor activity to isoproterenol. In the treated animals a significant decrease of the type I inhibitor was seen when isoproterenol was used in much higher doses than in control rats.
Subject(s)
Adrenergic beta-Agonists/pharmacology , Calcium Channel Blockers/pharmacology , Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors , Isoproterenol/pharmacology , Nifedipine/pharmacology , Peptides/drug effects , Peptides/physiology , Adrenergic beta-Antagonists/pharmacology , Animals , Cyclic AMP/metabolism , Dose-Response Relationship, Drug , Drug Interactions , Enzyme Inhibitors/metabolism , Frontal Lobe/drug effects , Frontal Lobe/metabolism , Hippocampus/drug effects , Hippocampus/metabolism , Intercellular Signaling Peptides and Proteins , Male , Peptides/metabolism , Propranolol/pharmacology , Rats , Rats, Wistar , Receptors, Adrenergic, beta/physiology , Stimulation, ChemicalABSTRACT
The response of GABA-modulin to various doses of diazepam and muscimol was used as an index of the sensitivity of central benzodiazepine and GABA-A receptors, respectively. Diazepam and muscimol induced a dose-dependent increase in cytosol GABA-modulin activity in rat nucleus accumbens, hippocampus and cerebellum. A single dose of ethanol (1 g/kg po) potentiated the action of diazepam and muscimol. Prolonged treatment with ethanol (5 g/kg/day for 21 days) did not affect the action of diazepam. In contrast, the effect of muscimol was greatly reduced. In the rats pretreated for 21 days with ethanol five times higher doses of muscimol than in control group were necessary to induce a statistically significant increase of GABA-modulin in the cytosol of the nucleus accumbens, hippocampus and cerebellum. Those results show that a single dose of ethanol enhances GABA-ergic transmission, whereas prolonged treatment with ethanol induces subsensitivity of GABA-A but not benzodiazepine receptors in the limbic system and in cerebellum.
Subject(s)
Brain/drug effects , Carrier Proteins/metabolism , Ethanol/pharmacology , Membrane Proteins , Membrane Transport Proteins , Organic Anion Transporters , Receptors, GABA-A/drug effects , Animals , Brain/metabolism , Diazepam/pharmacology , Dose-Response Relationship, Drug , Drug Synergism , GABA Plasma Membrane Transport Proteins , Injections, Intraperitoneal , Male , Muscimol/pharmacology , Rats , Rats, WistarABSTRACT
The response of an endogenous inhibitor of protein kinases (type II inhibitor) to clonidine was used as an index of sensitivity of central alpha 2-adrenoceptors. Low doses of clonidine (20-50 micrograms/kg) induced an increase in type II inhibitor activity in the nucleus accumbens, hippocampus and in the anterior and posterior hypothalamus by stimulating presynaptic alpha 2-adrenoceptors. Stimulation of postsynaptic alpha 2-adrenoceptors by high doses of clonidine 0.5-1.0 mg/kg resulted in a dose-dependent decrease in type II inhibitor activity. Prolonged treatment with ethanol (5 g/kg/day po for 21 days) greatly reduced the action of high doses of clonidine in all the examined brain areas, suggesting subsensitivity of postsynaptic alpha 2-adrenoceptors lasting for at least 48 h after the last ethanol administration. A single dose of ethanol induced a short lasting subsensitivity of postsynaptic alpha 2-adrenoceptors in the anterior hypothalamus. 12 h after administration of alcohol the response of type II inhibitor to high doses of clonidine in this brain area was the same as in untreated rats.
Subject(s)
Brain/drug effects , Ethanol/pharmacology , Receptors, Adrenergic, alpha/drug effects , Aminophylline/pharmacology , Animals , Brain/metabolism , Brain Stem/drug effects , Brain Stem/metabolism , Clonidine/pharmacology , Dose-Response Relationship, Drug , Hypothalamus/drug effects , Hypothalamus/metabolism , Male , Protein Kinase Inhibitors , Rats , Rats, Inbred Strains , Yohimbine/pharmacologyABSTRACT
Intracerebroventricular injection of 6-hydroxydopamine (6-OH-DA) prevented the development of the lypressin (LVP)-induced hypertension. Administration of 6-OH-DA to hypertensive rats significantly decreased, but did not normalize, blood pressure. A fourteen-day treatment with clonidine, guanethidine, reserpine, dihydralazine, propranolol and furosemide produced a transient decrease in blood pressure in LVP-hypertensive rats. Eight weeks after the withdrawal of hypotensive drugs blood pressure again reached the value corresponding to that in untreated LVP-hypertensive rats.
Subject(s)
Antihypertensive Agents/pharmacology , Hydroxydopamines/pharmacology , Hypertension/physiopathology , Animals , Brain/drug effects , Brain/metabolism , Cerebral Ventricles/drug effects , Cerebral Ventricles/physiology , Hydralazine/pharmacology , Hydroxydopamines/administration & dosage , Hypertension/chemically induced , Injections, Intraventricular , Lypressin , Male , Norepinephrine/metabolism , Oxidopamine , Propranolol/pharmacology , Rats , Rats, Inbred Strains , Reserpine/pharmacologySubject(s)
Azepines/pharmacology , Blood Pressure/drug effects , Morpholines/pharmacology , Motor Activity/drug effects , Oxazocines/pharmacology , Piperazines/pharmacology , Animals , Antihypertensive Agents , Female , Male , Mice , Mice, Inbred BALB C , Piperazine , Propanolamines/pharmacology , Rats , Tranquilizing AgentsABSTRACT
The influence of dihydralazine, propranolol, clonidine, furosemide and reserpine on the clearance of I125 hippurate in rats in alcohol intoxication was investigated. It was found that both in acute and subacute ethanol intoxication the renal blood flow was impeded. Reserpine and propranolol did not significantly change the half time of I125 hippurate in blood both in animals treated and not treated with alcohol. Furosemide prolonged the clearance of hippurate and increased kidney ischemia in alcohol intoxication. Dihydralazine and clonidine increased the effective renal blood flow in normal animals but not in acute and subacute ethanol intoxication.
