The guinea-pig isolated atrium as a model system for the central actions of selected CNS stimulant and depressant drugs. Part 1: 3,3-Diakylglutarimide homologues and related drugs.
The 3H-noradrenaline pretreated, spontaneously beating, guinea-pig atrial preparation has been used as a model system to study the presynaptic and postsynaptic actions of selected drugs with stimulant (bemegride, pentylenetetrazol, picrotoxin, strychnine and 4-methyl-4-n-propylpiperidine hydrochloride), depressant (pentobarbitone, hydroxydione, trimethadione, 3-methyl-3-n-alkylglutarimide where alkyl = butyl, amyl or hexyl, 4-methyl-4-n-propylpiperidone-2 hydrochloride, chlordiazepoxide and chlorpromazine) or dual stimulant-depressant (3-methyl-3-n-propylglutarimide and 5-ethyl-5-(1,3-dimethylbutyl) barbiturate and its (+) and (-) enantiomers) actions in the central nervous system of the mouse. 3H-Noradrenaline efflux and force and rate of atrial contraction were used as parameters of atrial function. With the exception of strychnine, picrotoxin and 4-methyl-4-n-propylpiperidine hydrochloride, which appear to act by different central mechanisms, there is good correspondence between the actions of the test drugs on the force of atrial contraction and in the CNS of the mouse. Thus, stimulant drugs increase and depressant drugs decrease the force of atrial contraction, while dual stimulant-depressant drugs in low concentrations increase, and in higher concentrations, decrease the inotropic response. A similarly good correspondence generally exists between mouse and atrium with respect to the relative stimulant and depressant potencies of the test drugs, additive stimulation or depression for pairs of like-acting drugs and 'analepsis' and 'anticonvulsant activity' for drugs with opposed central actions. No such relationships were found using tritium efflux or the chronotropic response as parameters of atrial function. Thus, the guinea-pig atrial preparation appears to be a good model system in which to demonstrate the acute CNS actions and interactions of the majority of the test drugs. Their positive and negative inotropic effects on the atrium have been explained in terms of a membrane phase distribution hypothesis of drug action, and their ability to facilitate or impede, respectively, the movement of Ca2/ across the atrial sarcolemmal membrane. It is proposed that these drugs may act by similar mechanisms at responsive sites in the brainstem reticular formation and related areas in the mouse. These may be primarily excitatory noradrenergic synapses integrated functionally with presynaptic or independent inhibitory GABAergic terminals.
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003292:Convulsants / Q000494:pharmacology; D066298:In Vitro Techniques; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects; D010433:Pentylenetetrazole / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D010881:Piperidones / Q000494:pharmacology*; D013237:Stereoisomerism
D014150:Antipsychotic Agents; D002492:Central Nervous System Depressants; D000697:Central Nervous System Stimulants; D003292:Convulsants; D010880:Piperidines; D010881:Piperidones; D010433:Pentylenetetrazole