Cardiovascular effects of GABA, GABA-aminotransferase inhibitors and valproic acid following systemic administration in rats, cats and dogs: pharmacological approach to localize the site of action.
The cardiovascular effects of GABA, sodium valproate (VPA) and inhibitors of GABA-aminotransferase (GABA-T), namely aminooxyacetic acid, gabaculine, gamma-acetylenic GABA, gamma-vinyl GABA and ethanolamine-O-sulphate (EOS), were studied in anesthetized rats, cats and dogs. All compounds were administered intravenously in dose levels previously shown as anticonvulsant active. In rats and cats, GABA (100-1000 mg/kg) caused a sustained fall of blood pressure and heart rate. A similar reaction was observed in dogs following maintenance infusion of the amino acid. The prolonged cardiovascular depression in response to GABA could be attenuated by subsequent administration of picrotoxin and bicuculline as well as by alpha-methyltyrosine, corynanthine, chlorpromazine and tripelennamine. Phentolamine, yohimbine, propranolol, vagotomy, atropine, cyproheptadine, apomorphine and haloperidol did not antagonize the cardiovascular effects of GABA. Administration of GABA-T inhibitors provoked prolonged hypotension and bradycardia, which could be partially counteracted by picrotoxin, bicuculline and, except in the case of EOS, by chlorpromazine. VPA, in high doses (300-400 mg/kg) exerted similar cardiovascular effects in rats as observed with GABA and GABA-T inhibitors. The prolonged cardiovascular depression caused by VPA could be counteracted by bicuculline and partially by chlorpromazine. Apomorphine led to a considerable potentiation of the effects of VPA. It is concluded that GABA, GABA-T inhibitors and VPA may induce cardiovascular depression at least in part by activation of GABA receptors and that the response is mediated predominantly by the central adrenergic system. Some indication was found that an interaction with peripheral histamine contributes to the cardiovascular effects of GABA.
D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors*; D000480:Alkynes; D000614:Aminocaproates / Q000494:pharmacology; D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002415:Cats; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D004285:Dogs; D004983:Ethanolamines / Q000494:pharmacology; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D000637:Transaminases / Q000037:antagonists & inhibitors*; D014635:Valproic Acid / Q000494:pharmacology*; D020888:Vigabatrin; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D000480:Alkynes; D000614:Aminocaproates; D003509:Cyclohexanecarboxylic Acids; D004983:Ethanolamines; D000625:Aminooxyacetic Acid; C012987:gabaculine; D005680:gamma-Aminobutyric Acid; C013785:4-amino-5-hexynoic acid; D014635:Valproic Acid; C020619:ethanolamine O-sulfate; D000637:Transaminases; D000612:4-Aminobutyrate Transaminase; D020888:Vigabatrin