RESUMO
Injection of the GABA antagonist, bicuculline methiodide into the posterior hypothalamus of rats has been shown to cause marked increases in heart rate and lesser elevations in blood pressure. Allylglycine is a potent inhibitor of the synthetic enzyme for GABA, glutamic acid decarboxylase, only after in vivo biotransformation into its active form, 2-keto-4-pentenoic acid, through a stereospecific amino acid oxidase. The posterior hypothalamus is thought to contain substantial activity only of L-amino acid oxidase. In this study, the stereoisomers of allylglycine were injected into the posterior hypothalamus at a site also shown to be reactive to bicuculline. Injection of L-allylglycine but not D-allylglycine caused substantial increases in heart rate but only slight increases in blood pressure. Injection of the GABA agonist muscimol prior to treatment with L-allylglycine prevented these cardiovascular changes. In another series of experiments, levels of GABA in the posterior hypothalamus and adjacent areas were measured 90 min after unilateral injection of L-allylglycine (12.5 or 25 micrograms), D-allylglycine (25 micrograms) or saline into the posterior hypothalamus. Only L-allylglycine caused increases in heart rate and blood pressure and decreases in levels of GABA. Quantitatively, the increases in heart rate at sacrifice were strongly correlated with the decreases in levels of GABA in the injected posterior hypothalamus (r = -0.94; P less than 0.002) but not in other regions.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Alilglicina/farmacologia , Glicina/análogos & derivados , Frequência Cardíaca/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo , Alilglicina/administração & dosagem , Animais , Pressão Sanguínea/efeitos dos fármacos , Masculino , Ratos , Ratos Endogâmicos , EstereoisomerismoRESUMO
Microinjection of the GABA antagonist bicuculline methiodide 1-25 ng into the posterior hypothalamus of urethane-anesthetized rats evoked sympathetically-mediated increases in heart rate of up to 150 beats/min and modest increases in blood pressure which could be prevented by prior local microinjection of muscimol 50 ng. Microinjection of picrotoxin but not strychnine produced similar effects. These results suggest that a latent sympathoexcitatory mechanism in this region is tonically inhibited by endogenous GABA.
Assuntos
Antagonistas GABAérgicos , Frequência Cardíaca/efeitos dos fármacos , Hipotálamo Posterior/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Anestesia , Animais , Bicuculina/análogos & derivados , Bicuculina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Carbacol/farmacologia , Masculino , Microinjeções , Ratos , Ratos EndogâmicosRESUMO
The hypothesis that endogenous gamma-aminobutyric acid (GABA) suppresses the activity of a latent hypothalamic sympathoexcitatory mechanism was tested by examining the effects of stereotaxic intrahypothalamic microinjection of drugs influencing GABAergic inhibition in anesthetized rats. Bicuculline methiodide (BMI) 1-25 ng, a competitive antagonist at post-synaptic GABA receptors, as well as isoniazid (INH) 35 and 70 micrograms and 3-mercaptopropionic acid (3MP) 0.02 microliter, inhibitors of GABA synthesis, all evoked marked increases in heart rate and modest pressor responses. However, while the effects of BMI appeared almost immediately and peaked within 10 min of injection, changes caused by INH or 3MP developed much more slowly, attaining a maximum 35-40 and 19 min after injection, respectively. The effects of BMI on heart rate were blocked by pretreatment with propranolol 2 mg/kg i.v. or hexamethonium 20 mg/kg i.v. plus atropine 2 mg/kg i.v. and were shown to be highly localized to the posterior hypothalamic nucleus and the adjacent lateral hypothalamus. In addition to the cardiovascular effects, BMI also elicited dose-related increases in respiratory rate which were independent of the heart rate changes although they followed a similar time course. The results support the notion that hypothalamic GABA inhibits a local mechanism capable of generating cardiorespiratory arousal.
Assuntos
Bicuculina/análogos & derivados , Hipotálamo/fisiologia , Sistema Nervoso Simpático/fisiologia , Ácido gama-Aminobutírico/fisiologia , Ácido 3-Mercaptopropiônico/farmacologia , Animais , Bicuculina/farmacologia , Interações Medicamentosas , Hipotálamo/efeitos dos fármacos , Isoniazida/farmacologia , Masculino , Muscimol/farmacologia , Inibição Neural , Ratos , Ratos EndogâmicosRESUMO
Gamma aminobutyric acid (GABA) may represent the single most prevalent neurotransmitter in the mammalian central nervous system. Consequently, it should come as little surprise that the neural circuitry concerned with regulating systemic arterial pressure through the autonomic nervous system utilizes a number of GABAergic inhibitory mechanisms which are anatomically and functionally distinct. This article will, first, summarize findings from our laboratory and other which suggest some of these roles in the mammalian brainstem, and, second, trace a line of research pointing to a particular GABAergic inhibitory mechanism in the forebrain that may have some relevance to experimental and human hypertension.