Assuntos
Ponte de Artéria Coronária , Oclusão de Enxerto Vascular/etiologia , Hipertrigliceridemia/complicações , Grau de Desobstrução Vascular/fisiologia , Idoso , Feminino , Sobrevivência de Enxerto/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Estatísticas não ParamétricasRESUMO
1. Intracellular electrophysiological techniques were employed to investigate the effects of nicotinic receptor stimulation on rat dorsolateral septal nucleus (DLSN) neurones in a submerged rat brain slice preparation. 2. Acetylcholine (in the presence of the muscarinic antagonist, atropine), nicotine or dimethylphenylpiperazinium (DMPP), applied either by pressure ejection or superfusion, produced predominantly a membrane potential hyperpolarization. 3. Following concentration-response comparisons, DMPP appeared to exhibit fewer desensitizing properties and greater efficacy than nicotine with half-maximal hyperpolarizing responses attainable at 3 and 10 microM, respectively. 4. Pharmacological analyses revealed that the agonist-induced membrane hyperpolarization was sensitive to antagonism by mecamylamine (50-100 microM) and neuronal bungarotoxin (0.2-0.3 microM), but not alpha-bungarotoxin (0.5-1.0 microM), curare (10-50 microM) or dihydro-beta-erythroidine (50-100 microM). 5. Hyperpolarizing responses to DMPP were found to reverse near the equilibrium potential for potassium and were sensitive to changes in extracellular potassium concentration as predicted by the Nernst equation. Under single-electrode voltage clamp, application of DMPP produced an outward current (75-100 pA) which approached reversal at around -88 mV. These findings indicated that the hyperpolarizing response to nicotinic receptor stimulation was mediated by changes in membrane permeability to potassium. 6. DMPP-induced membrane hyperpolarization resulted from a direct action on postsynaptic DLSN neurones since the response persisted under conditions of superfusion with calcium-free/high-magnesium media or tetrodotoxin; both conditions blocked orthodromically induced neurotransmission. The hyperpolarizing response remained unaltered in TTX but was diminished in calcium-free/high-magnesium media. Further studies revealed blockade of the DMPP response following intracellular injection of EGTA. This response was also sensitive to antagonism by various calcium-dependent potassium channel blockers including apamin, barium and tetraethylammonium. 7. Our studies reveal a novel class of CNS nicotinic receptor whose action upon stimulation by an agonist results in a membrane hyperpolarization via a calcium-dependent increase in potassium ion conductance.
Assuntos
Encéfalo/fisiologia , Receptores Nicotínicos/efeitos dos fármacos , Acetilcolina/farmacologia , Animais , Atropina/farmacologia , Bungarotoxinas/farmacologia , Iodeto de Dimetilfenilpiperazina/farmacologia , Relação Dose-Resposta a Droga , Técnicas In Vitro , Masculino , Mecamilamina/farmacologia , Potenciais da Membrana/efeitos dos fármacos , Nicotina/farmacologia , Canais de Potássio/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Tetrodotoxina/farmacologiaRESUMO
Acetylcholine activates both nicotinic and muscarinic receptors in the central nervous system. Although the action of acetylcholine at muscarinic receptor has been well characterized, relatively little is known at the cellular level concerning nicotinic receptor stimulation in brain. Central nicotinic receptors have been implicated in Alzheimer's disease, seizure activity, the generation of slow-wave theta rhythm in the hippocampus and the potential abuse liability of nicotine. At the neuronal level, nicotinic agonists have been most often associated with postsynaptically mediated excitation and membrane depolarization at various sites, including Renshaw spinal motoneurons, locus coeruleus and the medial habenular nucleus. Nicotine acting presynaptically can produce either excitation or inhibition indirectly through the release of endogeneous transmitters or modulators. Whereas a direct inhibitory effect of nicotine has been suggested by one in vivo extracellular recording study in rat cerebellar Purkinje neurons, the mechanism(s) underlying this action is not yet known. We now report our findings obtained using in vitro intracellular methods in a submerged brain slice preparation in which application of nicotinic agonists to rat dorsolateral septal neurons reveal a direct membrane hyperpolarization mediated by an increase in potassium conductance.