RESUMEN
Nodose neurons express sodium currents that can be differentiated based on their sensitivity to tetrodotoxin. Several studies have demonstrated significant differences in voltage-dependence and kinetics of activation and inactivation between tetrodotoxin-sensitive and tetrodotoxin-resistant currents. However, little is known about the slow inactivation. Using whole cell patch-clamp technique fast and slow inactivation of sodium currents were studied in cultured rat nodose neurons. Tetrodotoxin-resistant currents recovered much more rapidly after a 15-ms depolarization than tetrodotoxin-sensitive currents. However, repeated 5-ms depolarizations at 10 Hz induced a cumulative inhibition that was more prolonged in tetrodotoxin-resistant compared to tetrodotoxin-sensitive currents. Consistent with these findings, slow inactivation proceeded more rapidly and was more complete for the tetrodotoxin-resistant than for tetrodotoxin-sensitive currents. While the voltage-dependence of fast inactivation differed significantly between the pharmacologically distinct currents, the voltage-dependence of slow inactivation was similar for both sodium currents. We conclude that slow inactivation of sodium currents can be triggered by trains of brief depolarizations. The resulting prolonged decrease in membrane excitability may contribute to the different patterns of action potential generation observed in primary afferent neurons.
Asunto(s)
Activación del Canal Iónico/fisiología , Neuronas Aferentes/fisiología , Ganglio Nudoso/citología , Canales de Sodio/metabolismo , Sodio/metabolismo , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Animales , Activación del Canal Iónico/efectos de los fármacos , Masculino , Inhibición Neural/fisiología , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-Dawley , Tetrodotoxina/farmacologíaRESUMEN
1. The primary mechanism of activation of baroreceptors is mechanical deformation during vascular stretch. In addition, baroreceptor activity is modulated by ionic mechanisms and by neurohumoral and paracrine factors that act directly on the nerve endings. 2. Ionic mechanisms play a major role in causing baroreceptor activity to decline during a sustained increase in arterial pressure (adaptation) and in the suppression of activity that occurs after pressure returns to basal levels (post-excitatory depression). Activation of a 4-aminopyridine-sensitive K+ channel contributes to adaptation, whereas activation of an electrogenic sodium pump is responsible for post-excitatory depression. 3. Factors released from vascular endothelium exert powerful effects on baroreceptor sensitivity. Prostacyclin increases baroreceptor sensitivity and contributes to baroreceptor activation during vascular stretch. Nitric oxide, endothelin and oxygen-derived free radicals suppress baroreceptor activity particularly at high levels of arterial pressure. The sympathetic neurotransmitter norepinephrine modulates baroreceptor activity: a) indirectly through its vasoconstrictor action, b) directly by binding to alpha-adrenergic receptors on the nerve endings, and c)through release of a cyclooxygenase metabolite, possibly prostacyclin, from endothelium. 4. Endothelial dysfunction contributes to baroreceptor impairment in atherosclerosis and in chronic hypertension. Loss of the excitatory influence of prostacyclin and increased formation of free radicals and possibly endothelin contribute to the baroreceptor dysfunction. Platelets aggregating at sites of endothelial damage in the carotid sinus release a stable diffusible factor that impairs baroreceptor sensitivity. 5. Therapeutic interventions may alter baroreceptor sensitivity through paracrine mechanisms. Treatment of hypertension or atherosclerosis may improve baroreceptor sensitivity by restoring endothelial function. Antiplatelet agents may enhance baroreceptor sensitivity. Antidepressant agents may decrease baroreceptor sensitivity by inhibiting prostacyclin and/or stimulating nitric oxide formation, which may contribute to dysregulation of the circulation in patients treated for depression.
Asunto(s)
Endotelio Vascular/fisiología , Canales Iónicos/fisiología , Presorreceptores/fisiología , 4-Aminopiridina/farmacología , Animales , Arteriosclerosis/fisiopatología , Presión Sanguínea/fisiología , Seno Carotídeo/fisiología , Endotelio Vascular/efectos de los fármacos , Humanos , Hipertensión/fisiopatología , Presorreceptores/efectos de los fármacos , Conejos , ATPasa Intercambiadora de Sodio-Potasio/fisiologíaRESUMEN
1. The primary mechanism of activation of baroreceptors is mechanical deformation during vascular stretch. In addition, baroreceptor activity is modulated by ionic mechanisms and by neurohumoral and paracrine factors that act directly on the nerve endings. 2. Ionic mechanisms play a major role in causing baroreceptor activity to decline during a sustained increase in arterial pressure (adaptation) and in the suppression of activity that occurs after pressure returns to basal levels (post-excitatory depression). Activation of a 4-aminopyridine-sensitive K+ channel contributes to adaptation, whereas activation of an electrogenic sodium pump is responsible for post-excitatory depression. 3. Factors released from vascular endothelium exert powerful effects on baroreceptor sensitivity. Prostacyclin increases baroreceptor sensitivity and contributes to baroreceptor activation during vascular stretch. Nitric oxide, endothelin and oxygen-derived free radicals suppress baroreceptor activity particularly at high levels of arterial pressure. The sympathetic neurotransmitter norepinephrine modulates baroreceptor activity: a) indirectly through its vasoconstrictor action, b) directly by binding to alpha-adrenergic receptors on the nerve endings, and c)through release of a cyclooxygenase metabolite, possibly prostacyclin, from endothelium. 4. Endothelial dysfunction contributes to baroreceptor impairment in atherosclerosis and in chronic hypertension. Loss of the excitatory influence of prostacyclin and increased formation of free radicals and possibly endothelin contribute to the baroreceptor dysfunction. Platelets aggregating at sites of endothelial damage in the carotid sinus release a stable diffusible factor that impairs baroreceptor sensitivity. 5. Therapeutic interventions may alter baroreceptor sensitivity through paracrine mechanisms. Treatment of hypertension or atherosclerosis may improve baroreceptor sensitivity by restoring endothelial function. Antiplatelet agents may enhance baroreceptor sensitivity. Antidepressant agents may decrease baroreceptor sensitivity by inhibiting prostacyclin and/or stimulating nitric oxide formation, which may contribute to dysregulation of the circulation in patients treated for depression.