title: Chronic phenytoin treatment reduces rat carotid body chemosensory responses to acute hypoxia.
abstract: Ventilation is peripherally controlled by afferent activity arising from the peripheral chemoreceptors. In the rat, chemosensory activity is conveyed to the central nervous system through axons of neurons located in the nodose-petrosal-jugular-complex. These neurons have distinct electrophysiological properties, including a persistent Na+current. Acute blockade of this current with phenytoin and other anti-epileptic drugs reduces normoxic chemosensory activity and responses to acute hypoxia. However, because anti-epileptic therapy is prolonged and there is no information on the effects of chronic phenytoin treatment on peripheral chemosensory activity, we studied the effects of long-lasting phenytoin treatment (~25 days) on afferent chemosensory activity, on a wide range of oxygen inspiratory fractions. Osmotic pumps containing dissolved phenytoin (166mg/mL) or vehicle (daily flow: 60µL) were implanted subcutaneously in male adult Sprague Dawley rats. At the end of the treatment, the animals were anesthetized and carotid sinus nerve activity was recorded in vivo. Afferent chemosensory activity in normoxia was not significantly different between control (71.2±2.2Hz) and phenytoin treated (95.4±2.1Hz) rats. In contrast, carotid body chemosensory responses to acute hypoxic challenges were markedly reduced in phenytoin treated rats, specifically in the lowest part of the hypoxic range (control 133.5±18.0Hz vs phenytoin treated 50.2±29.4, at 5% FIO2). Chronic phenytoin treatment severely impaired the chemosensory responses to acute hypoxia, suggesting that long-term phenytoin treatment in patients may result in a reduced peripheral respiratory drive together with a reduction in the respiratory responses to hypoxic challenges.
authors.affiliation: Laboratorio de Fisiología Celular, Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Casilla 653, Santiago, Chile. Electronic address: jalcayag@uchile.cl.
authors.forename: Julio
authors.initials: J
authors.lastname: Alcayaga
authors.affiliation: Laboratorio de Neurobiología, Departamento de Ciencias Fisiológicas, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda 340, Santiago, Chile. Electronic address: mpoyarce@uc.cl.
authors.forename: María P
authors.initials: MP
authors.lastname: Oyarce
authors.affiliation: Unidad de Control Cardiorrespiratorio, Centro de Investigación Biomédica, Universidad Autónoma de Chile. Avda El Llano Subercaseaux 2801, 5° piso, San Miguel, Santiago, Chile. Electronic address: rodrigo.delrio@uautonoma.cl.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Del Rio
keywords: Carotid body; Chemosensory activity; Peripheral ventilatory drive; Petrosal ganglion; Phenytoin