Journal of Neurophysiology

Intermittent Hypoxia-Induced Sensitization of Central Chemoreceptors Contributes to Sympathetic Nerve Activity during Late Expiration in Rats

Yaroslav I. Molkov, Daniel B Zoccal, Davi J.A. Moraes, Julian F.R. Paton, Benedito H. Machado, Ilya A Rybak

Abstract

Hypertension elicited by chronic intermittent hypoxia (CIH) is associated with elevated activity of the thoracic sympathetic nerve (tSN) that exhibits an enhanced respiratory modulation reflecting a strengthened interaction between respiratory and sympathetic networks within the brainstem. Expiration is a passive process except for special metabolic conditions as hypercapnia when it becomes active through phasic excitation of abdominal motor nerves (AbN) in late expiration. An increase in CO2 evokes late-expiratory (late-E) discharges phase-locked to phrenic bursts with the frequency increasing quantally as hypercapnia increases. In rats exposed to CIH, the late-E discharges synchronized in AbN and tSN emerge in normocapnia. To elucidate the possible neural mechanisms underlying these phenomena we extended our computational model of the brainstem respiratory network by incorporating a population of pre-sympathetic neurons in the rostral ventrolateral medulla that received inputs from the pons, medullary respiratory compartments and retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG). Our simulations proposed that CIH-conditioning increases the CO2 sensitivity of RTN/pFRG neurons causing a reduction in both the CO2 threshold for emerging the late-E activity in AbN and tSN and the hypocapnic threshold for apnea. Using the in situ rat preparations we confirmed that CIH-conditioned rats under normal conditions exhibit synchronized late-E discharges in AbN and tSN similar to those observed in control rats during hypercapnia. Moreover, the hypocapnic threshold for apnea was significantly lowered in CIH-conditioned rats relative to control rats. We conclude that CIH may sensitize central chemoreception and this significantly contributes to the neural impetus for generation of sympathetic activity and hypertension.

  • respiration
  • CIH
  • sympathetic
  • modeling
  • hypertension