Intermittent Hypoxia-Induced Sensitization of Central Chemoreceptors

26 Hypertension elicited by chronic intermittent hypoxia (CIH) is associated with elevated 27 activity of the thoracic sympathetic nerve (tSN) that exhibits an enhanced respiratory modulation 28 reflecting a strengthened interaction between respiratory and sympathetic networks within the 29 brainstem. Expiration is a passive process except for special metabolic conditions as hypercapnia 30 when it becomes active through phasic excitation of abdominal motor nerves (AbN) in late 31 expiration. An increase in CO2 evokes late-expiratory (late-E) discharges phase-locked to phrenic 32 bursts with the frequency increasing quantally as hypercapnia increases. In rats exposed to CIH, 33 the late-E discharges synchronized in AbN and tSN emerge in normocapnia. To elucidate the 34 possible neural mechanisms underlying these phenomena we extended our computational model 35 of the brainstem respiratory network by incorporating a population of pre-sympathetic neurons in 36 the rostral ventrolateral medulla that received inputs from the pons, medullary respiratory 37 compartments and retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG). Our 38 simulations proposed that CIH-conditioning increases the CO2 sensitivity of RTN/pFRG neurons 39 causing a reduction in both the CO2 threshold for emerging the late-E activity in AbN and tSN 40 and the hypocapnic threshold for apnea. Using the in situ rat preparations we confirmed that 41 CIH-conditioned rats under normal conditions exhibit synchronized late-E discharges in AbN 42 and tSN similar to those observed in control rats during hypercapnia. Moreover, the hypocapnic 43 threshold for apnea was significantly lowered in CIH-conditioned rats relative to control rats. We 44 conclude that CIH may sensitize central chemoreception and this significantly contributes to the 45 neural impetus for generation of sympathetic activity and hypertension. 46