Chronic intermittent hypoxia impairs baroreflex control of heart rate but enhances heart rate responses to vagal efferent stimulation in anesthetized mice

Abstract

Z. Chronic intermittent hypoxia impairs baroreflex control of heart rate but enhances heart rate responses to vagal efferent stimulation in anesthetized mice. Am J Physiol Heart Circ Physiol 293: H997-H1006, 2007. First published March 23, 2007; doi:10.1152/ajpheart.01124.2006.-Chronic intermittent hypoxia (CIH) leads to increased sympathetic nerve activity and arterial hypertension. In this study, we tested the hypothesis that CIH impairs baroreflex (BR) control of heart rate (HR) in mice, and that decreased cardiac chronotropic responsiveness to vagal efferent activity contributes to such impairment. C57BL/6J mice were exposed to either room air (RA) or CIH (6-min alternations of 21% O2 and 5.7% O2, 12 h/day) for 90 days. After the treatment period, mice were anesthetized (Avertin) and arterial blood pressure (ABP) was measured from the femoral artery. Mean ABP (MABP) was significantly increased in mice exposed to CIH (98.7 Ϯ 2.5 vs. RA: 78.9 Ϯ 1.4 mmHg, P Ͻ 0.001). CIH increased HR significantly (584.7 Ϯ 8.9 beats/min; RA: 518.2 Ϯ 17.9 beats/min, P Ͻ 0.05). Sustained infusion of phenylephrine (PE) at different doses (0.1-0.4 g/min) significantly increased MABP in both CIH and RA mice, but the ABP-mediated decreases in HR were significantly attenuated in mice exposed to CIH (P Ͻ 0.001). In contrast, decreases in HR in response to electrical stimulation of the left vagus nerve (30 A, 2-ms pulses) were significantly enhanced in mice exposed to CIH compared with RA mice at low frequencies. We conclude that CIH elicits a sustained impairment of baroreflex control of HR in mice. The blunted BR-mediated bradycardia occurs despite enhanced cardiac chronotropic responsiveness to vagal efferent stimulation. This suggests that an afferent and/or a central defect is responsible for the baroreflex impairment following CIH. nucleus ambiguus; obstructive sleep apnea; cardiac ganglia OBSTRUCTIVE SLEEP APNEA (OSA) is associated with substantial morbidities involving the central nervous system and cardiovascular systems (43, 50). Chronic intermittent hypoxia (CIH), which epitomizes one of the characteristics of OSA, has been used as a useful model for OSA (18,41). Regarding the latter, of particular physiological and clinical importance, is baroreflex control of heart rate (HR) (baroreflex sensitivity). Attenuation of baroreflex sensitivity is closely associated with several clinical conditions, including heart failure (16, 25, 44), and is considered as an independent risk factor for cardiac failure and sudden death (22). Therefore, an increased understanding of the physiological and anatomical characteristics of CIHassociated changes of the baroreflex pathways is clearly needed for improved formulation of interventional strategies aimed at reducing the morbidity associated with OSA.Previously, we demonstrated that baroreflex control of the HR was significantly reduced following CIH in Fisher 344 (F344) young adult rats (29). In addition, we showed that vagal cardiac motor neurons in the nucleus ambiguus projecting to cardiac...

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“…These rats were anesthetized with an ip injection of sodium pentobarbital (40 mg·kg -1 ). The surgical procedure was in accordance with previous studies [17][18][19] . Briefly, supplemental doses of anesthetics (0.1 mL of 1% sodium pentobarbital) were administered every 30 min to prevent eye blinking and pedalwithdrawal reflexes.…”

Oxidative Stress in the Carotid Body: Implications for the Cardioventilatory Alterations Induced by Obstructive Sleep Apnea

“…Similarly, animals exposed to intermittent hypoxia show potentiated sympathetic discharges and vascular responses to hypoxia, and develop systemic hypertension (Dick et al, 2007;Fletcher et al, 1992, Greenberg et al, 1999, Zoccal et al, 2008. The autonomic hyperactivity is associated with a reduction of the efficiency of the baroreflex control of heart rate and alterations of heart rate variability in OSA patients (Narkiewicz et al, 1998b, Shiomi et al, 1996 and animals exposed to intermittent hypoxia (Lai et al, 2006;Lin et al, 2007;Rey et al, , 2008. Thus, it is likely that the enhanced sympathetic activity along with the reduction of the baroreflex efficiency would impair the regulation of heart rate and the vasomotor tone of blood vessels eliciting hypertension.…”

“…Thus, it is likely that the enhanced sympathetic activity along with the reduction of the baroreflex efficiency would impair the regulation of heart rate and the vasomotor tone of blood vessels eliciting hypertension. Besides that, it has been found that intermittent hypoxia produces parasympathetic withdrawal, attributed in part to neuronal loss in the vagal ambiguous nucleus (Lin et al, 2007, Yan et al, 2008.…”

Carotid Body Ablation Abrogates Hypertension and Autonomic Alterations Induced by Intermittent Hypoxia in Rats

“…enhances CB chemosensory discharge in normoxia and in response to hypoxia. 12,19,[23][24][25] Furthermore, it has been shown that arterial blood pressure (BP) rapidly increases after 3 to 4 days after CIH exposure, 14,[26][27][28] which is consistent with the time required to potentiate the neural discharges from the CB chemoreceptor during CIH .19,24 Despite all the advances related to the contribution of CB chemoreception to the cardiovascular consequences of CIH, there are no studies showing the role played by the CB chemoreflex once the hypertensive phenotype has become expressed because of CIH exposure. It is worth noting that it is fundamental from a translational perspective because in previous studies performed by Fletcher et al,20 the CBs were removed before the start of CIH and, therefore, before the development of systemic hypertension.…”

“…[8][9][10][11][12][13][14] Although the link between OSA and hypertension is well established, the mechanisms responsible for the autonomic imbalance and the hypertension are not entirely known. CIH produces oxidative stress, inflammation, and endothelial dysfunction that contribute to the hypertension.…”