Altered sympathetic reflexes and vascular reactivity in rats after exposure to chronic intermittent hypoxia

Abstract

Exposure to chronic intermittent hypoxia (CIH) yields persistent elevations in sympathetic nerve activity (SNA) and mean arterial pressure(MAP)with exaggerated sympathetic chemoreflexes. We examined the impact of CIH upon other sympathoexcitatory reflexes and a potential central mechanism underlying the altered regulation of SNA.Male Sprague-Dawley rats were exposed to CIH for 2 weeks (40 s at 6% O2 every 9 min, 8 h day⁻¹). After exposure to CIH, urethane-anaesthetized, vagotomized, ventilated, paralysed rats had significantly elevated MAP, splanchnic SNA, and rate of phrenic nerve discharge (PND; P<0.05). Elimination of SNA by ganglionic blockade produced a larger fall in MAP in rats exposed to CIH (P<0.05). Like acute hypoxia, stimulation of the sciatic nerve or the nasal mucosa evoked greater increases in SNA after exposure to CIH (P<0.05). In addition, acute hypoxia promoted exaggerated increases in PND amplitude after CIH (P<0.05). In contrast, the nasopharyngeal reflex evoked exaggerated increases in SNA during apnoea. These sympathoexcitatory reflexes are mediated by glutamatergic activation of the rostral ventrolateral medulla (RVLM), and accordingly, microinjections of glutamate into RVLM evoked larger increases in SNA after CIH (P<0.05). Paradoxically, none of these exaggerated acute rises in SNA was accompanied by enhanced pressor responses. Reduced adrenergic vascular reactivity may contribute to the blunted sympathetically mediated pressor responses, because bolus doses of phenylephrine evoked attenuated pressor responses after CIH (P<0.01).These data suggest exposure to CIH facilitates activation of SNA, potentially by changes within the RVLM. However, the exaggerated rises in SNA are not dependent upon stimulation of inspiratory drive. Although elevated SNA may contribute to CIH-induced hypertension, reduced adrenergic vascular reactivity buffers the cardiovascular impact of exaggerated acute rises in SNA.

Chronic intermittent hypoxia increases sympathetic control of blood pressure: role of neuronal activity in the hypothalamic paraventricular nucleus

“…It is presently unclear why this was not observed, but a possible explanation is that intrinsic vasoactive mechanisms in CIHexposed rats do not effectively maintain higher MAP when peripheral vessels are devoid of convergent adrenoceptormediated neurogenic vasomotor tone. Evidence in the literature supports this possibility (29,51,56,61,66). It could also be that the maintenance of higher MAP during ganglionic blockade requires structural remodeling of the vasculature, which has been documented to occur after 14 days of CIH (3) but might not have occurred in the present study after only 7 days of exposure.…”

Obstructive sleep apnea and insight into mechanisms of sympathetic overactivity

“…We believe that the beneficial SNA suppression is the result of both arterial baroreflex-mediated sympathoinhibition and suppression of chemoreceptor-mediated sympathoexcitation (11). Elegant studies by Schreihofer and colleagues have provided electrophysiological evidence that the central interaction between baroreceptor and chemoreceptor signals and the central respiratory modulation of SNA during acute hypoxia occurs in neurons of the caudal ventrolateral medulla (CVLM) (16,17).…”

Medullary Respiratory Network Drives Sympathetic Overactivity and Hypertension in Rats Submitted to Chronic Intermittent Hypoxia

“…41 At the central nervous system level, important alterations in mechanisms of neurotransmission in neuronal groups critically involved with the processing of sympathetic chemoreflex response, such as in the nucleus tractus solitarius, 42,43 the hypothalamus, 44,45 and the ventral medulla, have been reported. [46][47][48] These peripheral and central alterations of chemoreflex pathways induced by CIH contribute to the facilitation of sympathetic chemoreflex response, and it represents an important mechanism of long-lasting excitation of medullary presympathetic neurons in response to new episodes of hypoxia and sustained increase of baseline sympathetic outflow after CIH.…”