Increased vasopressin transmission from the paraventricular nucleus to the rostral medulla augments cardiorespiratory outflow in chronic intermittent hypoxia-conditioned rats

Abstract

A co-morbidity of sleep apnoea is hypertension associated with elevated sympathetic nerve activity (SNA) which may result from conditioning to chronic intermittent hypoxia (CIH). Our hypothesis is that SNA depends on input to the rostral ventrolateral medulla (RVLM) from neurons in the paraventricular nucleus (PVN) that release arginine vasopressin (AVP) and specifically, that increased SNA evoked by CIH depends on this excitatory input. In two sets of neuroanatomical experiments, we determined if AVP neurons project from the PVN to the RVLM and if arginine vasopressin (V 1A ) receptor expression increases in the RVLM after CIH conditioning (8 h per day for 10 days). In the first set, cholera toxin β subunit (CT-β) was microinjected into the RVLM to retrogradely label the PVN neurons. Immunohistochemical staining demonstrated that 14.6% of CT-β-labelled PVN neurons were double-labelled with AVP. In the second set, sections of the medulla were immunolabelled for V 1A receptors, and the V 1A receptor-expressing cell count was significantly greater in the RVLM (P < 0.01) and in the neighbouring rostral ventral respiratory column (rVRC) from CIH-than from room air (RA)-conditioned rats. In a series of physiological experiments, we determined if blocking V 1A receptors in the medulla would normalize blood pressure in CIH-conditioned animals and attenuate its response to disinhibition of PVN. Blood pressure (BP), heart rate (HR), diaphragm (D EMG ) and genioglossus muscle (GG EMG ) activity were recorded in anaesthetized, ventilated and vagotomized rats. The PVN was disinhibited by microinjecting a GABA A receptor antagonist, bicuculline (BIC, 0.1 nmol), before and after blocking V 1A receptors within the RVLM and rVRC with SR49059 (0.2 nmol). In RA-conditioned rats, disinhibition of the PVN increased BP, HR, minute D EMG and GG EMG activity and these increases were attenuated after blocking V 1A receptors. In CIH-conditioned rats, a significantly greater dose of blocker (0.4 nmol) was required to blunt these physiological responses (P < 0.05). Further, this dose normalized the baseline BP. In summary, AVP released by a subset of PVN neurons modulates cardiorespiratory output via V 1A receptors in the RVLM and rVRC, and increased SNA in CIH-conditioned animals depends on up-regulation of V 1A receptors in the RVLM. Abbreviations Ang II, angiotensin II; AT1, angiotensin 1 receptor; AVP, arginine vasopressin; BIC, bicuculline; CIH, chronic intermittent hypoxia; CT-β, cholera toxin β subunit; D EMG , diaphragm electromyographic recording; ET-1, endothelin 1; FITC, fluorescein isothiocyanate; GG EMG , genioglossal electromyographic recording; HO-1, haem oxygenase 1; HPA, hypothalamic pituitary axis; HR, heart rate; IML, intermediolateral; L-NAME, N G -nitro-L-arginine methyl ester; MAP, mean arterial pressure; MDA, malondialdehyde; nNOS, neuronal nitric oxide synthase; NO, Sadly Musa A. Haxhiu died before this work was published.

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

“…Not only do MnPO neurons heavily innervate the downstream hypothalamic PVN (39,58,59), but virus-mediated expression of a mutant JunD construct that interferes with FosB/⌬FosB transcriptional regulation in MnPO neurons largely prevents the sustained hypertension during normoxia resulting from 7 days of CIH (8). The latter is consistent with results from previous reports (7,9,25,27,53) and of the present study, which indicate that CIH tonically actives the downstream PVN.…”

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.…”

Chronic intermittent hypoxia alters glutamatergic control of sympathetic and respiratory activities in the commissural NTS of rats

“…There is evidence of plastic changes in peripheral (50) and central (16,27,32,35,60) components of chemosensory control of sympathetic and respiratory activities. The latter includes changes in the interaction between sympathetic and respiratory neuronal populations (1,59) and alterations in neurochemical mechanisms in important brain stem areas (30,31). Previous in vitro studies reported that glutamatergic signaling is altered in the NTS of rats submitted to CIH (20,32).…”