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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.

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Perinatal sepsis and inflammation trigger lung and brain injury in preterm infants, and associated apnea of prematurity. We hypothesized that endotoxin exposure in the immature lung would upregulate proinflammatory cytokine mRNA expression in the medulla oblongata and be associated with impaired respiratory control. Lipopolysaccharide (LPS, 0.1 mg/kg) or saline was administered intratracheally to rat pups and medulla oblongatas were harvested for quantifying expression of mRNA for proinflammatory cytokines. LPS-exposure significantly increased medullary mRNA for IL-1β and IL-6, and vagotomy blunted this increase in IL-1β, but not IL-6. Whole-body flow plethysmography revealed that LPS-exposed pups had an attenuated ventilatory response to hypoxia both before and after carotid sinus nerve transection. Immunochemical expression of IL-1β within the nucleus of the solitary tract and area postrema was increased after LPS-exposure. In summary, intratracheal endotoxin-exposure in rat pups is associated with upregulation of proinflammatory cytokines in the medulla oblongata that is vagally-mediated for IL-1β and associated with an impaired hypoxic ventilatory response.