Sympathetic dysregulation induced by postnatal intermittent hypoxia.

STUDY OBJECTIVES: Exposure to postnatal chronic intermittent hypoxia (pCIH), as experienced in sleep-disordered breathing, is a risk factor for developing cardiorespiratory diseases in adulthood. pCIH causes respiratory instability and motor dysfunction that persist until adult life. In this study, we investigated the impact of pCIH on the sympathetic control of arterial pressure in rats. METHODS AND RESULTS: Neonate male Holtzman rats (P0-1) were exposed to pCIH (6% O2 for 30 seconds, every 10 minutes, 8 h/day) during their first 10-15 days of life, while control animals were maintained under normoxia. In early adult life (P25-40), freely behaving pCIH animals (n = 13) showed higher baseline arterial pressure levels linked to augmented sympathetic-mediated variability than control animals (n = 12, p < 0.05). Using decerebrated in situ preparations, we found that juvenile pCIH rats exhibited a twofold increase in thoracic sympathetic nerve activity (n = 14) and elevated firing frequency of ventromedullary presympathetic neurons (n = 7) compared to control rats (n = 6-7, p < 0.05). This pCIH-induced sympathetic dysregulation was associated with increased HIF-1α (hypoxia-inducible factor 1 alpha) mRNA expression in catecholaminergic presympathetic neurons (n = 5, p < 0.05). At older age (P90-99), pCIH rats displayed higher arterial pressure levels and larger depressor responses to ganglionic blockade (n = 6-8, p < 0.05), confirming the sympathetic overactivity state. CONCLUSIONS: pCIH facilitates the vasoconstrictor sympathetic drive by mechanisms associated with enhanced firing activity and HIF-1α expression in ventromedullary presympathetic neurons. This excessive sympathetic activity persists until adulthood resulting in high blood pressure levels and variability, which contribute to developing cardiovascular diseases.

Short-Term Sustained Hypoxia Elevates Basal and Hypoxia-Induced Ventilation but Not the Carotid Body Chemoreceptor Activity in Rats.

Exposure to chronic sustained hypoxia (SH), as experienced in high altitudes, elicits an increase in ventilation, named ventilatory acclimatization to hypoxia (VAH). We previously showed that rats exposed to short-term (24 h) SH exhibit enhanced abdominal expiratory motor activity at rest, accompanied by augmented baseline sympathetic vasoconstrictor activity. In the present study, we investigated whether the respiratory and sympathetic changes elicited by short-term SH are accompanied by carotid body chemoreceptor sensitization. Juvenile male Holtzman rats (60-80 g) were exposed to SH (10% O2 for 24 h) or normoxia (control) to examine basal and hypoxic-induced ventilatory parameters in unanesthetized conditions, as well as the sensory response of carotid body chemoreceptors in artificially perfused in situ preparations. Under resting conditions (normoxia/normocapnia), SH rats (n = 12) exhibited higher baseline respiratory frequency, tidal volume, and minute ventilation compared to controls (n = 11, P < 0.05). SH group also showed greater hypoxia ventilatory response than control group (P < 0.05). The in situ preparations of SH rats (n = 8) exhibited augmented baseline expiratory and sympathetic activities under normocapnia, with additional bursts in abdominal and thoracic sympathetic nerves during late expiratory phase that were not seen in controls (n = 8, P < 0.05). Interestingly, basal and potassium cyanide-induced afferent activity of carotid sinus nerve (CSN) was similar between SH and control rats. Our findings indicate that the maintenance of elevated resting ventilation, baseline sympathetic overactivity, and enhanced ventilatory responses to hypoxia in rats exposed to 24 h of SH are not dependent on increased basal and sensorial activity of carotid body chemoreceptors.

Purinergic mechanisms of lateral parabrachial nucleus facilitate sodium depletion-induced NaCl intake.

Purinergic receptors are present in the lateral parabrachial nucleus (LPBN), a pontine structure involved in the control of sodium intake. In the present study, we investigated the effects of α,ß-methyleneadenosine 5'-triphosphate (α,ß-methylene ATP, selective P2X purinergic agonist) alone or combined with pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS, P2X purinergic antagonist) or suramin (non-selective P2 purinergic antagonist) injected into the LPBN on sodium depletion-induced 1.8% NaCl intake. Male Holtzman rats with stainless steel cannulas implanted into the LPBN were used. Sodium depletion was induced by treating rats with the diuretic furosemide (20mg/kg of body weight) followed by 24h of sodium-deficient diet. Bilateral injections of α,ß-methylene ATP (2.0 and 4.0nmol/0.2µl) into the LPBN increased sodium depletion-induced 1.8% NaCl intake (25.3±0.8 and 26.5±0.9ml/120min, respectively, vs. saline: 15.2±1.3ml/120min). PPADS (4nmol/0.2µl) alone into the LPBN did not change 1.8% NaCl intake, however, pretreatment with PPADS into the LPBN abolished the effects of α,ß-methylene ATP on 1.8% NaCl intake (16.9±0.9ml/120min). Suramin (2.0nmol/0.2µl) alone into the LPBN reduced sodium depletion-induced 1.8% NaCl intake (5.7±1.9ml/120min, vs. saline: 15.5±1.1ml/120min), without changing 2% sucrose intake or 24h water deprivation-induced water intake. The combination of suramin and α,ß-methylene ATP into the LPBN produced no change of 1.8% NaCl intake (15.2±1.2ml/120min). The results suggest that purinergic P2 receptor activation in the LPBN facilitates NaCl intake, probably by restraining LPBN mechanisms that inhibit sodium intake.