Three Days of Chronic Intermittent Hypoxia Induce ß1-Adrenoceptor Dependent Increases in Left Ventricular Contractility.

Sleep apnea is characterized by bouts of chronic intermittent hypoxia (CIH) that elicit sympathetic hyperactivity resulting in residual hypertension. We previously demonstrated that exposure to CIH increases cardiac output and sought to determine if enhanced cardiac contractility manifests prior to hypertension.Male Wistar rats were exposed to cyclical bouts of hypoxia (FiO2 = 0.05 nadir; 90 s) and normoxia (FiO2 = 0.21; 210 s) 8 h/day for 3 days (CIH; n = 6). Control animals (n = 7) were exposed to room air. Data are presented as mean ± SD and were analyzed using unpaired Student t-tests.Three-day exposure to CIH did not elicit changes in heart rate and blood pressure (p > 0.05). However, baseline left ventricular contractility (dP/dtMAX) was significantly increased in CIH-exposed animals compared with control (15300 ± 2002 vs. 12320 ± 2725 mmHg/s; p = 0.025), despite no difference in catecholamine concentrations. Acute ß1-adrenoceptor inhibition reduced contractility in CIH-exposed animals (-7604 ± 1298 vs. -4747 ± 2080 mmHg/s; p = 0.014), to levels equivalent to control, while preserving cardiovascular parameters. Sympathetic ganglion blockade (hexamethonium 25 mg/kg; i.v.) produced equivalent cardiovascular responses suggesting similar global sympathetic activity between groups. Interestingly, gene expression of the ß1-adrenoceptor pathway in cardiac tissue was unchanged.Our results suggest that CIH increases cardiac contractility via ß1-adrenoceptor dependent mechanisms prior to development of global sympathetic hyperactivity suggesting that positive cardiac inotropy contributes to the development of hypertension in CIH-exposed rats.

Manipulation of gut microbiota blunts the ventilatory response to hypercapnia in adult rats.

BACKGROUND: It is increasingly evident that perturbations to the diversity and composition of the gut microbiota have significant consequences for the regulation of integrative physiological systems. There is growing interest in the potential contribution of microbiota-gut-brain signalling to cardiorespiratory control in health and disease. METHODS: In adult male rats, we sought to determine the cardiorespiratory effects of manipulation of the gut microbiota following a 4-week administration of a cocktail of antibiotics. We subsequently explored the effects of administration of faecal microbiota from pooled control (vehicle) rat faeces, given by gavage to vehicle- and antibiotic-treated rats. FINDINGS: Antibiotic intervention depressed the ventilatory response to hypercapnic stress in conscious animals, owing to a reduction in the respiratory frequency response to carbon dioxide. Baseline frequency, respiratory timing variability, and the expression of apnoeas and sighs were normal. Microbiota-depleted rats had decreased systolic blood pressure. Faecal microbiota transfer to vehicle- and antibiotic-treated animals also disrupted the gut microbiota composition, associated with depressed ventilatory responsiveness to hypercapnia. Chronic antibiotic intervention or faecal microbiota transfer both caused significant disruptions to brainstem monoamine neurochemistry, with increased homovanillic acid:dopamine ratio indicative of increased dopamine turnover, which correlated with the abundance of several bacteria of six different phyla. INTERPRETATION: Chronic antibiotic administration and faecal microbiota transfer disrupt gut microbiota, brainstem monoamine concentrations and the ventilatory response to hypercapnia. We suggest that aberrant microbiota-gut-brain axis signalling has a modulatory influence on respiratory behaviour during hypercapnic stress. FUND: Department of Physiology and APC Microbiome Ireland, University College Cork, Ireland.

No evidence in support of a prodromal respiratory control signature in the TgF344-AD rat model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative condition disturbing major brain networks, including those pivotal to the motor control of breathing. The aim of this study was to examine respiratory control in the TgF344-AD transgenic rat model of AD. At 8-11 months of age, basal minute ventilation and ventilatory responsiveness to chemostimulation were equivalent in conscious wild-type (WT) and TgF344-AD rats. Under urethane anesthesia, basal diaphragm and genioglossus EMG activities were similar in WT and TgF344-AD rats. The duration of phenylbiguanide-induced apnoea was significantly shorter in TgF344-AD rats compared with WT. Following bilateral cervical vagotomy, diaphragm and genioglossus EMG responsiveness to chemostimulation were intact in TgF344-AD rats. Amyloid precursor protein C-terminal fragments were elevated in the TgF344-AD brainstem, in the absence of amyloid-ß accumulation or alterations in tau phosphorylation. Brainstem pro-inflammatory cytokine concentrations were not increased in TgF344-AD rats. We conclude that neural control of breathing is preserved in TgF344-AD rats at this stage of the disease.