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BACKGROUND: Within the lung, sympathetic nerve activity (SNA) has an important role in facilitating pulmonary vasodilation. As SNA is elevated in obesity, we aimed to assess the impact of sympathetic hyper-excitation on pulmonary vascular homeostasis in obesity, and its potential role in ameliorating the severity of pulmonary hypertension (PH); the well-documented 'obesity paradox' phenomenon. METHODS: Zucker obese and lean rats were exposed to normoxia or chronic hypoxia (CH-10% O2) for 2 weeks. Subsequently, pulmonary SNA (pSNA) was recorded (electrophysiology), or the pulmonary microcirculation was visualized using Synchrotron microangiography. Acute hypoxic pulmonary vasoconstriction (HPV) was assessed before and after blockade of ß1-adrenergic receptors (ARs) (atenolol, 3 mg kg(-1)) and ß1+ß2-adrenergic (propranolol, 2 mg kg(-1)). RESULTS: pSNA of normoxic obese rats was higher than lean counterparts (2.4 and 0.5 µV s, respectively). SNA was enhanced following the development of PH in lean rats, but more so in obese rats (1.7 and 6.8 µV s, respectively). The magnitude of HPV was similar for all groups (for example, ~20% constriction of the 200-300 µm vessels). Although ß-blockade did not modify HPV in lean rats, it significantly augmented the HPV in normoxic obese rats (ß1 and ß2 blockade), and more so in obese rats with PH (ß2-blockade alone). Western blots showed, while the expression of pulmonary ß1-ARs was similar for all rats, the expression of ß2-ARs was downregulated in obesity and PH. CONCLUSIONS: This study suggests that sympathetic hyper-excitation in obesity may have an important role in constraining the severity of PH and, thus, contribute in part to the 'obesity paradox' in PH.

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AIM: The peripheral chemoreflex is augmented in heart failure, and it may contribute to sympathoexcitation. This study aimed to investigate both the chemoreflex and the cardiac sympathetic nerve activity in the acute-stage post-myocardial infarction. METHODS: Myocardial infarction was induced in male adult Sprague-Dawley rats by permanent ligation of the left anterior descending coronary artery. Within-animal repeated measure assessment of normoxic and hypoxic ventilation patterns was determined with whole-body plethysmography and compared to sham-operated controls. Cardiac function, morphology and cardiac sympathetic nerve activity were determined 14 days later. RESULTS: Infarction induced increases in normoxic ventilation through increases in tidal volume within 3 days. At the same time points, the hypoxic ventilatory response to short durations (10 min) of hypoxia (8, 10 and 12% inspired O2 ) was blunted. At the end of the experiment (D14), increases in nerve activity, specifically through increased firing rate, and significant cardiac dysfunction (ejection fraction 43%) were observed in myocardial infarction (MI) group. CONCLUSIONS: An augmentation of normoxic ventilation caused by myocardial infarction occurs before the amplification of the hypoxic ventilatory response. It occurs much earlier following myocardial injury than previously demonstrated and may have a role in initiating cardiac sympathoexcitation. The difference in the augmentation of hypoxic response between early and late stages post-myocardial infarction suggest that the initial change in the chemoreflex is an alteration to the operating point of chemoreflex.

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AIM: Ghrelin has been implicated as a modulator of numerous physiological pathways. To date, there have not been any studies describing the role of ghrelin in modulating the chemoreflex control of pulmonary ventilation. Yet the respiratory system impacts, at least to some degree, on virtually all homeostatic control systems. Chronic hypoxia (CH) can cause fundamental changes in ventilatory control, evident by alterations in the acute hypoxia ventilatory response (HVR). As ghrelin plays an important role in metabolic homeostasis, which is tightly linked to ventilatory control, we hypothesized that ghrelin may modulate HVR, especially following CH. METHODS: Whole body plethysmography was used to measure the HVR (8% O(2) for 10 min) in male Sprague-Dawley rats (body wt ∼180-220 g) before and after 14 days of CH (CH=10% O(2)). During CH, rats received daily subcutaneous injections of either saline (control; n=5) or ghrelin (150 µg kg(-1) day(-1); n=5). The HVR was measured in another four rats that had received daily injections of ghrelin during normoxia for 7 days. RESULTS: Ghrelin did not significantly alter basal ventilatory drive or acute HVR in normoxic rats. However, the acute HVR was accentuated following CH in ghrelin-treated rats compared with saline-treated rats. CONCLUSIONS: These results describe the impact that ghrelin has in altering ventilatory control following CH and, although the mechanisms remain to be fully elucidated, provide guidance for future ghrelin-based studies interpreting physiological data indirectly related to the chemoreflex control of pulmonary ventilation.

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AIM: Hypoxia initiates an increase in ventilation (VE) through a cascade of events of which central nitric oxide (NO) has been implicated as an important neuromodulator. There have not been any reports describing the consequences of long-term imbalances in the central NO pathways on the modulation of the acute hypoxic ventilatory response (HVR). Chronic hypoxia (CH) can potentially modify the HVR, and so we hypothesized that central NO may be involved. In this study we describe the long-term role of central NO in the modulation of HVR before and after CH. METHODS: Male Sprague-Dawley rats (BW c. 200-320 g; n = 21) were implanted with an osmotic pump for continuous intracerebroventricular administration of either artificial cerebrospinal fluid (control), Nomega-nitro-L-arginine methyl ester (L-NAME) (150 microg kg(-1) day(-1)) or the NO-donor, 3-[4-morpholinyl]-sydnonimine-hydrochloride (SIN-1) (100 microg kg(-1) day(-1)). The VE response to acute poikilocapnic hypoxia (8% O2 for 20 min) was measured by plethysmography seven days after surgery, in normoxia, and again after 14 days of exposure to CH (CH = 12% O2). RESULTS: The magnitude of the HVR (c. 230% increase in VE) was unaltered by centrally infusing either L-NAME or SIN-1 for 1 week. CH did not modify the HVR, although baseline VE and HVR were shifted downward by L-NAME during CH - because of a reduction in the frequency component. CONCLUSIONS: These results suggest that long-term alterations in central NO levels may not alter the HVR under moderate CH, presumably because of the onset/development of compensatory mechanisms. However, NO appears to be an important component of the HVR following CH.

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