Patricia A. Cragg

The pH of brain extracellular fluid in the cat.

1. The blood supply to the medulla was determined by the injection of indian ink via the vertebral arteries. Virtually the whole medulla was supplied by penetrating vessels from the ventral surface. The highest density of small arterioles and venules was found close to the roots of XII and on the ventrolateral surface.

Early Ghrelin Treatment after Myocardial Infarction Prevents an Increase in Cardiac Sympathetic Tone and Reduces Mortality

Acute myocardial infarction (MI) initiates an increase in cardiac sympathetic nerve activity (CSNA), which ultimately exacerbates chronic cardiac dysfunction. Ghrelin (Ghr), a GH-releasing peptide, is an effective treatment for improving cardiac function in chronic heart failure. Ghr also suppresses renal sympathetic nerve activity (SNA) and, therefore, may have important therapeutic benefits in the early stages of acute MI: by reducing CSNA. In this study we hypothesized that early Ghr administration may prevent an increase in CSNA in the acute phase after MI. CSNA was continuously recorded in urethane-anaesthetized rats before and for 5 h after acute MI (or sham). MI was induced by ligation of the left anterior descending coronary artery. Rats received an injection of either saline or Ghr (150 microg/kg, sc) 1 min, or 2 h, after the infarct. CSNA remained stable during the 5-h recording duration in sham rats. MI induced a maximal 110% increase in SNA, which was prevented in rats that received Ghr 1 min after infarct. When Ghr was injected 2 h after MI (SNA had increased by approximately 85%), SNA decreased to pre-MI activity. Importantly, early Ghr administration significantly reduced the high mortality rate associated with MI (61% mortality in untreated MI rats cf. approximately 23% in Ghr-treated MI rats). These results show that early Ghr treatment prevents the increase in CSNA after MI, which may contribute to the improved chances of survival. Whether these early beneficial effects of Ghr also have long-term benefits for improving cardiac function is an area that requires further investigation.

Interaction of hypoxia and hypercapnia on ventilation, tidal volume and respiratory frequency in the anaesthetized rat

1. Ventilation (V̇E), tidal volume (VT), respiratory frequency (f) and arterial and end‐tidal gas tensions were measured in seventy‐one tracheostomized New Zealand white rats (∼ 405 g) anaesthetized with an initial dose of pentobarbitone followed by repeated small doses to ensure that a weak limb‐withdrawal reflex remained.

One Dose of Ghrelin Prevents the Acute and Sustained Increase in Cardiac Sympathetic Tone after Myocardial Infarction

Acute myocardial infarction (MI) increases sympathetic nerve activity (SNA) to the heart, which exacerbates chronic cardiac deterioration. The hormone ghrelin, if administered soon after an MI, prevents the increase in cardiac SNA and improves early survival prognosis. Whether these early beneficial effects of ghrelin also impact on cardiac function in chronic heart failure has not yet been addressed and thus was the aim of this study. MI was induced in Sprague Dawley rats by ligating the left coronary artery. One bolus of saline (n = 7) or ghrelin (150 μg/kg, sc, n = 9) was administered within 30 min of MI. Two weeks after the infarct (or sham; n = 7), rats were anesthetized and cardiac function was evaluated using a Millar pressure-volume conductance catheter. Cardiac SNA was measured using whole-nerve electrophysiological techniques. Untreated-MI rats had a high mortality rate (50%), evidence of severe cardiac dysfunction (ejection fraction 28%; P < 0.001), and SNA was significantly elevated (102% increase; P = 0.03). In comparison, rats that received a single dose of ghrelin after the MI tended to have a lower mortality rate (25%; P = NS) and no increase in SNA, and cardiac dysfunction was attenuated (ejection fraction of 43%; P = 0.014). This study implicates ghrelin as a potential clinical treatment for acute MI but also highlights the importance of therapeutic intervention in the early stages after acute MI. Moreover, these results uncover an intricate causal relationship between early and chronic changes in the neural control of cardiac function in heart failure.

Changes in pulmonary blood flow distribution in monocrotaline compared with hypoxia-induced models of pulmonary hypertension: assessed using synchrotron radiation.

Background We have previously described anatomical changes in pulmonary blood flow distribution in chronic hypoxic rats, associated with pulmonary arterial hypertension (PAH). Method In this study, we utilized synchrotron radiation microangiography to compare these changes in pulmonary blood flow with a PAH-model induced with monocrotaline (MCT), as the etiology for these two models of PAH is different. Three weeks after a subcutaneous injection of MCT (60 mg/kg) or vehicle (control), Sprague–Dawley rats were anesthetized, and microangiography was performed on the left lung to assess branching distribution of pulmonary blood flow and changes in vessel diameter during acute (8% O2 for 4 min) hypoxic pulmonary vasoconstriction – before and after sympathetic β-adrenoceptor blockade (propranolol, 2 mg/kg, intravenous). Comparisons were made with chronic hypoxic rats using data previously published. Results We observed that adverse changes in pulmonary blood flow were comparable for both chronic hypoxia and MCT models of PAH. Specifically, the number of opaque third and fourth generation vessels was significantly and equally fewer than that of control rats. The acute hypoxic pulmonary vasoconstriction was not altered in the hypertensive lung, though sympathetic modulation of pulmonary vasoreactivity was enhanced by chronic hypoxia, but not MCT. Conclusion In summary, we have demonstrated comparable adverse changes in pulmonary blood flow for chronic hypoxia and MCT models of PAH. In contrast, modulation of the hypoxic pulmonary vasoconstriction differs between the two PAH models, likely due to the impact that different pathological pathways have on the physiology of the whole organism. Such differences between models of PAH should be considered in future studies.

Is the second carotid body redundant

The carotid bodies (CB) are the main detectors of arterial hypoxia. In the rat, bilateral denervation of these chemoreceptors abolishes most of the hypoxic stimulation of ventilation (Martin-Body et al., 1985; Khrisanapant & Cragg, 1988). The response that remains is attributed to the numerous but tiny carotid-body-like paraganglia found throughout the thorax and abdomen by McDonald & Blewett (1981). A simplistic approach is to expect that each of the inputs from the various chemoreceptors will act together in a purely additive manner. Alternatively there may be redundancy within the multiplicity of chemoafferent inputs.

Effect of surfactant deficiency and surfactant replacement on airway patency in the piglet lung.

We investigated the effect of surfactant deficiency on airway patency and the effectiveness of surfactant replacement as either an instilled liquid bolus, a non-hygroscopic aerosol or a hygroscopic aerosol. Small airway patency was assessed in isolated piglet lungs by passing a continuous flow of gas though a cannulated airway. Occlusion was assessed by measuring increases in pressure in the cannula that resulted from airway obstruction. In surfactant-deficient conditions the amount of airway closure increased approximately three-fold. However, administration of exogenous surfactant as an instilled liquid bolus, non-hygroscopic aerosol or a hygroscopic aerosol decreased airway closure such that it was statistically similar to that recorded prior to induction of surfactant deficiency, although the instilled and hygroscopic aerosol surfactant both appeared superior to the non-hygroscopic aerosol. These experiments showed that pulmonary surfactant does have a role in maintaining airway patency and that airway closure induced by surfactant deficiency could be reduced by administration of surfactant in any of the aforementioned forms.

Role of Carotid Bodies in the Guinea-Pig

Guinea-pigs have a normal, possibly accentuated, hyperventilatory response to hypercapnia whereas that to hypoxia is delayed and extremely blunted (Blake & Banchero, 1985a,b; Alarie & Stock, 1988; Cragg & Menzies, 1992; Peebles & Cragg, 1995). Although these Guinea-pigs are low altitude dwellers, their breathing responses are typical of small mammals and humans adapted to high altitude (Monge & Leon-Velarde, 1991), where the adaptation is termed phenotypic because it requires prior exposure to long-term hypoxia. As Guinea-pigs originated some centuries ago from the high altitude habitats of South America, it is tempting to ask whether they have retained a genotypic adaptation to high altitude. The mechanism(s) responsible for the blunted ventilatory response to hypoxia in other mammals is controversial; much of the evidence indicates involvement of the carotid bodies (Bisgard & Neubauer, 1995).

β1‐Adrenoceptor, but not β2‐adrenoceptor, subtype regulates heart rate in type 2 diabetic rats in vivo

What is the central question of the study? The sympathetic system regulates heart rate via β‐adrenoceptors; this is impaired during diabetes. However, the specific β‐adrenoceptor subtype contributions in heart rate regulation in diabetes in vivo are unknown. What is the main finding and its importance? Telemetric recordings in conscious non‐diabetic and type 2 diabetic rats demonstrated that the β1‐adrenoceptor subtype, and not the β2‐adrenoceptor, regulated the lower resting heart rate and increased β‐adrenoceptor responsiveness in diabetes in vivo. This provides new physiological insight into the dysregulation of heart rate in type 2 diabetes, which is important for improving therapeutic strategies targeting the diabetic chronotropic incompetence.

Exogenous ghrelin accentuates the acute hypoxic ventilatory response after two weeks of chronic hypoxia in conscious rats

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.