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Exposure to chronic hypoxia (CH) leads to ventilatory acclimatisation to hypoxia (VAH) which is a time-dependent increase in breathing. This study examined the role of the GABAA receptor in establishing VAH. Rats were exposed to CH or control (normoxic) conditions for 10 days during which the GABAA receptor antagonist, bicuculline, was infused systemically or directly into the nucleus of the solitary tract (NTS). Acute breathing trials were then performed to measure resting ventilation and ventilatory chemoreflexes. Systemic administration of bicuculline caused reductions in breathing during acute hypoxia and acute hypercapnia in the control but not the CH animals. Continuous infusion of bicuculline in to the NTS caused a reduction in the acute hypoxic ventilatory response in animals exposed to CH but not in the control animals. The results indicate that exposure to CH alters the GABAA-mediated regulation of acute ventilatory chemoreflexes both in the NTS and elsewhere in the brain.

Exposure to chronic hypoxia (CH) leads to ventilatory acclimatisation to hypoxia (VAH) which is a time-dependent increase in breathing. This study examined the role of the GABAA receptor in establishing VAH. Rats were exposed to CH or control (normoxic) conditions for 10 days during which the GABAA receptor antagonist, bicuculline, was infused systemically or directly into the nucleus of the solitary tract (NTS). Acute breathing trials were then performed to measure resting ventilation and ventilatory chemoreflexes. Systemic administration of bicuculline caused reductions in breathing during acute hypoxia and acute hypercapnia in the control but not the CH animals. Continuous infusion of bicuculline in to the NTS caused a reduction in the acute hypoxic ventilatory response in animals exposed to CH but not in the control animals. The results indicate that exposure to CH alters the GABAA-mediated regulation of acute ventilatory chemoreflexes both in the NTS and elsewhere in the brain.

2. Abstract Adaptation to chronic hypoxia is in addition to ischemic preconditioning one of the two known cardioprotective mechanisms. The precise molecular basis of these processes is still not fully explained. There are some studies that suggest the possible involvement of the adenosinergic signaling system in this adaptation. In this work, we focused on the characterization of the adenosinergic system in the myocardium of rats adapted to two regimens of chronic hypoxia - a protective continuous normobaric hypoxia (CNH) and non-protective intermittent hypoxia (INH/R, 23 h hypoxia and 1 h normoxia). Initially, we compared the total amount of adenosine receptors in samples from different groups of adapted animals. We discovered changes mainly at A2B receptor, which increased at CNH and declined in INH/R. This result suggests the possible involvement of A2B receptors in cardioprotection afforded by adaptation to chronic hypoxia. Furthermore, we investigated the distribution of various types of adenosine receptors and transporters in the plasma membrane of cardiac cells. We observed that A2A and A3 localize in membrane microdomains together with membrane enzyme CD73 that produces adenosine in the extracellular space by degrading AMP. A1 and A2B receptors similarly as nucleoside transporters ENT1, ENT2 and...

The role of lipids and ROS in cardioprotective mechanism of chronic hypoxia Cardiovascular diseases, mainly ischemic heart disease is one of the most frequently cause of morbidity and mortality in developed countries. Therefore effective protection of the heart against ischemia and reperfusion injury is the crucial aim of experimental and clinical cardiology. One of the main streams of cardiovascular research is looking for possibilities of natural heart resistance augmentation. Adaptation to chronic hypoxia is one possibility how to protect the heart against ischemia-reperfusion injury. Chronic hypoxia increases resistance of the myocardium to acute deficiency of oxygen leading to vetricular arrythmias, postischemic contractile dysfunction and necrotic changes in the tissue. Recently, it has been shown that reactive oxygen species (ROS) play an important role in the cardioprotective mechanism of chronic hypoxia. It is known that oxidative stress has a harmful effect in acute ischemia-reperfusion however ROS generated during the adaptation to hypobaric intermittent chronic hypoxia play a role in the induction of cardioprotection. In this study, we demonstrated that adaptation of adult rats to chronic hypoxia increased the activity and protein abundance of manganese superoxide dismutase (MnSOD) in the...

The Bolivian Ornate Tinamou, Nothoprocta ornata, lives higher than 3300 m above sea level and must constantly deal with a restricted availability of atmospheric oxygen, i.e., chronic hypoxia. Interestingly enough, the Ornate Tinamou has a small heart to body ratio, which implies a reduced ability in transporting oxygenated blood to the tissues. In order to increase knowledge about the cardiorespiratory response of the Ornate Tinamou, heart rate (HR) and ventilation frequency (VR) were monitored during resting at 25 °C. The values were compared with those obtained in conditions known to elevate metabolism, i.e., lowered temperature and graded exercise. This was later compared with domestic chickens, Gallus gallus. Results showed a significant increase in HR at 4 °C, 305 ±42 bpm in the Ornate Tinamou when compared with HR at 25°C, 241± 48 bpm (330 ±42bpm and 239 ±32bpm in chicken). A significant increase in VR was only observed in chicken. As expected, with a progressive increase in running speed, a significant increase in HR in both species was observed. At 1,5 km h-1, HR in the Ornate Tinamou was 327 ±5,6 bpm and 342 ±8,5 in chicken. At 3,0 km h -1 HR was 383 ±15 bpm and 404 ±7,9, respectively. However, HR was not significantly higher in the Ornate Tinamou than in chicken, indicating that there must be other physiological adaptations involved in the sufficient oxygen delivery to tissues, e.g. a high blood oxygen affinity or a preference for anaerobic metabolism due to living in a chronic hypoxic environment.

Cardiovascular diseases, particularly acute myocardial infarction, are one of the leading causes of death in developed countries. It is well known that adaptation to chronic intermittent hypobaric hypoxia (IHH) confers long-lasting cardiac protection against acute ischemia/reperfusion injury. Protein kinase C (PKC) appears to play a role in its cardioprotective mechanism since the administration of general PKC inhibitor completely abolished the improvement of ischemic tolerance in IHH hearts. However, the involvement of individual PKC isoforms remains unclear. Therefore, the primary aim of this study was to investigate the potential involvement of PKCδ and PKCε, the most prevalent PKC isoforms in rat heart, in the mechanism of IHH-induced cardioprotection. We showed that IHH up- regulated PKCδ protein in left ventricle, enhanced its phosphorylation on Ser643 and increased its co-localization with markers of mitochondrial and sarcolemmal membranes. PKCδ subcellular redistribution induced by IHH as well as the infarct size-limiting effect of IHH was reversed by acute treatment with PKCδ inhibitor rottlerin. These data support the view that PKCδ plays a significant role in IHH-induced cardioprotection. On the other hand, adaptation to IHH decreased the PKCε total protein level without affecting its...

The goal of this thesis was to discover the influence of adaptation to chronic hypoxia on ischemic tolerance of heart - this experiment was carried out on two different hypertension kinds of laboratory rats. Spontaneously hypertensive rats (SHR) and rats from a conplastic strain SHR/OlaIpcv-mtBN/Crl , whose mitochondrial genome of the SHR strain was replaced with a mitochondrial genome of the normotensive strain Brown Norway, were exposed to continuous normobaric hypoxia (10% O2) for a period of 3 weeks. On the other hand, the control group of rats was kept in normoxia. At the end of the adaptation period, the ischemic tolerance of heart and the mitochondrial aconitase expression were examined. In the case of both hypertensive strains, the chronic hypoxia led to a significant drop in the size of a myocardial infarction and also to a drop in the number of reperfusion arrhythmias. In the case of the SHR strain, the incidence of ischemic arrhythmias decreased. Chronic hypoxia had no impact on the aconitase expression for both analysed strains. This thesis showed that the ischemic tolerance of heart can be enhanced in the case of the SHR strain. On the other hand, the mitochondrial genome of the SHR strain does not seem to play any significant role in protection mechanism. Key words: chronic hypoxia,...

Background: Pulmonary arterial hypertension (PAH) is a devastating disease characterized by increased pulmonary artery pressure, leading to right ventricle hypertrophy and ultimately heart failure and death. Sirtuin 1 (SIRT1) is an NAD+ dependent protein deacetylase that has been strongly implicated as a crucial link between longevity, stress response and maintenance of vascular health. In this thesis, we investigated the role of SIRT1 in the pulmonary vascular hypoxic response and the pathogenesis of pulmonary hypertension (PH) working under the hypothesis that SIRT1 plays a protective role in the pulmonary vasculature and that lack of SIRT1 would lead to worsening of PH in a model of chronic hypoxia (CH). Results: We determined that global SIRT1 knockout or SIRT1 catalytic inactivation resulted in a marked increase in right ventricle pressure and remodeling compared to wildtype mice in CH. Furthermore, hypoxia-induced erythrocytosis and pulmonary vascular remodeling were profoundly increased in both SIRT1 mouse lines. Subsequent molecular assessment revealed that SIRT1 knockout, but not inactivation, led to a significant increase in mRNA levels of hypoxia inducible factor (HIF)-1α and significantly higher activity in hypoxia, leading to elevated lactate dehydrogenase A (LDHA) and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) in the lungs. Interestingly, both knockout and inactivation of SIRT1 enhanced the activity of HIF2α in the hypoxic lungs and kidneys, leading to increased erythropoietin (EPO) and plasminogen activator inhibitor-1 (PAI-1). Moreover, SIRT1 knockout or inactivation was associated with a trend towards hypoxic-independent increases in HIF3α mRNA in the lungs. Prevention of glycolytic shift using dichloroacetate (DCA) did not result in improvement in this model, yet resveratrol (RSV), a SIRT1 activator/mimic, partially prevented PH only in absence of SIRT1 activity. Finally, selective endothelial cell SIRT1 deletion was sufficient to cause worse PH in the CH model. Conclusions: SIRT1 plays a protective role in the hypoxic response through transcriptional and non-transcriptional control of the hypoxia inducible factors, thus protecting against worse hypoxia-induced PH. SIRT1 could be a novel target for future therapies in PAH.

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