{'fraction_non_alphanumeric': 0.03162674181932049, 'fraction_numerical': 0.011429466103021762, 'mean_word_length': 5.738396624472574, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Exercise in hypoxic environments: the mechanism remains elusive

Alterations in cardiovascular and respiratory function are extremely important as we ascend to high altitude since the associated hypoxia leads to tachycardia, increased cardiac output and redistribution of blood flow at rest and to a greater extent during exercise (Mirrakhimov & Winslow, 1996). The cardiac output response is mediated primarily by tachycardia and, to a smaller degree, enhanced contractile function and venous return. Exercise challenges the cardiovascular system during acute hypoxia since reduced arterial oxygen alters the function of skeletal muscle, heart and certain regional vascular beds such as pulmonary arteries. 
 
Species-specific cardiovascular responses to exercise in a hypoxic environment that lowers arterial oxygen pressure (↓PO2) are a manifestation of several interactive mechanisms involving neural-humoral, local cardiac and direct vascular control (Fig. 1). In normoxic conditions, chronotropic, ionotropic and vascular responses are a function of altered autonomic outflow from the medullary cardiovascular brainstem centres (Med CV centres) activated by the exercise pressor reflex from muscle afferents (Musc Aff) as well as central command (CC) (Longhurst, 2003). Hypoxia during exercise stimulates arterial chemoreceptors, particularly the carotid bodies (CB), as well as medullary chemoreceptors (Med CR) to increase ventilation (↑VE), which, through a pulmonary stretch receptor (SR) mechanism, opposes peripheral chemoreflex changes in autonomic outflow (Longhurst, 2003). Thus, although hypoxic stimulation of the carotid bodies causes bradycardia and hypotension, this primary reflex is overshadowed by ventilatory responses that produce tachycardia and vasodilatation. Tachypnoea also lowers arterial carbon dioxide (↓PCO2), which, through a central medullary chemoreceptor mechanism, induces bradycardia and vasodilatation. Hypoxia-induced stimulation of aortic bodies (AB) causes tachycardia and vasoconstriction. Reduced arterial oxygen directly relaxes vascular smooth muscle in all circulations, except for the lung. The integrated response to hypoxia includes increases in heart rate, cardiac output and systolic blood pressure, while mean and diastolic arterial pressures remain constant or fall slightly. 
 
 
 
Figure 1 
 
 
 
Exercise enhances sympathetic (Symp) and reduces parasympathetic (Parasymp) outflow to the heart and cardiovascular system. The mechanism underlying the augmented cardiac responses during hypoxic exercise, however, is controversial and constitutes the focus of the careful study by Hopkins et al. (2003) in this issue of The Journal of Physiology. Like previous studies, the authors found that both cardiac output and heart rate increased more rapidly as workload increased during exercise. However, in contrast to previous work suggesting that hypoxia-induced alteration in cardiac function during dynamic exercise is related to altered autonomic function, Hopkins et al. (2003) did not observe an influence of either β-adrenoceptor blockade, i.e. noradrenaline (norepinephrine; NE) action, or cholinergic muscarinic (M) blockade of acetylcholine (ACh) action. Assuming that adequate blockade was achieved (an issue not tested), this study appears to challenge prevailing opinion of the importance of autonomic mechanisms underlying the heart rate and cardiac output responses during hypoxic exercise. Longitudinal assessment of haemodynamic responses and catecholamines by Hopkins et al. (2003) overcomes limitations of previous studies, but the investigation tested the importance of the two efferent branches separately. Since the two branches of the autonomic nervous system (ANS) can compensate for each other during reflex activation (Krasney, 1967), either sympathetic activation or parasympathetic withdrawal alone may be insufficient to produce the augmented cardiac changes associated with hypoxia. Combined β-adrenoceptor and muscarinic blockade would test this possibility. 
 
But, if not the ANS, what then are the mechanisms underlying changes in cardiac function during hypoxic exercise? The authors suggest a role for post-junctional β-adrenoceptors, since these receptors, in addition to their well-known vasoconstrictor function, can mediate inotropic and possibly chronotropic responses through their actions on myocytes and Purkinje fibres (Saitoh et al. 1995), particularly in children and young adults (Tanaka et al. 2001). 
 
Alternatively, enhanced venous return (↑VR) during hypoxic exercise may stimulate an atrial Bainbridge-like sino-atrial (SA) nodal stretch response (arrows in Fig. 1), although the importance of this reflex in humans is controversial (Longhurst, 2003). Variable changes in cardiac volume and filling pressure have been observed depending upon the altitude achieved and the extent of arterial hypoxaemia (Mirrakhimov & Winslow, 1996). Hopkins et al. (2003) did not measure cardiac filling pressures although they did find that compared to the normoxic group stroke volume was increased similarly during exercise in the hypoxic group despite the increase in heart rate and reduced cardiac filling time, suggesting that contractile function and/or venous return were augmented and that enhanced venous return and a Bainbridge-like response may have been present. 
 
Chemical mediators, other than catecholamines also may contribute to the enhanced chronotropic response during hypoxic exercise. For example, endothelin (Endo) released during hypoxia may stimulate the SA node (Mirrakhimov & Winslow, 1996; Ishikawa et al. 1988). Bradykinin (BK) released during hypoxic exercise stimulates spinal afferent systems that may reflexly enhance sympathoadrenal function to augment the chronotropic and maintain inotropic cardiac function (Longhurst, 2003). Although controversial, hypoxia-related increases in adenosine (Aden) likewise may be associated with reflex increases in heart rate (Longhurst, 2003). However, these reflex responses are mediated by increased sympathetic outflow, which Hopkins et al. (2003) suggest is not required for the hypoxia-related cardiac responses. As such, the causes of the augmented cardiac responses to hypoxic exercise will remain a mystery until additional carefully controlled human-based studies can be constructed to explore alternative mechanisms.