Orthostatic intolerance in the heat: are the α-adrenergic receptors the culprit?


Email: hart.emma@mayo.edu

Hyperthermia caused by increased environmental temperatures (passive heat stress) challenges the cardiovascular system to increase cutaneous blood flow, aiding heat dissipation, whilst simultaneously maintaining arterial pressure via elevations in cardiac output. These mechanisms are fundamental in preventing fatal increases in core body temperature. Indeed, during episodes of increased environmental temperatures, such as the Chicago heat wave in July 1995, the rate of cardiovascular-related mortality increases (Kaiser et al. 2007). Furthermore, heat stress diminishes an individual's tolerance to orthostatic stress, especially in different disease states such as hypertension and diabetes. Although a substantial body of literature examining acute cardiovascular adaptations to passive heat stress exists, the mechanisms underlying these reductions in orthostatic tolerance remain poorly understood.

The baroreflex modulates arterial pressure directly through changes in parasympathetic activity directed to the heart and via sympathetic vasoconstrictor activity directed towards the peripheral resistance arteriole. The sympathetic nerves also innervate the heart, thus alterations in sympathetic nerve activity causes additional changes in heart rate and stroke volume (via contractility). During heat stress, impairments at any stage in either baroreflex loop would logically limit the body's ability to cope with large changes in arterial pressure. In this context, diminished end-organ responsiveness results in a reduction in baroreflex function. Consequently, it is possible that the α-adrenergic receptors (mediating sympathetic vasoconstriction) become desensitised during passive heat stress. Certainly, recent studies indicate that in the cutaneous circulation the α-adrenergic receptors become desensitised during whole body heating (Wilson et al. 2002). However, since blood flow to the skeletal muscle is under direct control of the sympathetic baroreflex, it seems pertinent that decreased α-adrenergic sensitivity in the skeletal muscle vasculature may contribute to the increased rate of orthostatic intolerance during heat stress.

In a study in a recent issue of The Journal of Physiology, Keller et al. (2010) investigated whether passive limb heating in men alters α-adrenergic receptor sensitivity in the whole limb or the calf skeletal muscle. This research group has significantly contributed towards much of what we know about cardiovascular regulation during heat stress in healthy humans. They now present evidence that neither α1- nor α2-adrenergic receptor sensitivity is decreased during passive local heat stress in men. In fact, the absolute reduction in femoral vascular conductance in response to α1- and α2-adrenergic stimulation was greater during heat stress vs. normothermia at the highest dose of the specific agonist infused. This suggests that local heat stress might actually increase α-adrenergic receptor sensitivity. However, the interpretation of these data does depend on whether we focus on absolute change or percentage change in femoral vascular conductance (the correct way of expressing changes in blood flow remains an ongoing debate in this area). If we focus on the percentage reduction in blood flow in response to α-adrenergic receptor stimulation, the results indicate that only α2-adrenergic receptor sensitivity is increased. In addition to these findings in the whole limb, Keller et al. also demonstrate that α-adrenergic receptor sensitivity in the vasculature of the skeletal muscle is unchanged during heat stress.

The data of Keller and colleagues have several interesting implications. First, increased skeletal muscle temperature has been suggested to be involved in the sympatholysis evident during exercise. Since α-adrenergic receptor sensitivity was not decreased during local limb heating, this suggests that elevated muscle temperature alone cannot contribute to sympatholysis during exercise. Second, Keller et al. indicate that baseline calf muscle vascular conductance is increased during passive heat stress. This is interesting since (a) other studies indicate that whole body heat stress does not increase skeletal muscle blood flow in the arm (Johnson et al. 1976) and (b) whole body heat stress is usually accompanied by an increase in muscle sympathetic nerve activity. This suggests that sympathetic nerve activity was not elevated during local limb heating and consequently did not restrain increases in skeletal muscle blood flow. Therefore, local and whole body heat stress may cause two distinctly different cardiovascular and neural responses. Potentially, future studies could investigate whether skeletal muscle blood flow in the leg is elevated during whole body heat stress. If skeletal muscle blood flow does indeed increase during passive heat stress, this would add more strain on the cardiovascular system to maintain arterial pressure. Finally, because the α-adrenergic receptors are not desensitised in men during local heat stress, then it seems unlikely that α-adrenergic desensitisation contributes to orthostatic intolerance during whole body heat stress. However, these data can only be attributed to young healthy men. The question regarding whether α-adrenergic desensitisation occurs in the skeletal muscle vasculature of young women remains to be answered. Combined increases in skeletal muscle blood flow and reduced α-adrenergic receptor sensitivity in women might potentially contribute to a marked increase in orthostatic intolerance in women during heat stress.

Exactly what consequences these data have for our understanding of cardiovascular regulation during heat stress in patients with cardiovascular disease is unclear. This is related to the lack of knowledge regarding cardiovascular responses to heat stress, particularly in hypertensive humans. Kellogg et al. (1998) reported that the increase in cutaneous vascular conductance is similar in hypertensive and normotensive humans during whole body heat stress. However, arterial pressure was reduced in hypertensive individuals during hyperthermia. Thus, in hypertensive patients, increases in cardiac output are insufficient to counteract large reductions in peripheral resistance. Alterations in α-adrenergic receptor sensitivity in this population might also impair sympathetic baroreflex regulation. Furthermore, during heat stress cerebral blood flow appears to be reduced in healthy individuals despite no alteration in arterial pressure (this phenomenon might be explained by a decrease in central blood volume). Since there is an acute decrease in arterial pressure during heat stress in hypertensives, this might further compromise cerebral blood flow among these individuals, especially since some evidence in animals and humans suggest that gradual reductions in cerebral blood flow precede the development of hypertension (Cushing's reflex (Paton et al. 2009)). This puts hypertensive patients at an increased risk of suffering from an orthostatic episode during passive heat stress. Future studies should aim to examine whether the baroreflex control of blood pressure and cerebral blood flow is impaired in hypertensive individuals during hyperthermia caused by passive heat stress. Perhaps particular attention should be paid to the role of the α-adrenergic receptors in the skeletal muscle and/or cutaneous vasculature.