Hyperoxia blunts counterregulation in humans and differential control of the sympathetic nervous system

Wehrwein and colleagues recently reported that the counterregulatory response to insulin-induced hypoglycaemia was reduced significantly during hyperoxia in normal human volunteers (Wehrwein et al. 2010). Specifically, they showed that the increased plasma concentrations of growth hormone, glucagon, adrenaline, cortisol and noradrenaline that occur under the conditions of hyperinsulinaemic hypoglycaemia were suppressed during hyperoxia. The study provides support for the hypothesis that oxygen tension can modulate glucose homeostasis. Studies in animals, such as those cited by Wehrwein et al. as well as those that demonstrate that hypoxia activates adrenomedullary sympathetic nerve activity and adrenal catecholamine release (Biesold et al. 1989), provide additional support. In the subsequent discussion of the potential mechanisms and limitations of their findings, the authors seem to hold the view that the sympathetic outflow operates in a uniform manner. They propose that the suppression of the release of glucagon, adrenaline and noradrenaline may be associated with the observations made by Seals et al. (1991) that hyperoxia suppresses muscle sympathetic activity and by others that muscle sympathetic nerve activity is elevated during hypoglycaemia in man (Fagius et al. 1986). They imply that hyperoxia may induce generalised sympathoinhibition and so suppress the counterregulatory responses. However, recent studies in rats suggest that hypersinsulinaemia per se activates muscle sympathetic activity selectively (Bardgett et al. 2010). Furthermore, we have recently shown that neuroglucoprivation activates a subpopulation of spinally projecting neurones in the rostral ventrolateral medulla (RVLM) (Verberne & Sartor, 2010). The properties of the neurones that were activated by depriving the brain of glucose were fundamentally different from those that are classically regarded as presympathetic vasomotor neurones (Guyenet, 2006). Presympathetic vasomotor neurones are profoundly inhibited by activation of the baroreceptors. In contrast, the neurones that were activated by neuroglucoprivation were baroinsensitive and lacked cardiac rhythm. Wehrwein and colleagues speculated that in experiments by others in which carotid chemoreceptors were denervated, carotid sinus baroreceptors may have also been impaired. While they dismissed these concerns, our studies confirm that RVLM neurones that control adrenomedullary adrenaline secretion are not under arterial baroreceptor control. Taken together, these observations add to an expanding body of evidence that supports the view that the sympathetic outflow to the periphery is differentially controlled (Morrison, 2001). Goldstein, in a recent review, also emphasised that viewing the ‘sympathoadrenal’ system as an integral whole is erroneous (Goldstein, 2010). In summary, Wehrwein and colleagues demonstrate that hyperoxia modulates the counterregulatory response to hypoglycaemia. The underlying mechanism remains unclear and merits further investigation in animal experiments. However, the interpretation of their findings would be enhanced by consideration of the modern view that the sympathetic nervous system operates differentially to orchestrate specific patterns of sympathetic activity that are associated with homeostatic reflexes.