Hypoxia: just say NO?

Blood flow control in the skeletal muscle circulation is a complex balance between vasoconstrictor and vasodilatory mechanisms. This interplay is further complicated in cardiovascular pathology and stressors such as exercise or hypoxia. Specifically, in response to arterial hypoxaemia this balance is challenged by a reflex increase in muscle sympathetic nerve activity. α-Adrenergic responsiveness is preserved during hypoxia; without compensatory vasodilatation, sympathetic constriction will limit blood flow to skeletal muscle vascular beds. To maintain oxygen delivery, the sympathoadrenal response leads to a release of adrenaline from the adrenal glands; β2-mediated vasodilatation and downstream release of nitric oxide may be responsible for up to ∼50% of hypoxic dilatation at rest in humans (Weisbrod et al. 2001). In addition, animal research suggests unique interactions between adenosine, prostaglandins (PGs), and nitric oxide (NO) contribute to β-independent hypoxia-mediated dilatation (Ray et al. 2002). However, in humans adenosine does not appear to be obligatory (Casey et al. 2009) and the relative importance of NO and PG in hypoxic vasodilatation was previously unexplored. In a recent issue of The Journal of Physiology, Markwald and colleagues (2011) explored the question: Are nitric oxide and/or prostaglandins obligatory for hypoxia-mediated dilatation, and do they act synergistically? They looked at this issue from two perspectives: the contribution of NO and/or PG to the transition to hypoxia, and their importance during hypoxia. Whereas this approach introduced potential confounding changes in baseline flow that may make it difficult to interpret the true magnitude of the response, novel relationships between NO, PG and hypoxia were uncovered. On the surface, the authors’ methods appear to replicate previous work (Weisbrod et al. 2001); however Weisbrod et al. only assessed the importance of NO and only to vasodilatation during transition to hypoxia. By not testing the impact of nitric oxide synthase (NOS) inhibition during hypoxia, nor the potentially synergistic and/or compensatory role of vasodilating PGs, the original results were difficult to interpret. That is, what may have been observed as a non-significant independent effect of NO on hypoxic dilatation may actually have been a compensatory vasodilatory response of PGs. Along these lines, Markwald et al. (2011) showed that neither NO nor PG was obligatory for the vasodilator responses from normoxia to hypoxia, confirming previous results in NO (Weisbrod et al. 2001). This raises the question: under single inhibition, does the synthesis of another substance compensate to evoke normal vasodilatation? Novel findings from the current study showed under NOS blockade, this compensatory vasodilator is likely to be PG (and vice versa), as combined inhibition (NO, PG) abolished hypoxic vasodilatory responses during the transition (Markwald et al. 2011). Like previous studies, this approach alone did not assess the relative contribution of these mechanisms during steady-state hypoxia. Markwald and colleagues (2011) addressed this limitation by inhibiting NO and PGs during hypoxia. Using this novel approach, NO appears to be the main dilator during hypoxia, working independent of PGs. Vasodilating PGs do not appear to be obligatory given inhibition of cyclooxygenase (COX) by ketorolac did not have an effect on vasodilatation during hypoxia – that is, until there was a loss of NO. Whereas this is one interpretation of the data, it is important to acknowledge that part of NO-mediated dilatation may be evoked through PG receptors on the endothelium. In either case, these findings highlight the major contribution of NO during hypoxic dilatation and the compensatory nature between NO and PG in vascular control. This new knowledge may be quickly applied to states known for reduced NO bioavailability, such as ageing or cardiovascular disease. Along these lines, the Obese Zucker Rat (OZR) exhibits complete loss of hypoxia-mediated dilatation through NO (Goodwill et al. 2008). As a consequence, the animals increase the reliance on vasodilating prostacyclin for hypoxic dilatation (Goodwill et al. 2008). However, there appears to be a down-side to this compensation; not only is there an increase in PG-mediated dilatation, but also an increase in thromboxane-mediated vasoconstriction (Goodwill et al. 2008). Similarly, research shows an association between ageing and a shift away from PG-mediated dilatation to PG-mediated constriction (Taddei et al. 1997). Due to ketorolac's non-selectivity on the COX enzymes, the relative contribution of the two prostaglandins could not be addressed in the current study, although this balance of COX products may be far more important in disease states. It is also important to remember the current study was conducted under controlled conditions that included immediate inhibition of both adrenergic vasoconstriction (phentolamine) and β2-mediated dilatation (propranolol) (Markwald et al. 2011). Given net blood flow is a variable balance of both constrictor and dilator mechanisms, and that approximately 50% of hypoxic dilatation is β2-mediated (with a significant proportion achieved via NO), findings from the current study are limited in context. For example, little is known regarding what would happen if the order of such control drug infusions were reversed or, more importantly, what happens in real-life situations, when the sympathoadrenal systems are intact. This may be especially complicated in disease states, where increased basal sympathetic nerve activity has the potential to alter α- or β-adrenergic responsiveness. What we do know, thanks to the current study, is that the interplay between vasodilatory mechanisms is complex. This balance is likely to be further complicated when the adrenergic system is intact or sympathetic nerve activity is increased. Without a doubt, the data from Markwald et al. clearly demonstrate that when both NO and PG production are inhibited, the β-independent portion of hypoxic vasodilatation is effectively abolished. How this all plays out with an intact sympathoadrenal response – in health or disease – will certainly be an exciting story to follow.