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1 King's College London School of Medicine, Division of Asthma, Allergy and Lung Biology, London SE1 9RT, UK
(Received 10 June 2007;
accepted after revision 22 June 2007; first published online 20 July 2007)
Corresponding author J. P. T. Ward: King's College London School of Medicine, Division of Asthma, Allergy and Lung Biology, London SE1 9RT, UK. Email: jeremy.ward{at}kcl.ac.uk
The initial events that lead to vasoconstriction of the pulmonary vasculature in response to hypoxia (hypoxic pulmonary vasoconstriction; HPV) rather than the vasodilatation commonly seen in the systemic circulation remain fraught with controversy. Whilst there is a wide (but by no means universal) consensus that mitochondria are the ultimate O2 ‘sensors’ for HPV, there is somewhat violent disagreement concerning the signalling moieties and pathways that link them to vasoconstriction. The most contentious area concerns the role of mitochondrial-derived reactive O2 species (ROS), specifically superoxide and the more stable peroxide, the product of superoxide dismutase (SOD). Whilst some maintain that the initial signal for HPV is an hypoxia-induced decrease in mitochondrial ROS generation and a more reduced cellular redox state (the Redox hypothesis), others have proposed the opposite, that HPV is elicited by an increase in ROS generation (reviewed by Ward et al. 2004). However, a more recent hypothesis excludes any role for ROS, proposing instead that an increase in AMP/ATP ratio activates AMP kinase (Evans, 2006). Notably, attempts to measure ROS have fuelled the controversy, since there is no consensus as to what the various probes are measuring or where. Some of the evidence supporting a signalling role for ROS has been gained by use of antioxidants, SOD inhibitors, and exogenous SOD plus catalase (which degrades peroxide; see Fig. 1), but in many such studies, particularly in multicellular preparations, it is difficult to determine whether such agents are acting inside or outside the cell, and intracellular and extracellular ROS have different actions. The study of Hodyc et al. (2007) in this issue provides another twist to the story by investigating the effects of the membrane-permeable and (putatively) intracellular-acting SOD mimetic tempol on the hypoxic pressor response of perfused lungs of rat. Their key findings are that tempol suppresses HPV, and that this is not related to any interaction with nitric oxide or non-specific effect on basal tone. Importantly, tempol did not suppress tone induced by raised [K+], implying that this was not due to a non-specific reduction in vasoreactivity; it did, however, suppress angiotensin II-induced tone, though there is evidence that the signalling cascade for this agonist involves ROS (Hodyc et al. 2007).
The implications of these findings for HPV are not straightforward, except for the obvious and important point that they potentially support a critical role for intracellular superoxide and ROS in HPV, and that any interactions with nitric oxide and basal tone can be discounted. The reason for the lack of straightforwardness is that whether one believes that a rise or fall in ROS is responsible for HPV, it is generally assumed that peroxide is the signalling moiety. As Hodyc et al. (2007) discuss, it could therefore be argued that their results are in keeping with the Redox hypothesis of HPV, which proposes that ROS (peroxide) falls during hypoxia, since tempol would dismute superoxide to peroxide more rapidly, and might therefore prevent this fall and therefore HPV. As they suggest, however, this seems intuitively unlikely, since a key tenet of the Redox hypothesis is that superoxide generation is itself reduced in hypoxia. Moreover, on those grounds one would expect inhibition of SOD to mimic hypoxia and cause vasoconstriction, which it apparently does not (Weissmann et al. 2001). But then why should a SOD mimetic suppress HPV? Taking the results of Hodyc et al. (2007) in isolation, the most obvious interpretation is that superoxide itself acts as the signalling moiety for HPV. Although consistent with the reported suppressant effect of superoxide scavengers and antioxidants on HPV, this is apparently inconsistent with the finding that inhibition of SOD in the same preparation also suppresses HPV (Weissmann et al. 2001). A possible explanation, though perhaps unpalatable to some, is that superoxide and peroxide independently contribute to signalling in HPV (Fig. 1). This is not as outlandish as it may seem, since HPV is known to be a multifactorial phenomenon involving both an elevation in smooth muscle cytosolic [Ca2+] (which has been attributed to peroxide) and Rho kinase-mediated Ca2+ sensitization (Ward et al. 2004); notably superoxide, but not peroxide, has been shown to activate the latter in systemic arteries (Jin et al. 2004).
Anyone reading the literature regarding HPV is rapidly made aware of the complexity of the subject, and in particular the apparently conflicting data concerning the role (or otherwise) of mitochondria and ROS. The study of Hodyc et al. (2007), whilst a welcome addition, unfortunately does not clarify the situation, other than to add weight to the argument that ROS are centrally involved in HPV. Since it does not fit easily with any of the current hypotheses of HPV, it does, however, raise some fundamental questions that might, just might, eventually lead to clarification. One of these is whether the SOD mimetic tempol differentially inhibits the hypoxia-associated Ca2+ sensitization compared with the elevation of cytosolic [Ca2+]; if so, this might imply that superoxide and peroxide have independent signalling roles in HPV. However, first things first! Perhaps the most important point to clarify is whether tempol has as yet undetermined effects unrelated to its action as a SOD mimetic.
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Evans AM (2006). AMP-activated protein kinase underpins hypoxic pulmonary vasoconstriction and carotid body excitation by hypoxia in mammals. Exp Physiol 91, 821–827.
Hodyc D, 
norek M, Brtnick
T & Herget J (2007). Superoxide dismutase mimetic tempol inhibits hypoxic pulmonary vasoconstriction in rats independently of nitric oxide production. Exp Physiol; DOI: 10.1113/expphysiol.2007.037135.
Jin L, Ying Z & Webb RC (2004). Activation of Rho/Rho kinase signaling pathway by reactive oxygen species in rat aorta. Am J Physiol Heart Circ Physiol 287, H1495–H1500.
Ward JP, Snetkov VA & Aaronson PI (2004). Calcium, mitochondria and oxygen sensing in the pulmonary circulation. Cell Calcium 36, 209–220.[CrossRef][Medline]
Weissmann N, Winterhalder S, Nollen M, Voswinckel R, Quanz K, Ghofrani HA, Schermuly RT, Seeger W & Grimminger F (2001). NO and reactive oxygen species are involved in biphasic hypoxic vasoconstriction of isolated rabbit lungs. Am J Physiol Lung Cell Mol Physiol 280, L638–L645.
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