Rebuttal from Lena Lavie and Peretz Lavie

By arguing that only sympathetic activity is responsible for cardiovascular morbidities in OSAS, Kohler & Stradling (2012) conveniently ignore a vast literature linking SA with oxidative stress. A PubMed search using the terms ‘sympathetic’ and ‘oxidative stress’ in the title/abstract revealed 366 publications. The evidence that ROS initiate SA and regulate sympathetic outflow from autonomic ganglia is overwhelming. Although Kohler and Stradling cited Prabhakar et al. (2009) to support their argument that IH augments chemoreflex-stimulated sympathetic outflow by modulating oxygen sensing in the carotid body, they ignored the fact that the IH-mediated carotid body plasticity requires redox signalling, a fundamental finding indicated in the title. The mechanisms by which IH elevates ROS include activation of various NADPH oxidases, mitochondrial dysfunction, down-regulation of antioxidant enzymes, and AngII-dependent ROS formation resulting in hypertension (Lee & Griendling, 2008). Accordingly, in a double-blind placebo-controlled, randomized, crossover design, subjecting healthy humans to experimental IH increased blood pressure (BP) through activation of type I AngII (AT1) receptors and oxidative stress, and decreased nitric oxide (NO) metabolites. Moreover, treatment with losartan, an AT1 receptor blocker, abolished oxidative stress, improved NO bioavailability and prevented the IH-dependent increase in BP (Foster et al. 2010; Pialoux et al. 2011). Earlier, Mohan et al. (2001) demonstrated that decreased NO bioavailability was responsible for the increased sympathetic activation after 21 days of IH. These findings unequivocally support the involvement of ROS in elevating BP and augmenting sympathetic outflow under IH conditions. Although Kohler and Stradling accepted that ‘laboratory studies may support plausible hypothesis’ they doubted their ‘relevance to clinical medicine’. To support their position they cite failure of some studies to lessen cardiovascular risks by antioxidant treatments, while accepting the success of randomized controlled studies to treat hypertension in OSAS. We disagree with this position. First, although successful CPAP therapy attenuates BP and SA in OSAS, CPAP also attenuates ROS production and oxidative stress. Second, failure of clinical trials with antioxidants treatment to prevent cardiovascular events emphasizes the importance of laboratory studies to understand the complexity of various ROS sources, their intra/extracellular sites of action and their interactions with other ROS to promote cardiovascular diseases. Intakes of non-specific antioxidants, such as vitamin E, do not neutralize all ROS and cannot reverse oxidative stress in vivo. Furthermore, because of the heterogeneity of ROS sources and the polymorphism of the enzymes producing them, decreased concentrations in a particular ROS by an antioxidant do not imply that all other types of ROS will be abolished. Therefore, inhibiting the systems producing ROS, rather than scavenging ROS after being formed, is the appropriate approach to prevent cardiovascular sequelae. Targeting NADPH oxidases in vascular disease is an ongoing promising therapeutic methodology, which only laboratory research can provide (Drummond et al. 2011). Thus, it should be recognized that although SA contributes to hypertension and cardiovascular sequelae in OSAS, the dominant role of oxidative stress in activating SA is essential (Lavie & Lavie, 2012). Readers are invited to give their views on this and the accompanying CrossTalk articles in this issue by submitting a brief comment. Comments must not exceed 250 words, with a maximum of six references from peer reviewed publications only. To submit a comment, use the online form available in the centre panel on the HighWire site. If other responses have already been submitted, a ‘view comments’ link will be visible. All comments will be moderated to avoid duplication of responses, and those deemed to add significantly to the discussion will be published online-only as footnotes to the articles. Comments may be posted up to 6 weeks after publication of the article, at which point the discussion will close and authors will be invited to submit a ‘final word’. Questions about this call should be directed to Jerry Dempsey at jdempsey@wisc.edu. To submit a comment, go to: http://jp.physoc.org/letters/submit/jphysiol;590/12/2823 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.