Neurohumoral-renal interactions in blood pressure control

This issue of Acta Physiologica includes the first of a series of review articles summarizing the proceedings of the third conference on Neural, Hormonal and Renal Interactions in Blood Pressure Control, held from December 7–10, 2015 in the hill station of Mussoorie (Uttarakhand, India). The first two conferences were held in Samode (Rajasthan) in 2004 (Evans et al. 2005) and Mahabalipuram (Tamil Nadu) in 2008 (May & Evans 2010). The goal of these meetings has been to bring together experts in integrative cardiovascular biology to discuss the central questions that will drive future research in blood pressure control and the pathogenesis of hypertension in the coming decades. But these conferences have all been about more than just the science. They have also provided an opportunity for delegates to experience the rich and diverse culture and warm and hospitable peoples of India. Having experienced the wonders of the deserts of Rajasthan in 2004 and the seaside temples and rich Hindu culture of Mahabalipuram in 2008, we set off for the Gahwali Himalaya in 2015. The scientific programme included 35 oral presentations interspersed by sessions set aside for open discussion. The review articles in Acta Physiologica reflect the range of issues that were discussed in detail. Basically, most cases of hypertension, particularly of essential hypertension, are characterized by elevated peripheral resistance and normal cardiac output. The peripheral resistance vessel dysfunction can be primary or secondary. In the latter case, primary changes in brain or kidney functions may be the culprits providing ‘neurocentric’ and ‘renocentric’ concepts of the aetiology of hypertension. One of the major controversies in the debate between the renocentrics and the neurocentrics has been over the existence of alternative ‘brain baroreflex’ mechanisms, for example reflex control of arterial blood pressure driven by signals from sensors within the central nervous system itself. McBryde et al. discuss the various mechanisms that could underlie the putative ability of the brain to control arterial pressure via the function intracranial mechanoreceptors and chemoreceptors as well as through carotid body chemoreceptors (McBryde et al. 2016). Our understanding of the pathogenesis of hypertension is further complicated by the interactions between mother, placenta and foetus during critical windows in development that ‘programme’ later cardiovascular function in both child and mother (Paauw et al. 2016). Indeed, epigenetic factors render some of these programming effects intergenerational. Paauw et al. review this area and point the way forward to potential interventions that might be capable of ‘reprogramming’ cardiovascular function to reduce the risk of cardiovascular disease (Paauw et al. 2016). Bie and Evans attempt to reconcile the renocentric and neurocentric concepts that dominate our understanding of the pathogenesis of hypertension (Bie & Evans 2016). They identify aspects of these concepts that are at odds with each other, but also the increasing realizations that long-term control of blood pressure, both in normotension and hypertension, must be achieved through interaction between the brain and the kidney, and that essential hypertension sometimes is generated by primarily by the central nervous system, other times primarily by the kidney. Notably, details of specific molecular mechanisms responsible for the development of hypertension presently are available to a much larger extent in the kidney than in the brain. Often renal insufficiency is associated with hypertension due to dysfunction of the neurohumoral mechanisms of cardiovascular control. Underwood et al. (2016) focus on changes in neural activity driven by uraemic toxins via superoxide/nitric oxide imbalance and low-grade inflammation, and provide preliminary data in a rat model indicating augmented superoxide production within the hypothalamic paraventricular nucleus as a possible mediator of neurohumoral dysfunction. They suggest that this is but one example of mechanisms by which the uraemic state sensitizes CNS to sympathoexcitatory factors including renal afferent nerve inputs to the CNS and angiotensin II by the way of recruiting convergent superoxide-dependent and pro-inflammatory pathways. New targets for modulation of renal function, and thus cardiovascular function, continue to be identified. These include the inward rectifying potassium channels Kir4.1 and Kir5.1 (Palygin et al. 2016) which in the distal nephron appear to be critical elements of the regulation of the activity of the electroneutral sodium chloride cotransporter (NCC) and thus the interaction between NCC, the epithelial sodium channel (ENaC) and the renal outer medullary potassium channel (ROMK) in the physiological control of potassium excretion potentially explaining the effect of potassium intake on blood pressure (Hadchouel et al. 2016). Conductance and resistance vessels react to blood flow. Shihata et al. review the role of hemodynamic forces generated by local blood flow with emphasis on the transition from shear forces, stretch and pressure to endothelial inflammation, specifically highlighting evidence to suggest a role for caveolae/Cav-1 in these processes (Shihata et al. 2016). They conclude that although caveolae seem to play a major role, there is still a large gap in our knowledge regarding the details of endothelial transduction particularly with regard to the possible involvement of other transducers and to the nature of the intracellular pathways. By definition, essential hypertension is a diagnosis of exclusion, that is increased blood pressure without any apparent reason, calling for replacement by mechanistic explanations and strategies for specific treatments. The discussions at the meeting underlined the complexity of these tasks and the inadequacy of current concepts. Kidney or brain malfunctions as well as resistance vessel dysfunction may be primary perturbations in individual cases, but none of these three aetiologies seems to prevail. Appropriate interaction between quantitative studies not least of patients seems to be required for true progress which probably will include new avenues of communication between the brain and the kidney and vice versa. One of the highlights of the meeting in Mussoorie was a series of four pre-dinner lectures by notable Gahwali locals. We heard from Dr Rajesh Singh of the Garhwal Community Development and Welfare Society. Dr Singh and his wife Rajkumari Singh have run a charitable hospital in the hill station of Chamba for more than 20 years. They provide the sole medical service in the Tehri Garwhal area, so were able to describe in graphic detail the challenges of delivery of health care, including surgical services, in this remote part of India. The acclaimed local author Stephen Alter described his spiritual journey to sacred sites within the Himalaya, described in his recent book, Becoming a Mountain (Alter 2014). His journey started as part of his recovery from a brutal attack that he and his wife were subjected to in their home in Mussoorie. Krishnan Kutty, the Directors of the Hanifl Centre for Outdoor Education and Environmental Study, described his successful efforts to save the life of one of the members of an expedition he led to Banderpunch (20 800 feet), who suffered extreme altitude sickness. Finally, we heard from Dr Sejal Worah, Director of Programmes for the World Wildlife Fund India. She described the monumental challenges of sustainable development in India, presenting a message of hope for the future of the world's most populous country. The authors have no relevant conflict of interests. The conference organizers are very grateful to the following organizations for generous sponsorship: Millar Inc., Data Sciences International, and Somnomedics GmbH.