POINT:COUNTERPOINTThe dominant contributor to systemic hypertension: chronic activation of the sympathetic nervous system vs. activation of the intrarenal renin-angiotensin systemCounterpoint: Activation of the Intrarenal Renin-Angiotensin System is the Dominant Contributor to Systemic HypertensionL. Gabriel NavarL. Gabriel NavarChair, Department of Physiology Director, Center of Biomedical Research Excellence in Hypertension and Renal Biology Tulane University Health Sciences Center 1430 Tulane Avenue, SL39 New Orleans, LA 70112 e-mail: Published Online:01 Dec 2010https://doi.org/10.1152/japplphysiol.00182.2010aMoreSectionsPDF (137 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations Our discussion regarding the dominant mechanism responsible for hypertension calls to mind the famous poem, “The Blind Men and the Elephant,” by John Godfrey Saxe based on an ancient fable from India. In essence, the blind men described the elephant based on their specific encounter, thus concluding that the elephant was a wall, a spear, a snake, a tree, a fan, or a rope. The lesson is that our interpretations regarding a specific experience are very much dependent on how it presented itself. Because of my predoctoral and postdoctoral training experiences with Arthur Guyton (10) and the fact that my research has been highly focused on the cardinal role of the kidneys in the pathophysiology of hypertension, I support the concept that alterations in kidney function in hypertension are predominantly due to an inappropriately increased activity of the intrarenal renin-angiotensin system (RAS; Refs. 12, 17, 19, 21). While the nervous system is important (4, 5), I contend that chronic activation of the sympathetic nervous system is not the dominant contributor to hypertension, but may also contribute to the activation of the intrarenal RAS that is characteristic of many forms of hypertension (3, 19, 22).Hypertension is characterized by increased peripheral vascular resistance due to increased vascular smooth muscle contractile activity and endothelial dysfunction (15, 29), but it is more likely that the vasculature is the victim rather than the culprit of the injurious processes that occur in hypertension (27). The nervous system regulates blood pressure by integrating signals coming from all parts of the body and sending neural signals to various organ systems. However, there is limited evidence that chronic increases in sympathetic activity serve as the dominant contributor to most forms of hypertension. Because the neurocentric view is being addressed by Esler, Lambert, and Schlaich (6), I will defer further consideration of this issue to them. Nevertheless, it is important to point out that the successful treatment of resistant hypertension using catheter-based renal sympathetic denervation was restricted to selected patients that were resistant to standard therapy (14).Through its multiple actions, the kidneys exert a predominant role to regulate arterial pressure (10, 12, 19, 24). Importantly, transplantation studies have demonstrated that the hypertension follows the kidneys (9). There are many models of experimental hypertension but most of them involve procedures or genetic manipulations that activate the RAS (8, 11, 13, 22, 23). While enhanced activity of renal sympathetic nerves contributes to the magnitude of the hypertension, the hypertensive response is only attenuated and the increases in intrarenal ANG II are similar in denervated kidneys as in innervated kidneys (11). In chronic ANG II-infused rabbits, the hypertension was not altered by renal denervation and renal sympathetic nerve activity was not changed (2). Furthermore, there was a general augmentation of vascular reactivity leading to augmented depressor responses to ganglionic blockade, but there was not an increased renal sympathetic activity (18). These studies have not shown differences in renal sympathetic nerve activity among rabbits with various forms of hypertension (2, 18). Prior renal denervation did not blunt the hypertension, suggesting that the sympathetic nervous system does not exert a direct role in the development of ANG II-induced hypertension (18).Derangements in kidney function that prevent maintenance of balance between salt excretion and salt intake vary from overt renal disease causing reduced excretory capability to transport derangements causing excess sodium reabsorption. Importantly, the studies of monogenetic diseases demonstrate that mutations associated with hypertension are consistently associated with altered tubular reabsorptive function (16). Liddle's syndrome, characterized by overactive amiloride sensitive sodium channels in the principal cells of collecting ducts, is a classic example (26). These single gene mutations demonstrate that transport alterations can cause hypertension independent of neural contributions. Although most forms of hypertension involve multiple gene effects, the final consequences are strikingly similar in that an inappropriate stimulation of tubular reabsorption leads to sodium retention and hypertension (19, 22, 26). Inappropriate activation of the intrarenal RAS is a very powerful hypertensinogenic mechanism because the pleiotropic actions of ANG II lead to increased renal vascular resistance, decreased renal blood flow, and glomerular filtration rate, increased aldosterone release and increased fractional sodium reabsorption at both proximal and distal nephron segments (12, 17, 20, 24, 30).Excess salt retention may also be caused by derangements in neurohormonal communication pathways that maintain normal renal function (19). When inappropriately activated, however, these signals may alter renal hemodynamics and/or tubular transport to prevent appropriate sodium excretion at normal arterial pressure. The excess salt and volume retention leads to increased arterial pressure which then elicits a pressure natriuresis response (Fig. 2), allowing the kidneys to restore sodium homeostasis but at the cost of an elevated arterial pressure (19, 22).Fig. 2.Pressure-natriuresis relationships and the responses to increases in salt intake or activation of the intrarenal renin-angiotensin system (RAS). Each pressure natriuresis relationship represents the acute responses in sodium excretion to changes in arterial pressure with all other systems maintained. The suppressed relationship occurs when there is overactivation of sodium retaining mechanisms such as increased RAS. The steeper curve represents the relationship when sodium retaining mechanisms are suppressed or sodium excretory mechanisms are activated such as with RAS inhibition or increased ANP. In normal individuals, a high salt intake leads to a shift in the pressure-natriuresis curve represented as arrow 1 such that sodium excretion increases with only small increases in arterial pressure. When the RAS is not appropriately suppressed, a high salt intake must lead to an increased arterial pressure to maintain sodium balance represented as arrow 2. If there is an augmented activation of the RAS, then even normal salt intake may require an increase in blood pressure to allow maintenance of sodium balance as depicted by arrow 3. While many other systems can modulate the magnitude of the responses, the final outcome always has to be the blood pressure where sodium balance can be maintained.Download figureDownload PowerPointThe RAS has a powerful role because it is both an intrarenal system and a powerful extrarenal system that influences essentially every organ system (20, 24). In addition to the liver, the proximal tubular cells also produce abundant angiotensinogen that help maintain intratubular and renal interstitial ANG II concentrations greater than those in the systemic circulation (12, 25, 28). Furthermore, renin is formed in cells of the juxtaglomerular apparatus and also in principal cells of the collecting ducts, allowing secretion into the tubular fluid to form ANG I from angiotensinogen derived from the proximal nephron (23–25). Thus, the ANG II-mediated increased vascular resistance along with increased tubular reabsorption mediated by an augmented intratubular RAS leads to a sustained decreased sodium excretion and hypertension (10, 19).An enhanced intrarenal RAS leads to enhanced ANG II throughout the body, thus contributing to increased cardiac contractility, increased peripheral vascular resistance, increased aldosterone release, and hypertensinogenic actions throughout the body (3, 12). Importantly, the pressure natriuresis mechanism, which is responsible for restoring sodium balance when there is inappropriate salt retention (10), does not escape the powerful influence of an augmented RAS (17, 19). As depicted in Fig. 2, augmented intrarenal ANG II levels suppress sodium excretion at any arterial pressure (17, 19). Nevertheless, with sufficient increases in arterial pressure, the increases in sodium excretion restore sodium balance, but again only at the expense of an elevated arterial pressure. The dominant role of the RAS in hypertension is reflected by the fact that blockade of the RAS with ACE inhibitors, ARBs, or the newer renin inhibitor is rapidly being recognized as one of the most effective antihypertensive therapeutic strategies (1, 7).Conclusion.In summary, many interacting physiological systems provide homeostatic regulation of arterial pressure, and derangements in any one of them can contribute to hypertension. While the nervous system provides regulatory inputs and stability to the blood pressure mechanisms, the primary responsibility for the long-term regulation of arterial pressure is vested in the kidneys' capability to integrate endocrine, neural, and hemodynamic inputs to maintain sodium balance and arterial blood pressure. Of the many mechanisms contributing to these alterations, the RAS axis plays a most vital role in regulating both sodium balance and blood pressure through its pleotropic actions on multiple vascular, endocrine, and renal mechanisms. Accordingly, it is the intrarenal/intratubular RAS that is the final dominant arbiter responsible for hypertension!GRANTSThe author's research has been supported by grants from National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, American Heart Association, and NCRR.ACKNOWLEDGMENTSI thank Debbie Olavarrieta for assistance in the preparation of the manuscript.REFERENCES1. 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Hypertension 54: 120–126, 2009.Crossref | PubMed | ISI | Google Scholar Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Cited ByDevelopment and validation of a nomogram model for individualized prediction of hypertension risk in patients with type 2 diabetes mellitus23 January 2023 | Scientific Reports, Vol. 13, No. 1Assessment of plasma catecholamines in patients with dysmetabolic iron overload syndromeJournal of Applied Biomedicine, Vol. 20, No. 4Screening of potential spike glycoprotein / ACE2 dual antagonists against COVID-19 in silico molecular dockingJournal of Virological Methods, Vol. 301The sympathies of the body: functional organization and neuronal differentiation in the peripheral sympathetic nervous system10 November 2021 | Cell and Tissue Research, Vol. 386, No. 3ANTIHYPERTENSIVE PHARMACOTHERAPY IN HYPERTENSIVE PATIENTS AT A TERTIARY CARE TEACHING HOSPITAL AND MEDICAL COLLEGE IN INDIA7 November 2021 | Asian Journal of Pharmaceutical and Clinical ResearchIdentification and action mechanism of low-molecular-weight peptides derived from Atlantic salmon (Salmo salar L.) skin inhibiting angiotensin I–converting enzymeLWT, Vol. 150Brain and kidney GHS-R1a underexpression is associated with changes in renal function and hemodynamics during neurogenic hypertensionMolecular and Cellular Endocrinology, Vol. 518Altered renal medullary blood flow: A key factor or a parallel event in control of sodium excretion and blood pressure?7 April 2020 | Clinical and Experimental Pharmacology and Physiology, Vol. 47, No. 8Interaction mechanism of egg white- derived ACE inhibitory peptide TNGIIR with ACE and its effect on the expression of ACE and AT1 receptorFood Science and Human Wellness, Vol. 9, No. 1Role of ACE2 Gene Expression in Renin Angiotensin System and Its Importance in Covid-19: In Silico Approach1 January 2020 | Brazilian Archives of Biology and Technology, Vol. 63Definition of hypertension‐associated oral pathogens in NHANES29 May 2019 | Journal of Periodontology, Vol. 90, No. 8Neuroimmune crosstalk in the pathophysiology of hypertension20 March 2019 | Nature Reviews Cardiology, Vol. 16, No. 8Plant-Based Ethnopharmacological Remedies for Hypertension in Suriname30 January 2019Morphological and Functional Characteristics of Blood and Lymphatic Vessels9 May 2019Evidence against a crucial role of renal medullary perfusion in blood pressure control of hypertensive rats10 November 2018 | The Journal of Physiology, Vol. 597, No. 1Median preoptic nucleus excitatory neurotransmitters in the maintenance of hypertensive stateBrain Research Bulletin, Vol. 142Influence of age and gender on blood pressure variability and baroreflex sensitivity in a healthy population in the Indian sub-continent14 July 2018 | Journal of Basic and Clinical Physiology and Pharmacology, Vol. 29, No. 4Hyperglycaemia induced by chronic i.p . and oral glucose loading leads to hypertension through increased Na + retention in proximal tubule7 December 2017 | Experimental Physiology, Vol. 103, No. 2Renin-angiotensin system inhibitors and risk of fractures: a prospective cohort study and meta-analysis of published observational cohort studies27 July 2017 | European Journal of Epidemiology, Vol. 32, No. 11Hemodynamic responses to mental stress during salt loading6 April 2016 | Clinical Physiology and Functional Imaging, Vol. 37, No. 6ACE inhibitors and the risk of fractures: a meta-analysis of observational studies19 December 2016 | Endocrine, Vol. 55, No. 3Normotension, hypertension and body fluid regulation: brain and kidney19 June 2016 | Acta Physiologica, Vol. 219, No. 1Different blood pressure responses to opioids in 3 rat hypertension models: role of the baseline status of sympathetic and renin–angiotensin systemsCanadian Journal of Physiology and Pharmacology, Vol. 94, No. 11Peroxisome proliferator-activated receptor-α stimulation by clofibrate favors an antioxidant and vasodilator environment in a stressed left ventriclePharmacological Reports, Vol. 68, No. 4Reply1 March 2016 | Experimental Physiology, Vol. 101, No. 3Sympathetic regulation of blood pressure in normotension and hypertension: when sex matters1 February 2016 | Experimental Physiology, Vol. 101, No. 2Blood Pressure: Return of the Sympathetics?7 January 2016 | Current Hypertension Reports, Vol. 18, No. 1Sympathetic overactivity occurs before hypertension in the two-kidney, one-clip model14 December 2015 | Experimental Physiology, Vol. 101, No. 1The roles of sensitization and neuroplasticity in the long-term regulation of blood pressure and hypertensionAlan Kim Johnson, Zhongming Zhang, Sarah C. 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