The sympathetic nerve activity (SNA) is augmented in hypertension. SNA is regulated by neuronal nitric oxide synthase (nNOS) or endothelial nitric oxide synthase (eNOS) activity in hypothalamic paraventricular nuclei (PVN) and/or brainstem rostral ventrolateral medulla. High nNOS or eNOS activity within these brain regions lowers the SNA, whereas low cerebral nNOS and/or eNOS activity causes SNA augmentation. We hypothesize that the decreased cerebral nNOS/eNOS activity, which allows the enhancement of SNA, leads to the augmentation of renal eNOS/nNOS activity. Similarly, when the cerebral nNOS/eNOS activity is increased and SNA is suppressed, the renal eNOS/nNOS activity is suppressed as well. The activation of endothelial alpha(2)-adrenoceptors, may be a possible mechanism involved in the proposed regulation. Another possible mechanism might be based on nitric oxide, which acts as a neurotransmitter that tonically activates afferent renal nerves, leading to a decreased nNOS activity in PVN. Furthermore, the importance of the renal nNOS/eNOSactivity during renal denervation is discussed. In conclusion, the presented hypothesis describes the dual organ-specific role of eNOS/nNOS activity in blood pressure regulation and suggests possible connection between cerebral NOS and renal NOS via activation or inhibition of SNA, which is an innovative idea in the concept of pathophysiology of hypertension.

Institute of Pharmacol Clin Pharmacol Faculty of Medicine Comenius University Bratislava Slovak Republic

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ASHAB I, PEER G, BLUM M, WOLLMAN Y, CHERNIHOVSKY T, HASSNER A, SCHWARTZ D, CABILI S, SILVERBERG D, IAINA A. Oral administration of L-arginine and captopril in rats prevents chronic renal failure by nitric oxide production. Kidney Int. 1995;47:1515–1521. doi: 10.1038/ki.1995.214. PubMed DOI

AZIZI M, SAPOVAL M, GOSSE P, MONGE M, BOBRIE G, DELSART P, MIDULLA M, MOUNIER-VÉHIER C, COURAND PY, LANTELME P, DENOLLE T, DOURMAP-COLLAS C, TRILLAUD H, PEREIRA H, PLOUIN P-F, CHATELLIER G. Optimum and stepped care standardised antihypertensive treatment with or without renal denervation for resistant hypertension (DENERHTN): a multicentre, open-label, randomised controlled trial. Lancet. 2015;385:1957–1965. doi: 10.1016/S0140-6736(14)61942-5. PubMed DOI

BARMAN SM, YATES BJ. Deciphering the neural control of sympathetic nerve activity: status report and directions for future research. Front Neurosci. 2017;11:730. doi: 10.3389/fnins.2017.00730. PubMed DOI PMC

BENCZE M, BEHULIAK M, ZICHA J. The impact of four different classes of anesthetics on the mechanisms of blood pressure regulation in normotensive and spontaneously hypertensive rats. Physiol Res. 2013;62:471–478. doi: 10.33549/physiolres.932637. PubMed DOI

BHATT DL, KANDZARI DE, O’NEILL WW, D’AGOSTINO R, FLACK JM, KATZEN BT, LEON MB, LIU M, MAURI L, NEGOITA M, COHEN SA, OPARIL S, ROCHA-SINGH K, TOWNSEND RR, BAKRIS GL. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370:1393–1401. doi: 10.1056/NEJMoa1402670. PubMed DOI

CACANYIOVA S, KRISTEK F, GEROVA M, KRENEK P, KLIMAS J. Effect of chronic nNOS inhibition on blood pressure, vasoactivity, and arterial wall structure in Wistar rats. Nitric Oxide. 2009;20:304–310. doi: 10.1016/j.niox.2009.03.002. PubMed DOI

CAMPESE VM, KOGOSOV E. Renal afferent denervation prevents hypertension in rats with chronic renal failure. Hypertension. 1995;25:878–882. doi: 10.1161/01.HYP.25.4.878. PubMed DOI

CHAN SH, CHAN JY. Brain stem NOS and ROS in neural mechanisms of hypertension. Antioxid Redox Signal. 2014;20:146–163. doi: 10.1089/ars.2013.5230. PubMed DOI

CHEN W, DU H, LU J, LING Z, LONG Y, XU Y, XIAO P, GYAWALI L, WOO K, YIN Y, ZRENNER B. Renal artery vasodilation may be an indicator of successful sympathetic nerve damage during renal denervation procedure. Sci Rep. 2016;6:37218. doi: 10.1038/srep37218. PubMed DOI PMC

CHINTALA MS, CHIU PJ, VEMULAPALLI S, WATKINS RW, SYBERTZ EJ. Inhibition of endothelial derived relaxing factor (EDRF) aggravates ischemic acute renal failure in anesthetized rats. Naunyn Schmiedebergs Arch Pharmacol. 1993;348:305–310. doi: 10.1007/BF00169160. PubMed DOI

DRÁBKOVÁ N, HOJNÁ S, ZICHA J, VANĚČKOVÁ I. Contribution of selected vasoactive systems to blood pressure regulation in two models of chronic kidney disease. Physiol Res. 2020;69:405–414. doi: 10.33549/physiolres.934392. PubMed DOI PMC

ELESGARAY R, CANIFFI C, SAVIGNANO L, ROMERO M, Mac LAUGHLIN M, ARRANZ C, COSTA MA. Renal actions of atrial natriuretic peptide in spontaneously hypertensive rats: the role of nitric oxide as a key mediator. Am J Physiol Renal Physiol. 2012;302:F1385–F1394. doi: 10.1152/ajprenal.00624.2011. PubMed DOI

FABER JE. Effects of althesin and urethan-chloralose on neurohumoral cardiovascular regulation. Am J Physiol. 1989;256:R757–R765. doi: 10.1152/ajpregu.1989.256.3.R757. PubMed DOI

FUKUTA H, MITSUI R, TAKANO H, HASHITANI H. Exercise-induced sympathetic dilatation in arterioles of the guinea pig tibial periosteum. Auton Neurosci. 2019;217:7–17. doi: 10.1016/j.autneu.2018.12.006. PubMed DOI

GEROVÁ M. Nitric oxide-compromised hypertension: facts and enigmas. Physiol Res. 2000;49:27–35. PubMed

GEROVÁ M, MASÁNOVÁ C, PAVLÁSEK J. Inhibition of NO synthase in the posterior hypothalamus increases blood pressure in the rat. Physiol Res. 1995;44:131–134. PubMed

GUYTON AC. Dominant role of the kidneys and accessory role of whole-body autoregulation in the pathogenesis of hypertension. Am J Hypertens. 1989;2:575–585. doi: 10.1093/ajh/2.7.575. PubMed DOI

KIM SW, LEE J, PAEK YW, KANG DG, CHOI KC. Decreased nitric oxide synthesis in rats with chronic renal failure. J Korean Med Sci. 2000;15:425–430. doi: 10.3346/jkms.2000.15.4.425. PubMed DOI PMC

KISHI T. Regulation of the sympathetic nervous system by nitric oxide and oxidative stress in the rostral ventrolateral medulla: 2012 Academic Conference Award from the Japanese Society of Hypertension. Hypertens Res. 2013;36:845–851. doi: 10.1038/hr.2013.73. PubMed DOI

KRUM H, SCHLAICH M, WHITBOURN R, SOBOTKA PA, SADOWSKI J, BARTUS K, KAPELAK B, WALTON A, SIEVERT H, THAMBAR S, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009;373:1275–1281. doi: 10.1016/S0140-6736(09)60566-3. PubMed DOI

KVANDOVA M, BARANCIK M, BALIS P, PUZSEROVA A, MAJZUNOVA M, DOVINOVA I. The peroxisome proliferator-activated receptor gamma agonist pioglitazone improves nitric oxide availability, renin-angiotensin system and aberrant redox regulation in the kidney of pre-hypertensive rats. J Physiol Pharmacol. 2018;69:231–243. PubMed

LI H, FÖRSTERMANN U. Uncoupling of endothelial NO synthase in atherosclerosis and vascular disease. Curr Opin Pharmacol. 2013;13:161–167. doi: 10.1016/j.coph.2013.01.006. PubMed DOI

LÍŠKOVÁ S, BALIŠ P, MIČUROVÁ A, KLUKNAVSKÝ M, OKULIAROVÁ M, PUZSEROVÁ A, ŠKRÁTEK M, SEKAJ I, MAŇKA J, VALOVIČ P, BERNATOVÁ I. Effect of iron oxide nanoparticles on vascular function and nitric oxide production in acute stress-exposed rats. Physiol Res. 2020;69:1067–1083. doi: 10.33549/physiolres.934567. PubMed DOI PMC

LIU J-L, MURAKAMI H, ZUCKER IH. Angiotensin II - nitric oxide interaction on sympathetic outflow in conscious rabbits. Circ Res. 1998;82:496–502. doi: 10.1161/01.RES.82.4.496. PubMed DOI

MATSUOKA H, NISHIDA H, NOMURA G, VLIET BNV, TOSHIMA H. Hypertension induced by nitric oxide synthesis inhibition is renal nerve dependent. Hypertension. 1994;23:971–975. doi: 10.1161/01.HYP.23.6.971. PubMed DOI

McBRYDE FD, LIU BH, ROLOFF EV, KASPAROV S, PATON JFR. Hypothalamic paraventricular nucleus neuronal nitric oxide synthase activity is a major determinant of renal sympathetic discharge in conscious Wistar rats. Exp Physiol. 2018;103:419–428. doi: 10.1113/EP086744. PubMed DOI

MISCHEL NA, SUBRAMANIAN M, DOMBROWSKI MD, LLEWELLYN-SMITH IJ, MUELLER PJ. (In)activity-related neuroplasticity in brainstem control of sympathetic outflow: unraveling underlying molecular, cellular, and anatomical mechanisms. Am J Physiol Heart Circ Physiol. 2015;309:H235–H243. doi: 10.1152/ajpheart.00929.2014. PubMed DOI PMC

ORESCANIN Z, MILOVANOVIĆ SR. Effect of L-arginine on the relaxation caused by sodium nitroprusside on isolated rat renal artery. Acta Physiol Hung. 2006;93:271–283. doi: 10.1556/APhysiol.93.2006.4.3. PubMed DOI

OSBORN JW, AVERINA VA, FINK GD. Current computational models do not reveal the importance of the nervous system in long-term control of arterial pressure. Exp Physiol. 2009;94:389–396. doi: 10.1113/expphysiol.2008.043281. PubMed DOI PMC

OSBORN JW, JACOB F, GUZMAN P. A neural set point for the long-term control of arterial pressure: beyond the arterial baroreceptor reflex. Am J Physiol Regul Integr Comp Physiol. 2005;288:R846–R855. doi: 10.1152/ajpregu.00474.2004. PubMed DOI

PARK S, HARRISON-BERNARD LM. Augmented renal vascular nNOS and renin protein expression in angiotensin type 1 receptor null mice. J Histochem Cytochem. 2008;56:401–414. doi: 10.1369/jhc.2007.950220. PubMed DOI PMC

PATEL KP, XU B, LIU X, SHARMA NM, ZHENG H. Renal denervation improves exaggerated sympathoexcitation in rats with heart failure: a role for neuronal nitric oxide synthase in the paraventricular nucleus. Hypertension. 2016;68:175–184. doi: 10.1161/HYPERTENSIONAHA.115.06794. PubMed DOI PMC

ROSSI NF, MALISZEWSKA-SCISLO M, CHEN H, BLACK SM, SHARMA S, RAVIKOV R, AUGUSTYNIAK RA. Neuronal nitric oxide synthase within paraventricular nucleus: blood pressure and baroreflex in two-kidney, one-clip hypertensive rats. Exp Physiol. 2010;95:845–857. doi: 10.1113/expphysiol.2009.051789. PubMed DOI PMC

THOMSON SC. Nitric oxide mediates anomalous tubuloglomerular feedback in rats fed high-NaCl diet after subtotal nephrectomy. Am J Physiol Renal Physiol. 2019;316:F223–F230. doi: 10.1152/ajprenal.00066.2018. PubMed DOI PMC

VAVŘÍNOVÁ A, BEHULIAK M, BENCZE M, VODIČKA M, ERGANG P, VANĚČKOVÁ I, ZICHA J. Sympathectomy-induced blood pressure reduction in adult normotensive and hypertensive rats is counteracted by enhanced cardiovascular sensitivity to vasoconstrictors. Hypertens Res. 2019;42:1872–1882. doi: 10.1038/s41440-019-0319-2. PubMed DOI

VAZIRI ND, NI Z, OVEISI F. Upregulation of renal and vascular nitric oxide synthase in young spontaneously hypertensive rats. Hypertension. 1998a;31:1248–1254. doi: 10.1161/01.HYP.31.6.1248. PubMed DOI

VAZIRI ND, NI Z, WANG XQ, OVEISI F, ZHOU XJ. Downregulation of nitric oxide synthase in chronic renal insufficiency: role of excess PTH. Am J Physiol Renal Physiol. 1998b;274:F642–F649. doi: 10.1152/ajprenal.1998.274.4.F642. PubMed DOI

ZHANG K, MAYHAN WG, PATEL KP. Nitric oxide within the paraventricular nucleus mediates changes in renal sympathetic nerve activity. Am J Physiol. 1997;273:R864–R872. doi: 10.1152/ajpregu.1997.273.3.R864. PubMed DOI