The cardiovascular control involves a bidirectional functional connection between the brain and heart. We hypothesize that this connection could be extended to other organs using endocrine and autonomic nervous systems (ANS) as communication pathways. This implies a neuroendocrine interaction controlling particularly the cardiovascular function where the enzymatic cascade of the renin-angiotensin system (RAS) plays an essential role. It acts not only through its classic endocrine connection but also the ANS. In addition, the brain is functionally, anatomically, and neurochemically asymmetric. Moreover, this asymmetry goes even beyond the brain and it includes both sides of the peripheral nervous and neuroendocrine systems. We revised the available information and analyze the asymmetrical neuroendocrine bidirectional interaction for the cardiovascular control. Negative and positive correlations involving the RAS have been observed between brain, heart, kidney, gut, and plasma in physiologic and pathologic conditions. The central role of the peptides and enzymes of the RAS within this neurovisceral communication, as well as the importance of the asymmetrical distribution of the various RAS components in the pathologies involving this connection, are particularly discussed. In conclusion, there are numerous evidences supporting the existence of a neurovisceral connection with multiorgan involvement that controls, among others, the cardiovascular function. This connection is asymmetrically organized.
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Aiso M Potter WZ Saavedra JM. Axonal transport of angiotensin-converting enzyme in the rat striatonigral pathway. Brain Res 447 195–199 1988.
Banegas I Prieto I Alba F Vives F Araque A Segarra AB Duran R de Gasparo M Ramirez M. Angiotensinase activity is asymmetrically distributed in the amygdala hippocampus and prefrontal cortex of the rat. Behav Brain Res 156 321–326 2005.
Banegas I Prieto I Vives F Alba F de Gasparo M Duran R Luna J de D Segarra AB Hermoso F Ramirez M. Asymmetrical response of aminopeptidase A and nitric oxide in plasma of normotensive and hypertensive rats with experimental hemiparkinsonism. Neuropharmacology 56 573–579 2009.
Banegas I. Prieto I Segarra AB Duran R Vives F Alba F Luna JD de Gasparo M Wangesteen R Ruiz-Bailen M Ramirez-Sanchez M. Blood pressure increased dramatically in hypertensive rats after left hemisphere lesions with 6-hydroxydopamine. Neurosci Lett 500 148–150 2011.
Baylis BW Tranmer BI Ohtaki M. Central and autonomic nervous system links to the APUD system (and their APUDomas). Semin Surg Oncol 9 387–393 1993.
Belcheva I Belcheva S Petkov VV Petkov VD. Asymmetry in behavioral responses to cholecystokinin microinjected into rat nucleus accumbens and amygdala. Neuropharmacology 33 995–1002 1994.
Bernard Claude. Etude sur la physiologie du coeur. La science experimentale 316–366 1878.
Bonaz B. Inflammatory bowel diseases: a dysfunction of brain-gut interactions? Minerva Gastroenterol Dietol 59 241–259 2013.
Booth LC May CN Yao ST. The role of the renal afferent and efferent nerve fibers in heart failure. Front Physiol 6 270 2015.
Borson-Chazot F Jordan D Fevre-Montange M Kopp N Tourniaire J Rouzioux JM Veisseire M Mornex R. TRH and LH-RH distribution in discrete nuclei of the human hypothalamus: evidence for a left prominence of TRH. Brain Res 382 433–436 1986.
Crumeyrolle-Arias M Jaglin M Bruneau A Vancassel S Cardona A Dauge V Naudon L Rabot S. Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats. Psychoneuroendocrinology 42 207–217 2014.
Dicker D Maya I Vasilevsky V Gofman M Markowitz D Beilin V Sarid M Yosefy C. Blood pressure variability in acute ischemic stroke depends on hemispheric stroke location. Blood Press 15 151–156 2006.
Diz DI Ferrario CM. Bidirectional transport of angiotensin II binding sites in the vagus nerve. Hypertension 11 I139–I143 1988.
Dockray GJ. Enteroendocrine cell signalling via the vagus nerve. Curr Opin Pharmacol 13 954–958 2013.
Fandriks L. The renin-angiotensin system and the gastrointestinal mucosa. Acta Physiol (Oxf) 201 157–167 2011.
Fontes MA Martins Lima A Santos RA. Brain angiotensin-(1-7)/Mas axis: A new target to reduce the cardiovascular risk to emotional stress. Neuropeptides 56 9–17 2016.
Fujiwara Y Kubo M Kohata Y Yamagami H Tanigawa T Watanabe K Watanabe T Tominaga K Arakawa T. Association between left-handedness and gastrointestinal symptoms. Digestion 84 114–118 2011.
Gao J Marc Y Iturrioz X Leroux V Balavoine F Llorens-Cortes C. A new strategy for treating hypertension by blocking the activity of the brain renin-angiotensin system with aminopeptidase A inhibitors. Clin Sci (Lond) 127 135–148 2014.
Gerendai I Halasz B. Asymmetry of the neuroendocrine system. News Physiol Sci 16 92–95 2001.
Grenham S Clarke G Cryan JF Dinan TG. Brain-gut-microbe communication in health and disease. Front Physiol 2 94 2011.
Grisk O. Sympatho-renal interactions in the determination of arterial pressure: role in hypertension. Exp Physiol 90 183–187 2005.
Hachinski VC Oppenheimer SM Wilson JX Guiraudon C Cechetto DF. Asymmetry of sympathetic consequences of experimental stroke. Arch Neurol 49 697–702 1992.
Hallberg M. Neuropeptides: metabolism to bioactive fragments and the pharmacology of their receptors. Med Res Rev 35 464–519 2015.
Hernandez J Prieto I Segarra AB de Gasparo M Wangensteen R Villarejo AB Banegas I Vives F Cobo J Ramirez-Sanchez M. Interaction of neuropeptidase activities in cortico-limbic regions after acute restraint stress. Behav Brain Res 287 42–48 2015.
Hidalgo M Prieto I Abriouel H Cobo A Benomar N Galvez A Martinez-Canamero M. Effect of virgin and refined olive oil consumption on gut microbiota. Comparison to butter. Food Res Int 64 553–559 2014.
Holmqvist S Chutna O Bousset L Aldrin-Kirk P Li W Bjorklund T Wang ZY Roybon L Melki R Li JY. Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol 128 805–820 2014.
Holzer P Farzi A. Neuropeptides and the microbiota-gut-brain axis. Adv Exp Med Biol 817 195–219 2014.
Ito M Adachi-Akahane S. Inter-organ communication in the regulation of lipid metabolism: focusing on the network between the liver intestine and heart. J Pharmacol Sci 123 312–317 2013.
Jose PA Raj D. Gut microbiota in hypertension. Curr Opin Nephrol Hypertens 24 403–409 2015.
Kabouridis PS Pachnis V. Emerging roles of gut microbiota and the immune system in the development of the enteric nervous system. J Clin Invest 125 956–964 2015.
Kato T Ishihara H Shimizu A Yokosawa H Ishii S Komiya Y. The axonal transport of dipeptidyl aminopeptidase II angiotensin-converting enzyme and other peptidases in rat sciatic nerves. Neurosci Res 4 241–248 1987.
Klingelhofer J Sander D. Cardiovascular consequences of clinical stroke. Baillieres Clin Neurol 6 309–335 1997.
Kopp UC Cicha MZ Smith LA. Impaired responsiveness of renal mechanosensory nerves in heart failure: role of endogenous angiotensin. Am J Physiol Regul Integr Comp Physiol 284 R116–R124 2003.
Lane RD Wallace JD Petrosky PP Schwartz GE Gradman AH. Supraventricular tachycardia in patients with right hemisphere strokes. Stroke 23 362–366 1992.
Lee SW Gerdes L Tegeler CL Shaltout HA Tegeler CH. A bihemispheric autonomic model for traumatic stress effects on health and behavior. Front Psychol 5 843 2014.
Lis CG Gaviria M. Vascular dementia hypertension and the brain. Neurol Res 19 471–480 1997.
McCraty R Shaffer F. Heart Rate Variability: New Perspectives on Physiological Mechanisms Assessment of Selfregulatory Capacity and Health risk. Glob Adv Health Med 4 46–61 2015.
Michas G Micha R Zampelas A. Dietary fats and cardiovascular disease: putting together the pieces of a complicated puzzle. Atherosclerosis 234 320–328 2014.
Min J Farooq MU Greenberg E Aloka F Bhatt A Kassab M Morgan JP Majid A. Cardiac dysfunction after left permanent cerebral focal ischemia: the brain and heart connection. Stroke 40 2560–2563 2009.
Morris DL Montgomery SM Galloway ML Pounder RE Wakefield AJ. Inflammatory bowel disease and laterality: is left handedness a risk? Gut 49 199–202 2001.
Nagai M Hoshide S Kario K. The insular cortex and cardiovascular system: a new insight into the brain-heart axis. J Am Soc Hypertens 4 174–182 2010.
Oppenheimer S. Cerebrogenic cardiac arrhythmias: cortical lateralization and clinical significance. Clin Auton Res 16 6–11 2006.
Pearse AG Polak JM. Neural crest origin of the endocrine polypeptide (APUD) cells of the gastrointestinal tract and pancreas. Gut 12 783–788 1971.
Prieto I Martinez A Martinez JM Ramirez MJ Vargas F Alba F Ramirez M. Activities of aminopeptidases in a rat saline model of volume hypertension. Horm Metab Res 30 246–248 1998.
Prieto I Villarejo AB Segarra AB Banegas I Wangensteen R Martinez-Canamero M de Gasparo M Vives F Ramirez-Sanchez M. Brain heart and kidney correlate for the control of blood pressure and water balance: role of angiotensinases. Neuroendocrinology 100 198–208 2014a.
Prieto I Hidalgo M Cobo A Segarra AB Ramirez M Galvez A Vives F Martinez-Canamero M. BAM-PTH1038-Comparative study of the effect of virgin olive oil and butter on the intestinal microbiota and diverse parameters related to metabolic syndrome. XIVth International Congress of Bacteriology and Applied Microbiology. Montreal Canada International Union of Microbiological Societies Congresses 1268 2014b.
Ramirez M Prieto I Vives F de Gasparo M Alba F. Neuropeptides neuropeptidases and brain asymmetry. Curr Protein Pept Sci 5 497–506 2004.
Ramirez M Prieto I Alba F Vives F Banegas I de Gasparo M. Role of central and peripheral aminopeptidase activities in the control of blood pressure: a working hypothesis. Heart Fail Rev 13 339–353 2008.
Ramirez-Sanchez M Prieto I Wangensteen R Banegas I Segarra AB Villarejo AB Vives F Cobo J de Gasparo M. The renin-angiotensin system: new insight into old therapies. Curr Med Chem 20 1313–1322 2013.
Ramsay DS Woods SC. Clarifying the roles of homeostasis and allostasis in physiological regulation. Psychol Rev 121 225–247 2014.
Rodgers H. Stroke Handb Clin Neurol 110 427–433 2013.
Rueda I Banegas I Prieto I Wangensteen R Segarra AB Villarejo AB De Gasparo M Luna JD Vives F Ruiz-Bailen M Ramirez-Sanchez M. Handedness and gender influence blood pressure in young healthy men and women: A pilot study. Endocr Regul 50 10–15 2016.
Saavedra JM. Angiotensin II AT(1) receptor blockers as treatments for inflammatory brain disorders. Clin Sci (Lond) 123 567–590 2012.
Sander D Klingelhofer J. Changes of circadian blood pressure patterns and cardiovascular parameters indicate lateralization of sympathetic activation following hemispheric brain infarction. J Neurol 242 313–318 1995.
Segarra AB Ruiz-Sanz JI Ruiz-Larrea MB Ramirez-Sanchez M de Gasparo M Banegas I Martinez-Canamero M Vives F Prieto I. The profile of fatty acids in frontal cortex of rats depends on the type of fat used in the diet and correlates with neuropeptidase activities. Horm Metab Res 43 86–91 2011.
Segarra AB Prieto I Banegas I Villarejo AB Wangensteen R de Gasparo M Vives F Ramirez-Sanchez M. Asymmetrical effect of captopril on the angiotensinase activity in frontal cortex and plasma of the spontaneously hypertensive rats: expanding the model of neuroendocrine integration. Behav Brain Res 230 423–427 2012.
Segarra AB Prieto I Banegas I Villarejo AB Wangensteen R de Gasparo M Vives F Ramirez-Sanchez M. The brain-heart connection: frontal cortex and left ventricle angiotensinase activities in control and captopril-treated hypertensive rats-a bilateral study. Int J Hypertens 2013:156179 2013.
Segarra AB Hernandez J Prieto I de Gasparo M Ramirez-Sanchez M. Neuropeptidase activities in plasma after acute restraint stress. Interaction with cortico-limbic areas. Acta Neuropsychiatr 28 239–243 2016.
Shoemaker JK Goswami R. Forebrain neurocircuitry associated with human reflex cardiovascular control. Front Physiol 6 240 2015.
Shoemaker JK Norton KN Baker J Luchyshyn T. Forebrain organization for autonomic cardiovascular control. Auton Neurosci 188 5–9 2015.
Smeda JS. Analysis of cerebrovascular sympathetic nerve density in relation to stroke development in spontaneously hypertensive rats. Stroke 21 785–789 1990.
Soros P Hachinski V. Cardiovascular and neurological causes of sudden death after ischaemic stroke. Lancet Neurol 11 179–188 2012.
Soufer R Bremner JD Arrighi JA Cohen I Zaret BL Burg MM Goldman-Rakic P. Cerebral cortical hyperactivation in response to mental stress in patients with coronary artery disease. Proc Natl Acad Sci U S A 95 6454–6459 1998.
Sullivan RM Gratton A. Lateralized effects of medial prefrontal cortex lesions on neuroendocrine and autonomic stress responses in rats. J Neurosci 19 2834–2840 1999.
Tashev R Stefanova M. Hippocampal asymmetry in angiotensin II modulatory effects on learning and memory in rats. Acta Neurobiol Exp (Wars) 75 48–59 2015.
Thayer JF Lane RD. Claude Bernard and the heart-brain connection: further elaboration of a model of neurovisceral integration. Neurosci Biobehav Rev 33 81–88 2009.
Toga AW Thompson PM. Mapping brain asymmetry. Nat Rev Neurosci 4 37–48 2003.
Villarejo AB Ramirez-Sanchez M Segarra AB Martinez-Canamero M Prieto I. Influence of extra virgin olive oil on blood pressure and kidney angiotensinase activities in spontaneously hypertensive rats. Planta Med 81 664–669 2015.
Williams DP Cash C Rankin C Bernardi A Koenig J Thayer JF. Resting heart rate variability predicts self-reported difficulties in emotion regulation: a focus on different facets of emotion regulation. Front Psychol 6 261 2015.
Xavier CH Beig MI Ianzer D Fontes MA Nalivaiko E. Asymmetry in the control of cardiac performance by dorsomedial hypothalamus. Am J Physiol Regul Integr Comp Physiol 304 R664–R674 2013.
Xu B Zheng H Patel KP. Enhanced activation of RVLM-projecting PVN neurons in rats with chronic heart failure. Am J Physiol Heart Circ Physiol 302 H1700–H1711 2012.
Zamrini EY Meador KJ Loring DW Nichols FT Lee GP Figueroa RE Thompson WO. Unilateral cerebral inactivation produces differential left/right heart rate responses. Neurology 40 1408–1411 1990.
Zhou X Frohlich ED. Analogy of cardiac and renal complications in essential hypertension and aged SHR or L-NAME/SHR. Med Chem 3 61–65 2007.