Neuroendocrinology. 2014;100(2-3):198-208. doi: 10.1159/000368835.

Brain, heart and kidney correlate for the control of blood pressure and water balance: role of angiotensinases.

Prieto I1, Villarejo AB, Segarra AB, Banegas I, Wangensteen R, Martinez-Cañamero M, de Gasparo M, Vives F, Ramírez-Sánchez M.
  • 1Unit of Physiology, University of Jaén, Jaén, Spain.



The renin-angiotensin system (RAS) plays a major role in the control of blood pressure (BP) and water balance by coordinating brain, heart and kidney functions, connected with each other by hormonal and neural mechanisms through the autonomic nervous system (ANS). RAS function may be monitored by the study of the enzymes (angiotensinases) involved in the metabolism of its active peptides. In order to study the relationship between the brain-heart-kidney axis and the control of BP and water balance, we analyzed the correlation of angiotensinase activities, assayed as arylamidase activities, between hypothalamus, left ventricle, renal cortex and renal medulla, collected from Wistar-Kyoto and spontaneously hypertensive rats, treated or not treated with L-NAME [N(G)-nitro-L-arginine methyl ester]. This compound not only inhibits the formation of nitric oxide but also disrupts the normal function of the ANS activating the sympathetic nervous system (SNS) to increase BP. In addition, to assess the influence of the SNS, we studied the effect of its blockade by treatment of both strains with propranolol. The present results support the notion that RAS function of the brain-heart-kidney axis, as reflected by the activities of angiotensinases, is reciprocally connected by afferent and efferent mechanisms between these locations, presumably through the ANS. These results reveal new aspects of neuroendocrine regulation possibly involving the ANS.

PMID: 25323445



Blood pressure (BP) and hydroelectrolytic balance (HB) are regulated by neurovisceral mechanisms, which connect bidirectionally brain, heart and kidney through the autonomic nervous system (ANS) (1, 2). The renin-angiotensin-aldosterone system (RAAS) plays a major role in this control mechanism by coordinating the functions of these various organs (3). The functional status of the RAAS may be monitored by the analysis of angiotensinases, the enzymes implicated in the metabolism of angiotensin peptides (4). These enzymes may act at the neuroeffector junction through secretory processes from nerve terminals of the ANS or from tissue cells regulated by the same neural connections.


This study was conducted to analyze the role of the ANS together with the angiotensinase activities in the integrative mechanisms that control BP and HB. We studied the degree of correlation of these enzymatic activities, determined fluorimetrically as arylamidase activities (5), between the anterior hypothalamus (AHt) and the left ventricle (VT), renal cortex (RC) or renal medulla (RM) of normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) treated or not with L-NAME (a sympathetic activator) or propranolol (a sympathetic blocker). The resulting pattern of correlations after the treatments of normotensive and hypertensive animals suggested the functional status of the ANS, allowing to differentiate a possible activation of the sympathetic or parasympathetic branch.


On the whole, the effects of the treatment with the sympathetic activator L-NAME were reversed after sympathetic blockade with propranolol. This reveals a clear involvement of the ANS in the response.


The comparison between the AHt and the RM in control normotensive rats revealed a strong negative correlation between both tissues presumably mediated by the parasympathetic system. On the contrary, the results obtained in SHR demonstrated a marked positive correlation between AHt and RM when these animals were treated with propranolol suggesting the involvement of the parasympathetic branch in these conditions. Moreover, there was an over-activation of the sympathetic system in the connection observed between AHt and RC under L-NAME treatment in SHR.


When we evaluated the enzymatic activities obtained in the AHt with those obtained in VT in normotensive WKY rats treated with propranolol, the results suggested an activated connection between both tissues probably through the parasympathetic system. In contrast, in SHR, the results suggested an activated negative connection of angiotensinase activities between AHt and VT after L-NAME treatment through the sympathetic branch of the ANS (figure 1).


 ms fig1

Figure 1. Summary of the main consequences observed in the present study differentiating the possible involvement of the two branch of the autonomic nervous system. Sympathetic (red lines) or parasympathetic (blue lines) activation are indicated with the predominance of positive (+) or negative (-) correlation of angiotensinase activities between hypothalamus and ventricle, renal cortex or renal medulla. (±) indicates no clear predominance between positive and negative correlations.


In conclusion, these results demonstrated the participation of the angiotensin-metabolizing enzymes in the interactive regulatory mechanisms that connect bilaterally brain, heart and kidney through the ANS in order to control BP and HB.



  1. Villarejo AB, Segarra AB, Ramírez M, Banegas I, Wangensteen R, de Gasparo M, Cobo J, Alba F, Vives F, Prieto, I: Angiotensinase and vasopressinase activities in hypothalamus, plasma, and kidney after inhibition of angiotensin-converting enzyme: basis for a new working hypothesis. Horm Metab Res 2012;44:152-154.
  2. Segarra AB, Prieto I, Banegas I, Villarejo AB, Wangensteen R, de Gasparo M, Vives F, Ramírez-Sánchez 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; 2013:156179.
  3. de Gasparo M, Speth RC, Baltatu OC, Vanderheyden P: Brain RAS: Hypertension and Beyond. Int. J Hypertens 2013;2013:157180.
  4. Ramírez 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 2008;13:339-353.
  5. Ramírez M, Prieto I, Banegas I, Segarra AB, Alba F: Neuropeptidases Methods Mol Biol 2011;789:287-294.


Acknowledgements: This work was supported by the Ministry of Science and Innovation through project no. SAF 2008 04685 C02 01.



Manuel Ramírez-Sánchez

Unit of Physiology

University of Jaén

23071 Jaén, SPAIN

Tel: 34-953-212302

Fax: +34 953 212943


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