Abstract
Vasopressin (VP) is a neurohypophyseal peptide best known for its role in maintaining osmotic and cardiovascular homeostasis. The main sources of VP are the supraoptic and paraventricular (PVN) nuclei of the hypothalamus, which coexpress the vasopressin V1a and V1b receptors (V1aR and V1bR). Here, we investigated the level of expression of VP and VP receptors in the PVN of borderline hypertensive rats (BHRs), a key integrative nucleus for neuroendocrine cardiovascular control. Experiments were performed in male BHRs and Wistar rats (WRs) equipped with a radiotelemetry device for continuous hemodynamic recording under baseline conditions and after saline load without or with stress. Autonomic control of the circulation was evaluated by spectral analysis of blood pressure (BP) and heart rate (HR) variability and baroreceptor reflex sensitivity (BRS) using the sequence method. Plasma VP was determined by radioimmunoassay, and VP, V1aR, and V1bR gene expression was determined by RT-qPCR. Under baseline conditions, BHRs had higher BP, lower HR, and stronger BRS than WRs. BP and HR variability was unchanged. In the PVN, overexpression of the VP and V1bR genes was found, and plasma VP was increased. Saline load downregulated V1bR mRNA expression without affecting VP mRNA expression or plasma VP and BP. Adding stress increased BP, HR, and low-frequency sympathetic spectral markers and decreased plasma VP without altering the level of expression of VP and VP receptors in the PVN. It follows that overexpression of VP and V1bR in the PVN is a characteristic trait of BHRs and that sympathetic hyperactivity underlies stress-induced hypertension.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Burbach JP, Van Tol HH, Bakkus MH, Schmale H, Ivell R. Gene regulation in the magnocellular hypothalamo-neurohypophysial system. Physiol Rev. 2001;81:1197–267.
Burbach JP, Van Tol HH, Bakkus MH, Schmale H, Ivell R. Quantitation of vasopressin mRNA and oxytocin mRNA in hypothalamic nuclei by solution hybridization assays. J Neurochem. 1986;47:1814–21.
Japundzic-Zigon N. Vasopressin and oxytocin in control of the cardiovascular system. Curr Neuropharmacol. 2013;11:218–30.
Dampney RA, Michelini LC, Li DP, Pan HL. Regulation of sympathetic vasomotor activity by the hypothalamic paraventricular nucleus in normotensive and hypertensive states. Am J Physiol Heart Circ Physiol. 2018;315:H1200–14.
Pyner S. Neurochemistry of the paraventricular nucleus of the hypothalamus: implications for cardiovascular regulation. J Chem Neuroanat. 2009;38:197–208.
Gouzènes L, Desarménien MG, Hussy N, Richard P, Moos FC. Vasopressin regularizes the phasic firing pattern of rat hypothalamic magnocellular vasopressin neurons. J Neurosci. 1998;18:1879–85.
Ludwig M, Leng G. Dendritic peptide release and peptide-dependent behaviours. Nat Rev Neurosci. 2006;7:126–36.
Son SJ, Filosa JA, Potapenko ES, Biancardi VC, Zheng H, Patel KP, et al. Dendritic peptide release mediates interpopulation crosstalk between neurosecretory and preautonomic networks. Neuron. 2013;78:1036–49.
Ribeiro N, Panizza Hdo N, Santos KM, Ferreira-Neto HC, Antunes VR. Salt-induced sympathoexcitation involves vasopressin V1a receptor activation in the paraventricular nucleus of the hypothalamus. Am J Physiol Regul Integr Comp Physiol. 2015;309:R1369–79.
Lozić M, Tasić T, Martin A, Greenwood M, Šarenac O, Hindmarch C, et al. Over-expression of V1A receptors in PVN modulates autonomic cardiovascular control. Pharm Res. 2016;114:185–95.
El-Werfali W, Toomasian C, Maliszewska-Scislo M, Li C, Rossi NF. Haemodynamic and renal sympathetic responses to V1b vasopressin receptor activation within the paraventricular nucleus. Exp Physiol. 2015;100:553–65.
Lawler JE, Cox RH, Sanders BJ, Mitchell VP. The borderline hypertensive rat: A model for studying the mechanisms of environmentally induced hypertension. Health Psychol. 1988;7:137–47.
Kilkenny C, Browne W, Cuthill IC, Emerson M, Altman DG. NC3Rs Reporting Guidelines Working Group. Animal research: reporting in vivo experiments: the ARRIVE guidelines. Br J Pharmacol. 2010;160:1577–9.
McGrath JC, Drummond GB, McLachlan EM, Kilkenny C, Wainwright CL. Guidelines for reporting experiments involving animals: the ARRIVE guidelines. Br J Pharmacol. 2010;160:1573–6.
Bajić D, Loncar-Turukalo T, Stojicić S, Sarenac O, Bojić T, Murphy D, et al. Temporal analysis of the spontaneous baroreceptor reflex during mild emotional stress in the rat. Stress. 2010;13:142–54.
Turukalo TL, Bajic D, Zigon NJ. Temporal sequence parameters in isodistributional surrogate data: model and exact expressions. IEEE Trans Biomed Eng. 2011;58:16–24.
Milutinović S, Murphy D, Japundzić-Zigon N. The role of central vasopressin receptors in the modulation of autonomic cardiovascular controls: a spectral analysis study. Am J Physiol Regul Integr Comp Physiol. 2006;291:R1579–91.
Parati G, Ulian L, Santucciu C, Omboni S, Mancia G. Blood pressure variability, cardiovascular risk and antihypertensive treatment. J Hypertens Suppl. 1995;13:S27–34.
Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Eur Heart J. 1996;17:354–81.
Japundzic-Zigon N. Physiological mechanisms in regulation of blood pressure fast frequency variations. Clin Exp Hypertens. 1998;20:359–88.
Husain MK, F. N, Shapiro M, Kagan A, Glick SM. Radioimmunoassay of arginine vasopressin in human plasma. J Clin Endocrinol Metab. 1973;37:616–25.
Paxinos G, Watson C. The rat brain in stereotaxic coordinates. USA: Elsevier Academic Press; 2005.
Yamada Y, Yamamura Y, Chihara T, Onogawa T, Nakamura S, Yamashita T, et al. OPC-21268, a vasopressin V1 antagonist, produces hypotension in spontaneously hypertensive rats. Hypertension. 1994;23:200–4.
Johnston CI. Vasopressin in circulatory control and hypertension. J Hypertens. 1985;3:557–69.
Yi SS, Kim HJ, Do SG, Lee YB, Ahn HJ, Hwang IK, et al. Arginine vasopressin (AVP) expressional changes in the hypothalamic paraventricular and supraoptic nuclei of stroke-prone spontaneously hypertensive rats. Anat Cell Biol. 2012;45:114–20.
Swords BH, Wyss JM, Berecek KH. Central vasopressin receptors are upregulated by deoxycorticosterone acetate. Brain Res. 1991;559:10–6.
Jackiewicz E, Szczepanska-Sadowska E, Dobruch J. Altered expression of angiotensin AT1a and vasopressin V1a receptors and nitric oxide synthase mRNA in the brain of rats with renovascular hypertension. J Physiol Pharmacol. 2004;55:725–37.
van Tol HH, van den Buuse M, de Jong W, Burbach JP. Vasopressin and oxytocin gene expression in the supraoptic and paraventricular nucleus of the spontaneously hypertensive rat (SHR) during development of hypertension. Brain Res. 1988;464:303–11.
Jung HJ, Kwon TH. Molecular mechanisms regulating aquaporin-2 in kidney collecting duct. Am J Physiol Ren Physiol. 2016;311:F1318–28.
Fujisawa Y, Miyatake A, Hayashida Y, Aki Y, Kimura S, Tamaki T, et al. Role of vasopressin on cardiovascular changes during hemorrhage in conscious rats. Am J Physiol. 1994;267:H1713–8.
Imai Y, Kim CY, Hashimoto J, Minami N, Munakata M, Abe K. Role of vasopressin in neurocardiogenic responses to hemorrhage in conscious rats. Hypertension. 1996;27:136–43.
Japundzic-Zigon N. Effects of nonpeptide V1a and V2 antagonists on blood pressure fast oscillations in conscious rats. Clin Exp Hypertens. 2001;23:277–92.
Altura BM, Altura BT. Actions of vasopressin, oxytocin, and synthetic analogs on vascular smooth muscle. Fed Proc. 1984;43:80–6.
Brizzee BL, Walker BR. Vasopressinergic augmentation of cardiac baroreceptor reflex in conscious rats. Am J Physiol. 1990;258:R860–8.
Shapiro RE, Miselis RR. The central neural connections of the area postrema of the rat. J Comp Neurol. 1985;234:344–64.
Imai Y, Nolan PL, Johnston CI. Johnston, Endogenous vasopressin modulates the baroreflex sensitivity in rats. Clin Exp Pharmacol Physiol. 1983;10:289–92.
Hasser EM, Bishop VS. Reflex effect of vasopressin after blockade of V1 receptors in the area postrema. Circ Res. 1990;67:265–71.
Sampey DB, Burrell LM, Widdop RE. Widdop. Vasopressin V2 receptor enhances gain of baroreflex in conscious spontaneously hypertensive rats. Am J Physiol. 1999;276:R872–9.
Japundžić-Žigon NLM, Šarenac O, Murphy D. Vasopressin & Oxytocin in Control of the Cardiovascular System: An Updated Review. Curr Neuropharmacol. 2020;18:14–33.
Hurbin A, Boissin-Agasse L, Orcel H, Rabié A, Joux N, Desarménien MG, et al. The V1a and V1b, but not V2, vasopressin receptor genes are expressed in the supraoptic nucleus of the rat hypothalamus, and the transcripts are essentially colocalized in the vasopressinergic magnocellular neurons. Endocrinology. 1998;139:4701–7.
Hurbin A, Orcel H, Alonso G, Moos F, Rabié A. The vasopressin receptors colocalize with vasopressin in the magnocellular neurons of the rat supraoptic nucleus and are modulated by water balance. Endocrinology. 2002;143:456–66.
Folkow B. Physiological aspects of primary hypertension. Physiol Rev. 1982;62:347–504.
DiBona GF, Rios LL. Mechanism of exaggerated diuresis in spontaneously hypertensive rats. Am J Physiol. 1978;235:409–16.
Koepke JP, DiBona GF. High sodium intake enhances renal nerve and antinatriuretic responses to stress in spontaneously hypertensive rats. Hypertension. 1985;7:357–63.
Koepke JP, Jones S, DiBona GF. Stress increases renal nerve activity and decreases sodium excretion in Dahl rats. Hypertension. 1988;11:334–8.
DiBona GF, Jones SY. Renal manifestations of NaCl sensitivity in borderline hypertensive rats. Hypertension. 1991;17:44–53.
Julien C, Malpas SC, Stauss HM. Sympathetic modulation of blood pressure variability. J Hypertens. 2001;19:1707–12.
Japundzic N, Grichois ML, Zitoun P, Laude D, Elghozi JL. Spectral analysis of blood pressure and heart rate in conscious rats: effects of autonomic blockers. J Auton Nerv Syst. 1990;30:91–100.
Akselrod S, Gordon D, Ubel FA, Shannon DC, Berger AC, Cohen RJ. Power spectrum analysis of heart rate fluctuation: a quantitative probe of beat-to-beat cardiovascular control. Science. 1981;213:220–2.
Malliani A, Lombardi F, Pagani M, Cerutti S. Power spectral analysis of cardiovascular variability in patients at risk for sudden cardiac death. J Cardiovasc Electrophysiol. 1994;5:274–86.
Japundžić-Žigon N, Šarenac O, Lozić M, Vasić M, Tasić T, Bajić D, et al. Sudden death: neurogenic causes, prediction and prevention. Eur J Prev Cardiol. 2018;25:29–39.
Brown DR, Li SG, Lawler JE, Randall DC. Sympathetic control of BP and BP variability in borderline hypertensive rats on high- vs. low-salt diet. Am J Physiol. 1999;277:R650–7.
Yagi K, Onaka T. Suppressive vasopressin response to emotional stress: the neuroactive substance that may be involved. Ann N Y Acad Sci. 1993;689:685–8.
Krause EG, Pati D, Frazier CJ. Chronic salt-loading reduces basal excitatory input to CRH neurons in the paraventricular nucleus and accelerates recovery from restraint stress in male mice. Physiol Behav. 2017;176:189–94.
Koshimizu TA, Nakamura K, Egashira N, Hiroyama M, Nonoguchi H, Tanoue A. Vasopressin V1a and V1b receptors: from molecules to physiological systems. Physiol Rev. 2012;92:1813–64.
Michel MC, Wieland T, Tsujimoto G. How reliable are G-protein-coupled receptor antibodies? Naunyn Schmiedebergs Arch Pharmacol. 2009;379:385–8.
Hamdani N, van der Velden J. Lack of specificity of antibodies directed against human beta-adrenergic receptors. Naunyn Schmiedebergs Arch Pharmacol. 2009;379:403–7.
Jositsch G, Papadakis T, Haberberger RV, Wolff M, Wess J, Kummer W. Suitability of muscarinic acetylcholine receptor antibodies for immunohistochemistry evaluated on tissue sections of receptor gene-deficient mice. Naunyn Schmiedebergs Arch Pharmacol. 2009;379:389–95.
Benicky J, Hafko R, Sanchez-Lemus E, Aguilera G, Saavedra JM. Six commercially available angiotensin II AT1 receptor antibodies are non-specific. Cell Mol Neurobiol. 2012;32:1353–65.
Hafko R, Villapol S, Nostramo R, Symes A, Sabban EL, Inagami T, et al. Commercially available angiotensin II At2 receptor antibodies are nonspecific. PLoS ONE. 2013;8:e69234.
Grimsey NL, Goodfellow CE, Scotter EL, Dowie MJ, Glass M, Graham ES. Specific detection of CB1 receptors; cannabinoid CB1 receptor antibodies are not all created equal! J Neurosci Methods. 2008;171:78–86.
Gautron L. On the necessity of validating antibodies in the immunohistochemistry literature. Front Neuroanat. 2019;13:46
Landgraf R, Neumann ID. Vasopressin and oxytocin release within the brain: a dynamic concept of multiple and variable modes of neuropeptide communication. Front Neuroendocrinol. 2004;25:150–76.
Kashiwazaki A, Fujiwara Y, Tsuchiya H, Sakai N, Shibata K, Koshimizu TA. Subcellular localization and internalization of the vasopressin V1B receptor. Eur J Pharmacol. 2015;765:291–9.
Acknowledgements
Serbian Ministry of Education, Science and Technological Development (MPNT/III/41013 BS, OS, NJZ). British Heart Foundation (RG/11/28714, DM; FS/12/5/29339, DM). BBSRC (BB/J005452/1, DM, OS). Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior—Brasil (CAPES)—(Finance Code 001, ASM, JAR)
Author information
Authors and Affiliations
Contributions
All authors contributed to the design and execution of the study, the analysis of the data, and the reporting and writing of the paper.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Savić, B., Martin, A., Mecawi, A.S. et al. Vasopressin and v1br gene expression is increased in the hypothalamic pvn of borderline hypertensive rats. Hypertens Res 43, 1165–1174 (2020). https://doi.org/10.1038/s41440-020-0469-2
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41440-020-0469-2