Neuropeptide changes in the suprachiasmatic nucleus in primary hypertension indicate functional impairment of the biological clock

Abnormalities in autonomic activity resulting in disturbances of the diurnal rhythm of many physiologic processes were recently revealed in hypertensive patients. These findings suggest deteriorations in the functioning of the suprachiasmatic nucleus (SCN), which is known to be the biological clock of mammals. To test this hypothesis, we carried out an immunocytochemical study of the SCN of primary hypertension patients who had died due to myocardial infarction or brain hemorrhage, and compared them with those of individuals with a normal blood pressure who had never had any autonomic disturbances and died from myocardial infarction after chest trauma or from hypothermia. We found that the staining for the three main neuronal populations of the SCN; i.e., vasopressin, vasoactive intestinal polypeptide, and neurotensin, reduced by more than 50% in the hypertensives compared with controls. The present data indicate a serious dysregulation of the biological clock in hypertensive patients. Such a disturbance may cause a harmful hemodynamic imbalance with a negative effect on circulation, especially in the morning, when the inactivity‐activity balance changes. The difficulty in adjusting from inactivity to activity might be involved in the morning clustering of cardiovascular events. J. Comp. Neurol. 431:320–330, 2001. © 2001 Wiley‐Liss, Inc.

[1]  Y. Postnov,et al.  Hypothalamic neurosecretory nuclei and nucleus habenularis of epithalamus in essential hypertension , 2004, Virchows Archiv A.

[2]  A. Loewy,et al.  Suprachiasmatic nucleus: a central autonomic clock , 1999, Nature Neuroscience.

[3]  Masaki Tanaka,et al.  Functional Morphology of the Suprachiasmatic Nucleus , 1999, Frontiers in Neuroendocrinology.

[4]  A. Kalsbeek,et al.  GABA release from suprachiasmatic nucleus terminals is necessary for the light-induced inhibition of nocturnal melatonin release in the rat , 1999, Neuroscience.

[5]  F. Scheer,et al.  Light and Diurnal Cycle Affect Human Heart Rate: Possible Role for the Circadian Pacemaker , 1999, Journal of biological rhythms.

[6]  H. Romijn,et al.  Anatomical and functional demonstration of a multisynaptic suprachiasmatic nucleus adrenal (cortex) pathway , 1999, The European journal of neuroscience.

[7]  Mark J. Zylka,et al.  A Molecular Mechanism Regulating Rhythmic Output from the Suprachiasmatic Circadian Clock , 1999, Cell.

[8]  D. Swaab,et al.  Postmortem tracing reveals the organization of hypothalamic projections of the suprachiasmatic nucleus in the human brain , 1998, The Journal of comparative neurology.

[9]  D. Weaver The Suprachiasmatic Nucleus: A 25-Year Retrospective , 1998, Journal of biological rhythms.

[10]  A. Kalsbeek,et al.  The suprachiasmatic nucleus-paraventricular nucleus interactions: a bridge to the neuroendocrine and autonomic nervous system. , 1998, Progress in brain research.

[11]  M. Coculescu,et al.  Vasopressin neurotransmission and the control of circadian rhythms in the suprachiasmatic nucleus. , 1998, Progress in brain research.

[12]  O. Tochikubo,et al.  Circadian variation of hemodynamics and baroreflex functions in patients with essential hypertension. , 1997, Hypertension research : official journal of the Japanese Society of Hypertension.

[13]  D. Swaab,et al.  Distribution of vasopressin and vasoactive intestinal polypeptide (VIP) fibers in the human hypothalamus with special emphasis on suprachiasmatic nucleus efferent projections , 1997, The Journal of comparative neurology.

[14]  G. Drolet,et al.  Chronic stress induces sensitization in sympathoadrenal responses to stress in borderline hypertensive rats. , 1997, The American journal of physiology.

[15]  A. Kalsbeek,et al.  Oxytocin innervation of spinal preganglionic neurons projecting to the superior cervical ganglion in the rat , 1997, Cell and Tissue Research.

[16]  M. Hofman,et al.  Morphometric analysis of vasopressin and vasoactive intestinal polypeptide neurons in the human suprachiasmatic nucleus: influence of microwave treatment , 1996, Brain Research.

[17]  L. Renaud,et al.  GABA and glutamate mediate rapid neurotransmission from suprachiasmatic nucleus to hypothalamic paraventricular nucleus in rat. , 1996, The Journal of physiology.

[18]  J. D. Miller,et al.  New insights into the mammalian circadian clock. , 1996, Sleep.

[19]  A. Kalsbeek,et al.  A Diurnal Rhythm of Stimulatory Input to the Hypothalamo–Pituitary–Adrenal System as Revealed by Timed Intrahypothalamic Administration of the Vasopressin V1Antagonist , 1996, The Journal of Neuroscience.

[20]  D F Swaab,et al.  Suprachiasmatic nucleus of the human brain: An immunocytochemical and morphometric analysis , 1996, The Anatomical record.

[21]  K. Kario,et al.  Nocturnal fall of blood pressure and silent cerebrovascular damage in elderly hypertensive patients. Advanced silent cerebrovascular damage in extreme dippers. , 1996, Hypertension.

[22]  M. Freund-Mercier,et al.  Oxytocin and vasopressin binding sites in the hypothalamus of the rat: Histoautoradiographic detection , 1995, Brain Research Bulletin.

[23]  M. Herold,et al.  Impaired nocturnal secretion of melatonin in coronary heart disease , 1995, The Lancet.

[24]  J. Palacios,et al.  In situ hybridization for vasopressin mRNA in the human supraoptic and paraventricular nucleus; quantitative aspects of formalin-fixed paraffin-embedded tissue sections as compared to cryostat sections , 1995, Journal of Neuroscience Methods.

[25]  D F Swaab,et al.  Image analyser-assisted morphometry of the locus coeruleus in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. , 1995, Brain : a journal of neurology.

[26]  B. Wallin,et al.  Central nervous system noradrenergic control of sympathetic outflow in normotensive and hypertensive humans. , 1995, Clinical and experimental hypertension.

[27]  R. Kronauer,et al.  Sensitivity of the Human Circadian Pacemaker to Moderately Bright Light , 1994, Journal of biological rhythms.

[28]  O. Tochikubo,et al.  Circadian variation of haemodynamics in patients with essential hypertension: comparison between early morning and evening , 1994, Journal of hypertension.

[29]  D. Swaab,et al.  Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients. , 1994, Neuroendocrinology.

[30]  M Munakata,et al.  Altered frequency-dependent characteristics of the cardiac baroreflex in essential hypertension. , 1994, Journal of the autonomic nervous system.

[31]  S. Shibata,et al.  Neurochemical organization of circadian rhythm in the suprachiasmatic nucleus , 1994, Neuroscience Research.

[32]  A. Coca,et al.  Circadian rhythm and blood pressure control: physiological and pathophysiological factors. , 1994, Journal of hypertension. Supplement : official journal of the International Society of Hypertension.

[33]  Y. Nakayama,et al.  Circadian variation of arginine-vasopressin messenger RNA in the rat suprachiasmatic nucleus. , 1994, Brain research. Molecular brain research.

[34]  L. Renaud,et al.  Ultrastructural evidence for intra‐ and extranuclear projections of GABAergic neurons of the suprachiasmatic nucleus , 1994, The Journal of comparative neurology.

[35]  A Malliani,et al.  Altered dynamics of the circadian relationship between systemic arterial pressure and cardiac sympathetic drive early on in mild hypertension. , 1994, Clinical science.

[36]  M. Hofman,et al.  Diurnal and Seasonal Rhythms of Neuronal Activity in the Suprachiasmatic Nucleus of Humans , 1993, Journal of biological rhythms.

[37]  F. Dudek,et al.  Cellular communication in the circadian clock, the suprachiasmatic nucleus , 1993, Neuroscience.

[38]  M. Markman,et al.  Projections of the suprachiasmatic nucleus to stress‐related areas in the rat hypothalamus: A light and electron microscopic study , 1993, The Journal of comparative neurology.

[39]  F. Abboud,et al.  Sympathetic-nerve activity during sleep in normal subjects. , 1993, The New England journal of medicine.

[40]  R. Moore Organization of the primate circadian system. , 1993, Journal of biological rhythms.

[41]  C. Rivier,et al.  Immunocytochemical and in situ hybridization detection of hypothalamic neuropeptides from postmortem unfixed rat brains , 1992, Neuroscience Letters.

[42]  A. Beaudet,et al.  Association of neurotensin receptors with VIP‐containing neurons and serotonin‐containing axons in the suprachiasmatic nucleus of the rat , 1992, Synapse.

[43]  D. Carter,et al.  Nuclear mechanisms mediate rhythmic changes in vasopressin mRNA expression in the rat suprachiasmatic nucleus. , 1992, Brain research. Molecular brain research.

[44]  Anna Wirz-Justice,et al.  A human phase-response curve to light , 1991, Neuroscience Letters.

[45]  Julio A. Panza,et al.  Circadian variation in vascular tone and its relation to α-sympathetic vasoconstrictor activity , 1991 .

[46]  A. Quyyumi,et al.  Circadian variation in vascular tone and its relation to alpha-sympathetic vasoconstrictor activity. , 1991, The New England journal of medicine.

[47]  G. Jennings,et al.  Increased regional sympathetic nervous activity in human hypertension: causes and consequences. , 1990, Journal of hypertension. Supplement : official journal of the International Society of Hypertension.

[48]  Y. Imai,et al.  Circadian blood pressure variations under different pathophysiological conditions. , 1990, Journal of hypertension. Supplement : official journal of the International Society of Hypertension.

[49]  N. Feinstein,et al.  Vasopressinergic innervation of the mouse suprachiasmatic nucleus: An immuno‐electron microscopic analysis , 1990, The Journal of comparative neurology.

[50]  T. Lang,et al.  [Sleep and hypertension. An epidemiologic study in 7,901 workers]. , 1990, Archives des maladies du coeur et des vaisseaux.

[51]  A. Mimran,et al.  Diabetic nephropathy in normotensive patients , 1990, Journal of hypertension. Supplement : official journal of the International Society of Hypertension.

[52]  G. Schillaci,et al.  Circadian blood pressure changes and left ventricular hypertrophy in essential hypertension. , 1990, Circulation.

[53]  T. Pickering The clinical significance of diurnal blood pressure variations. Dippers and nondippers. , 1990, Circulation.

[54]  B. Bagni,et al.  Circadian rhythms of atrial natriuretic peptide, renin, aldosterone, cortisol, blood pressure and heart rate in normal and hypertensive subjects. , 1990, Journal of hypertension.

[55]  H. Albers,et al.  Single unit response of suprachiasmatic neurons to arginine vasopressin (AVP) is mediated by a V1-like receptor in the hamster , 1989, Brain Research.

[56]  Y. Imai,et al.  Involvement of the hypothalamo—pituitary—adrenal axis in the control of circadian blood pressure rhythm , 1988, Journal of hypertension. Supplement : official journal of the International Society of Hypertension.

[57]  E. O’Brien,et al.  DIPPERS AND NON-DIPPERS , 1988, The Lancet.

[58]  P. J. van der Sluis,et al.  Immunochemical detection of peptides and proteins on press‐blots after direct tissue gel isoelectric focusing , 1988, Electrophoresis.

[59]  P. J. van der Sluis,et al.  Press-blotting on gelatin-coated nitrocellulose membranes. A method for sensitive quantitative immunodetection of peptides after gel isoelectric focusing. , 1987, Journal of immunological methods.

[60]  A. Dyer,et al.  Do hypertensive patients have a different diurnal pattern of electrolyte excretion? , 1987, Hypertension.

[61]  J. Mai,et al.  Neurotensin in the human brain , 1987, Neuroscience.

[62]  E. Braunwald,et al.  Circadian variation in the frequency of onset of acute myocardial infarction. , 1985, The New England journal of medicine.

[63]  P. Rabins,et al.  Prevalence and Significance of Cardiovascular Disease and Hypertension in Elderly Patients With Dementia and Depression , 1985, Journal of the American Geriatrics Society.

[64]  J. Sowers,et al.  Enhanced 24-hour norepinephrine and renin secretion in young patients with essential hypertension: relation with the circadian pattern of arterial blood pressure. , 1985, The American journal of cardiology.

[65]  B. Folkow Physiological aspects of primary hypertension. , 1982, Physiological reviews.

[66]  A. Pol The hypothalamic suprachiasmatic nucleus of rat: Intrinsic anatomy , 1980 .

[67]  A. N. van den Pol The hypothalamic suprachiasmatic nucleus of rat: Intrinsic anatomy , 1980, The Journal of comparative neurology.

[68]  T. Klumpp Penicillin and Streptomycin. , 1946, American journal of public health and the nation's health.