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Current Hypertension Reports
Published in: Current Hypertension Reports 2/2016

01-02-2016 | Hypertension and Metabolic Syndrome (J Sperati, Section Editor)

Ghrelin and Blood Pressure Regulation

Authors: Yuanjie Mao, Takeshi Tokudome, Ichiro Kishimoto

Published in: Current Hypertension Reports | Issue 2/2016

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Abstract

Ghrelin is a growth hormone-releasing polypeptide that was first isolated from the rat stomach in 1999. High expression of growth hormone secretagogue receptor, the ghrelin receptor, in the heart, kidney, and blood vessels provides evidence of ghrelin activity in blood pressure regulation. Circulating ghrelin concentrations are reported to be inversely correlated with blood pressure, and the acute and chronic effects of ghrelin in decreasing blood pressure have been reported in animals with normal blood pressure, healthy individuals, animals and patients with heart failure, and animals with hypertension. The mechanism by which ghrelin regulates blood pressure appears to be related to modulation of the autonomic nervous system, direct vasodilatory activities, and kidney diuresis. Thus, modulation of the signaling pathway through ghrelin may provide a novel concept for treating hypertension. In this review, we discuss the current evidence and potential mechanisms of ghrelin activity in blood pressure regulation.
Literature
1.
Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402(6762):656–60.CrossRefPubMed
2.
3.
Pöykkö SM, Kellokoski E, Hörkkö S, Kauma H, Kesäniemi YA, Ukkola O. Low plasma ghrelin is associated with insulin resistance, hypertension, and the prevalence of type 2 diabetes. Diabetes. 2003;52(10):2546–53.CrossRefPubMed
4.
Matsumura K, Tsuchihashi T, Fujii K, Abe I, Iida M. Central ghrelin modulates sympathetic activity in conscious rabbits. Hypertension. 2002;40(5):694–9.CrossRefPubMed
5.
Nagaya N, Kojima M, Uematsu M, Yamagishi M, Hosoda H, Oya H, et al. Hemodynamic and hormonal effects of human ghrelin in healthy volunteers. Am J Physiol Regul Integr Comp Physiol. 2001;280(5):1483–7.
6.
Nagaya N, Miyatake K, Uematsu M, Oya H, Shimizu W, Hosoda H, et al. Hemodynamic, renal, and hormonal effects of ghrelin infusion in patients with chronic heart failure. J Clin Endocrinol Metab. 2001;86(12):5854–9.CrossRefPubMed
7.
Nagaya N, Uematsu M, Kojima M, Ikeda Y, Yoshihara F, Shimizu W, et al. Chronic administration of ghrelin improves left ventricular dysfunction and attenuates development of cardiac cachexia in rats with heart failure. Circulation. 2001;104(12):1430–5.CrossRefPubMed
8.•
Aoki H, Nakata M, Dezaki K, Lu M, Gantulga D, Yamamoto K, et al. Ghrelin counteracts salt-induced hypertension via promoting diuresis and renal nitric oxide production in Dahl rats. Endocr J. 2013;60(5):571–81. Demonstrated the long term effects of ghrelin in promoting diuresis and blood pressure regulation.CrossRefPubMed
9.
Li ZF, Guo ZF, Yang SG, Zheng X, Cao J, Qin YW. Circulating ghrelin and ghrelin to obestatin ratio are low in patients with untreated mild-to-moderate hypertension. Regul Pept. 2010;165(2–3):206–9.CrossRefPubMed
10.
Chang L, Ren Y, Liu X, Li WG, Yang J, Geng B, et al. Protective effects of ghrelin on ischemia/reperfusion injury in isolated rat heart. J Cardiovasc Pharmacol. 2004;43(2):165–70.CrossRefPubMed
11.
Karcz-Socha I, Zwirska-Korczala K, Zembala M, Borgiel-Marek H, Karcz K. Ghrelin PYY 3-36 serum changes in left ventricular hypertrophic, insulin-resistant, hypertensive obese patients. Obes Facts. 2011;4(5):386–92.CrossRefPubMed
12.
Greenman Y, Rouach V, Limor R, Gilad S, Stern N. Testosterone is a strong correlate of ghrelin levels in men and postmenopausal women. Neuroendocrinology. 2009;89(1):79–85.CrossRefPubMed
13.
Shiiya T, Nakazato M, Mizuta M, Matsukara S, Mondal MS, Tanaka M, et al. Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion. J Clin Endocrinol Metab. 2002;87(1):240–4.CrossRefPubMed
14.
David E, David S, Frayo RS, Breen PA, Marina K, Dellinger EP, et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med. 2002;346(21):1623–30.CrossRef
15.
Monti V, Carlson JJ, Hunt SC, Adams TD. Relationship of ghrelin and leptin hormones with body mass index and waist circumference in random sample of adults. J Am Diet Assoc. 2006;106(6):822–8.CrossRefPubMed
16.
Sondergaard E, Gormsen LC, Nellemann B. Visceral fat mass is a strong predictor of circulating ghrelin levels in premenopausal women. Eur J Endocrinol. 2009;160(3):375–9.CrossRefPubMed
17.
Tschöp M, Weyer CW, Tataranni PA, Devanarayan V, Ravussin E, Heiman M. Circulating ghrelin levels are decreased in human obesity. Diabetes. 2001;50(4):707–9.CrossRefPubMed
18.
Vendrell J, Broch M, Vilarrasa N, Molina A, Gómez JM, Gutiérrez C, et al. Resistin, adiponectin, ghrelin, leptin and proinflammatory cytokines: relationships in obesity. Obes Res. 2004;12(6):962–71.CrossRefPubMed
19.
Skoczylas A, Adamczak M, Chudek J, Wiecek A. Cilazapril increases plasma ghrelin concentration in obese patients with arterial hypertension. Endokrynol Pol. 2010;61(1):21–7.PubMed
20.
Oner-Iyidoğan Y, Koçak H, Gürdöl F, Oner P, Issever H, Esin D. Circulating ghrelin levels in obese women: a possible association with hypertension. Scand J Clin Lab Invest. 2007;67(5):568–76.CrossRefPubMed
21.•
Stępień M, Wlazeł RN, Paradowski M, Banach M, Rysz M, Misztal M, et al. Serum concentrations of adiponectin, leptin, resistin, ghrelin and insulin and their association with obesity indices in obese normo- and hypertensive patients—pilot study. Arch Med Sci. 2012;8(3):431–6. Suggested that obesity could be a stronger determinant of ghrelin secretion than hypertension.PubMedCentralPubMed
22.•
Hamada N, Nishi Y, Tajiri Y, Setoyama K, Kamimura R, Miyahara K, et al. Disrupted regulation of ghrelin production under antihypertensive treatment in spontaneously hypertensive rats. Circ J. 2012;76(6):1423–9. Indicated that the circulating levels of ghrelin are controlled by the ambient vascular tone and vice versa.CrossRefPubMed
23.
Mundinger TO, Cummings DE, Taborsky Jr GJ. Direct stimulation of ghrelin secretion by sympathetic nerves. Endocrinology. 2006;147(6):2893–901.CrossRefPubMed
24.
Zhao TJ, Sakata I, Li RL, Liang G, Richardson JA, Brown MS, et al. Ghrelin secretion stimulated by {beta}1-adrenergic receptors in cultured ghrelinoma cells and in fasted mice. Proc Natl Acad Sci U S A. 2010;107(36):15868–73.PubMedCentralCrossRefPubMed
25.
Engelstoft MS, Park WM, Sakata I, Kristensen LV, Husted AS, Osborne-Lawrence S, et al. Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells. Mol Metab. 2013;2(4):376–92.PubMedCentralCrossRefPubMed
26.
Gagnon J, Anini Y. Insulin and norepinephrine regulate ghrelin secretion from a rat primary stomach cell culture. Endocrinology. 2012;153(8):3646–56.CrossRefPubMed
27.
Gagnon J, Anini Y. Glucagon stimulates ghrelin secretion through the activation of MAPK and EPAC and potentiates the effect of norepinephrine. Endocrinology. 2013;154(2):666–74.CrossRefPubMed
28.
Hosoda H, Kangawa K. The autonomic nervous system regulates gastric ghrelin secretion in rats. Regul Pept. 2008;146(1–3):12–8.CrossRefPubMed
29.
Broglio F, Gottero C, Van Koetsveld P, Prodam F, Destefanis S, Benso A, et al. Acetylcholine regulates ghrelin secretion in humans. J Clin Endocrinol Metab. 2004;89(5):2429–33.CrossRefPubMed
30.
Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes. 2001;50(8):1714–9.CrossRefPubMed
31.
Griffen SC, Oostema K, Stanhope KL, Graham J, Styne DM, Glaser N, et al. Administration of Lispro insulin with meals improves glycemic control, increases circulating leptin, and suppresses ghrelin, compared with regular/NPH insulin in female patients with type 1 diabetes. J Clin Endocrinol Metab. 2006;91(2):485–91.CrossRefPubMed
32.
Ryber L, Obrink K, Houe N, Frystyk J, Jørgensen JO. Serum ghrelin levels are suppressed in hypopituitary patients following insulin-induced hypoglycaemia irrespective of GH status. Clin Endocrinol (Oxf). 2006;65(2):210–4.CrossRef
33.
Iwakura H, Akamizu T, Ariyasu H, Irako T, Hosoda K, Nakao K, et al. Effects of ghrelin administration on decreased growth hormone status in obese animals. Am J Physiol Endocrinol Metab. 2007;293(3):E819–25.CrossRefPubMed
34.
Enomoto M, Nagaya N, Uematsu M, Okumura H, Nakagawa E, Ono F, et al. Cardiovascular and hormonal effects of subcutaneous administration of ghrelin, a novel growth hormone-releasing peptide, in healthy humans. Clin Sci. 2003;105(4):431–5.CrossRefPubMed
35.
Nagaya N, Moriya J, Yasumura Y, Uematsu M, Ono F, Shimizu W, et al. Effects of ghrelin administration on left ventricular function, exercise capacity, and muscle wasting in patients with chronic heart failure. Circulation. 2004;110(24):3674–9.CrossRefPubMed
36.
Shimizu Y, Nagaya N, Teranishi Y, Imazu M, Yamamoto H, Shokawa T, et al. Ghrelin improves endothelial dysfunction through growth hormone-independent mechanisms in rats. Biochem Biophys Res Commun. 2003;310(3):830–5.CrossRefPubMed
37.
Okumura H, Nagaya N, Enomoto M, Nakagawa E, Oya H, Kangawa K. Vasodilatory effect of ghrelin, an endogenous peptide from the stomach. J Cardiovasc Pharmacol. 2002;39(6):779–83.CrossRefPubMed
38.
Wiley KE, Davenport AP. Comparison of vasodilators in human internal mammary artery: ghrelin is a potent physiological antagonist of endothelin-1. Br J Pharmacol. 2002;136(8):1146–52.PubMedCentralCrossRefPubMed
39.
Iantorno M, Chen H, Kim JA, Tesauro M, Lauro D, Cardillo C, et al. Ghrelin has novel vascular actions that mimic PI 3-kinase-dependent actions of insulin to stimulate production of NO from endothelial cells. Am J Physiol Endocrinol Metab. 2007;292(3):E756–64.CrossRefPubMed
40.
Lin Y, Matsumura K, Fukuhara M, Kagiyama S, Fujii K, Iida M. Ghrelin acts at the nucleus of the solitary tract to decrease arterial pressure in rats. Hypertension. 2004;43(5):977–82.CrossRefPubMed
41.
Mao Y, Tokudome T, Kishimoto I. Ghrelin as a treatment for cardiovascular diseases. Hypertension. 2014;64(3):450–4.CrossRefPubMed
42.
Soeki T, Kishimoto I, Schwenke DO, Tokudome T, Horio T, Yoshida M, et al. Ghrelin suppresses cardiac sympathetic activity and prevents early left ventricular remodeling in rats with myocardial infarction. Am J Physiol Heart Circ Physiol. 2008;294(1):H426–32.CrossRefPubMed
43.
Mao Y, Tokudome T, Otani K, Kishimoto I, Nakanishi M, Hosoda H, et al. Ghrelin prevents incidence of malignant arrhythmia after acute myocardial infarction through vagal afferent nerves. Endocrinology. 2012;153(7):3426–34.CrossRefPubMed
44.
Yasuda T, Masaki T, Kakuma T, Yoshimatsu H. Centrally administered ghrelin suppresses sympathetic nerve activity in brown adipose tissue of rats. Neurosci Lett. 2003;349(2):75–8.CrossRefPubMed
45.
Mano-Otagiri A, Ohata H, Iwasaki-Sekino A, Nemoto T, Shibasaki T. Ghrelin suppresses noradrenaline release in the brown adipose tissue of rats. J Endocrinol. 2009;201(3):341–9.CrossRefPubMed
46.•
Prior LJ, Davern PJ, Burke SL, Lim K, Armitage JA, Head GA. Exposure to a high-fat diet during development alters leptin and ghrelin sensitivity and elevates renal sympathetic nerve activity and arterial pressure in rabbits. Hypertension. 2014;63(2):338–45. Proposed that ghrelin acutely reduced mean arterial pressure by central reducing sympathetic nerve activity to the heart or to nonrenal vasculature.CrossRefPubMed
47.•
Sato T, Nakashima Y, Nakamura Y, Ida T, Kojima M. Continuous antagonism of the ghrelin receptor results in early induction of salt-sensitive hypertension. J Mol Neurosci. 2011;43(2):193–9. Demonstrated that continuous antagonism of the ghrelin receptor results in hypertension and increases in sympathetic nervous activity.CrossRefPubMed
48.
Tan DY, Meng S, Manning Jr RD. Role of neuronal nitric oxide synthase in Dahl salt-sensitive hypertension. Hypertension. 1999;33(1Pt2):456–61.CrossRefPubMed
49.•
Mao Y, Tokudome T, Kishimoto I, Otani K, Nishimura H, Yamaguchi O, et al. Endogenous ghrelin attenuates pressure overload-induced cardiac hypertrophy via a cholinergic anti-inflammatory pathway. Hypertension. 2015;65(6):1238–44. Demonstrated that the modulation of parasympathetic nervous activity by ghrelin plays a role in the pressure overload-induced cardiac hypertrophy.CrossRefPubMed
50.
Callaghan B, Kosari S, Pustovit RV, Sartor DM, Ferens D, Ban K, et al. Hypotensive effects of ghrelin receptor agonists mediated through a novel receptor. Br J Pharmacol. 2014;171(5):1275–86.PubMedCentralCrossRefPubMed
51.
Broad J, Callaghan B, Sanger GJ, Brock JA, Furness JB. Analysis of the ghrelin receptor-independent vascular actions of ulimorelin. Eur J Pharmacol. 2015;752:34–9.CrossRefPubMed
52.
Xu X, Ding F, Pang J, Gao X, Xu RK, Hao W, et al. Chronic administration of hexarelin attenuates cardiac fibrosis in the spontaneously hypertensive rat. Am J Physiol Heart Circ Physiol. 2012;303(6):H703–11.CrossRefPubMed
53.
Metadata
Title
Ghrelin and Blood Pressure Regulation
Authors
Yuanjie Mao
Takeshi Tokudome
Ichiro Kishimoto
Publication date
01-02-2016
Publisher
Springer US
Published in
Current Hypertension Reports / Issue 2/2016
Print ISSN: 1522-6417
Electronic ISSN: 1534-3111
DOI
https://doi.org/10.1007/s11906-015-0622-5

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