Growth Hormone and Hexarelin Prevent Endothelial Vasodilator Dysfunction in Aortic Rings of the Hypophysectomized Rat

Rossoni, Giuseppe; Locatelli,; Colonna, De Gennaro; Torsello, Antonio; Schweiger, F; Boghen, M.; Nilsson, Mia; Bernareggi, Micaela; Ee, Müller; Berti, F.

doi:10.1097/00005344-199909000-00021

Cited by 27 publications

(19 citation statements)

References 17 publications

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“…Chronic treatment with GH results in improved vascular function (10). It has also been demonstrated that substitution with thyroxine (T 4 ) and GH is required for the increase in BP and for the normal adaptation of the structure of the heart and the vessels in Hx rats (9).…”

Section: Introductionmentioning

confidence: 99%

GH and IGF-I regulate the expression of endothelial nitric oxide synthase (eNOS) in cardiovascular tissues of hypophysectomized female rats

Wickman

Jonsdottir

Bergström

et al. 2002

European Journal of Endocrinology

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Objective: This study explored whether short-term replacement therapy with growth hormone (GH) affects blood pressure (BP), heart rate (HR) and endothelial nitric oxide synthase (eNOS) expression in cardiovascular tissues in hypophysectomized (Hx) female rats. Design and Methods: BP, HR and the expression of eNOS in the aorta, caval vein and heart were studied in Hx female rats and in Hx female rats that underwent 7 days treatment with GH and thyroxine þ glucocorticoids ð½T 4 þ GCÞ: Insulin-like growth factor-I (IGF-I) was included in a second experimental protocol to explore the indirect effect of GH. The expression and localisation of eNOS was analysed by immunoblotting and immunohistochemistry. Results: Decreased BP (Hx 98^1; Intact 129^3 mmHg; P , 0:05), HR (Hx 297^14; Intact 399^31 beats=min; P , 0:05) and unchanged eNOS expression was demonstrated in Hx compared with intact rats. None of the hormones affected BP, but both GH and IGF-I increased HR compared with Hx rats (GH 358^10; IGF-I 337^7; Hx 306^11 beats=min; P , 0:05). Replacement of GH, GH þ ½T 4 þ GC and IGF-I resulted in an increased aortic eNOS expression (GH 161^24; GH þ ½T 4 þ GC 177^25; IGF-I 153^21; Hx 109^7%; P , 0:05), whereas in caval vein only GH þ ½T 4 þ GC affected eNOS expression. None of the hormones changed the level of eNOS in the heart. eNOS was localised in the intima layer of the aorta, whereas in the caval vein eNOS was localised in all cell layers. Conclusions: These findings support the suggested positive role of GH in the regulation of the cardiovascular homeostasis. The observed up-regulation of eNOS, and presumably an increased NO bioavailability, may result in improved endothelial and cardiovascular function.

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Section: Introductionmentioning

confidence: 99%

GH and IGF-I regulate the expression of endothelial nitric oxide synthase (eNOS) in cardiovascular tissues of hypophysectomized female rats

Wickman

Jonsdottir

Bergström

et al. 2002

European Journal of Endocrinology

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“…Pre-administration of ghrelin in vivo greatly ameliorated the damaged heart function, attenuated myocardial injury, and apoptosis through inhibition of ER stress [170]. The role of hexarelin on the protection against cardiac ischemia has been reported earlier [67,68,171]. Rats pre-treated with ghrelin or hexarelin for 7 days in vivo prior to in vitro I/R injury showed an improvement in cardiac function [172].…”

Section: Ghrelin and Hexarelin Promote Mitochondrial Activity And Biomentioning

confidence: 88%

“…Hexarelin has many physiological actions independent of growth hormone such as the protection against cardiac ischemia and impairment of vascular endothelium function in the hearts of GH-deficient rats [67,68]. GHS-R1a seems to mediate the action of hexarelin.…”

Section: Growth Hormone Secretagogues (Ghs)mentioning

confidence: 99%

Implications of ghrelin and hexarelin in diabetes and diabetes-associated heart diseases

et al. 2015

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Ghrelin and its synthetic analog hexarelin are specific ligands of growth hormone secretagogue (GHS) receptor. GHS have strong growth hormone-releasing effect and other neuroendocrine activities such as stimulatory effects on prolactin and adrenocorticotropic hormone secretion. Recently, several studies have reported other beneficial functions of GHS that are independent of GH. Ghrelin and hexarelin, for examples, have been shown to exert GH-independent cardiovascular activity. Hexarelin has been reported to regulate peroxisome proliferator-activated receptor gamma (PPAR-γ) in macrophages and adipocytes. PPAR-γ is an important regulator of adipogenesis, lipid metabolism, and insulin sensitization. Ghrelin also shows protective effects on beta cells against lipotoxicity through activation of phosphatidylinositol-3 kinase/protein kinase B, c-Jun N-terminal kinase ( JNK) inhibition, and nuclear exclusion of forkhead box protein O1. Acylated ghrelin (AG) and unacylated ghrelin (UAG) administration reduces glucose levels and increases insulinproducing beta cell number, and insulin secretion in pancreatectomized rats and in newborn rats treated with streptozotocin, suggesting a possible role of GHS in pancreatic regeneration. Therefore, the discovery of GHS has opened many new perspectives in endocrine, metabolic, and cardiovascular research areas, suggesting the possible therapeutic application in diabetes and diabetic complications especially diabetic cardiomyopathy. Here, we review the physiological roles of ghrelin and hexarelin in the protection and regeneration of beta cells and their roles in the regulation of insulin release, glucose, and fat metabolism and present their potential therapeutic effects in the treatment of diabetes and diabetic-associated heart diseases. Disciplines Medicine and Health Sciences Publication DetailsMosa, R., Zhang, Z., Shao, R., Deng, C., Chen, J. & Chen, C. (2015). Implications of ghrelin and hexarelin in diabetes and diabetes-associated heart diseases. Endocrine, 49 (2) AbstractGhrelin and its synthetic analog hexarelin are specific ligands of growth hormone secretagogue (GHS) receptor. GHS have strong growth hormone-releasing effect and other neuroendocrine activities such as stimulatory effects on prolactin and adrenocorticotropic hormone secretion. Recently, several studies have reported other beneficial functions of GHS that are independent of GH. Ghrelin and hexarelin, for examples, have been shown to exert GH-independent cardiovascular activity. Hexarelin has been reported to regulate peroxisome proliferator-activated receptor gamma (PPAR-γ) in macrophages and adipocytes. PPAR-γ is an important regulator of adipogenesis, lipid metabolism, and insulin sensitization. Ghrelin also shows protective effects on beta cells against lipotoxicity through activation of phosphatidylinositol-3 kinase/protein kinase B, c-Jun N-terminal kinase (JNK) inhibition, and nuclear exclusion of forkhead box protein O1. Acylated ghrelin (AG) and unacylated ghrelin (UAG) administration redu...

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“…Besides affecting cardiac structure and contractility (Fazio et al 1997, Longobardi et al 2000, Barreto-Filho et al 2002, both experimental and clinical GH deficiency has been associated with increased systemic vascular resistance (Fazio et al 1997, Longobardi et al 2000 and abnormal vascular reactivity (Rossoni et al 1999, Evans et al 2000, Capaldo et al 2001. Accordingly, an increased prevalence of hypertension (Barreto-Filho et al 2002) and atherosclerotic disease (Pfeifer et al 1999) has been reported among patients with GH deficiency, and hypopituitary patients show increased cardiovascular morbidity and mortality (Rosen & Bengtsson 1990).…”

Section: Introductionmentioning

confidence: 99%

“…Accordingly, an increased prevalence of hypertension (Barreto-Filho et al 2002) and atherosclerotic disease (Pfeifer et al 1999) has been reported among patients with GH deficiency, and hypopituitary patients show increased cardiovascular morbidity and mortality (Rosen & Bengtsson 1990). GH treatment in GH deficient states has been shown to normalize systemic vascular resistance (Boger et al 1996, Longobardi et al 2000, arterial stiffness (Smith et al 2002), endothelial and/or endothelium-independent vasodilation (Rossoni et al 1999, Evans et al 2000, Capaldo et al 2001, and may reverse markers of early atherosclerosis (Pfeifer et al 1999).…”

Section: Introductionmentioning

confidence: 99%

Growth hormone-induced blood pressure decrease is associated with increased mRNA levels of the vascular smooth muscle KATP channel

Tivesten¹,

Barlind²,

Caidahl³

et al. 2004

Journal of Endocrinology

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Growth hormone (GH) deficiency is associated with abnormal vascular reactivity and development of atherosclerosis. GH treatment in GH deficient states restores systemic vascular resistance, arterial compliance, endothelium-dependent and endothelium-independent vasodilation, and may reverse markers of early atherosclerosis. However, very little is known about the molecular mechanisms underlying these effects. In the present study, male Sprague Dawley rats were hypophysectomized and treated for two weeks with GH (recombinant human GH, 2 mg/kg/day) or saline as s.c. injections twice daily. GH decreased aortic systolic blood pressure compared with saline-treated animals, while the diastolic blood pressure was not significantly changed. GH treatment increased cardiac output as determined by Dopplerechocardiography and the calculated systemic vascular resistance was markedly reduced. In order to identify GH-regulated genes of importance for vascular function, aortic mRNA levels were analyzed by the microarray technique and correlated to the systolic blood pressure levels. Using this approach, we identified 18 GHregulated genes with possible impact on vascular tone and atherogenesis. In particular, mRNA levels of the inwardly rectifying potassium channel Kir6·1 and the sulfonylurea receptor 2B, which together form the vascular smooth muscle ATP-sensitive potassium channel, were both upregulated by GH treatment and highly correlated to systolic blood pressure. Our findings establish a major role for GH in the regulation of vascular physiology and gene expression. Increased expression of the ATP-sensitive potassium channel, recently shown to be crucial in the regulation of vascular tone, constitutes a possible mechanism by which GH governs vascular tone.

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Growth Hormone and Hexarelin Prevent Endothelial Vasodilator Dysfunction in Aortic Rings of the Hypophysectomized Rat

Cited by 27 publications

References 17 publications

GH and IGF-I regulate the expression of endothelial nitric oxide synthase (eNOS) in cardiovascular tissues of hypophysectomized female rats

GH and IGF-I regulate the expression of endothelial nitric oxide synthase (eNOS) in cardiovascular tissues of hypophysectomized female rats

Implications of ghrelin and hexarelin in diabetes and diabetes-associated heart diseases

Growth hormone-induced blood pressure decrease is associated with increased mRNA levels of the vascular smooth muscle KATP channel

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