Hexarelin, a growth hormone secretagogue, protects the isolated rat heart from ventricular dysfunction produced by exposure to calcium-free medium

Rossoni, Giuseppe; Locatelli, Vittorio; Colonna, Vito De Gennaro; Müller, Eugenio E.; Berti, F.

doi:10.1006/phrs.2000.0665

Cited by 11 publications

(7 citation statements)

References 16 publications

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“…Thus, when the isolated perfused heart preparation was subjected to L-type Ca 2ϩ channel blockade, the developed pressure significantly decreased (as expected), yet coinfusion of ghrelin with diltiazem restored developed pressure to vehicle control levels. In this context, in vivo subcutaneous administration of hexarelin for 7 days has been reported to precondition and protect subsequent isolated perfused heart preparations against calcium overload-induced increases in left ventricular end-diastolic pressure in normal rats subjected to low Ca 2ϩ perfusion/normal Ca 2ϩ reperfusion (29) or to ischemia-reperfusion injury in hypophysectomized rats (17). Furthermore, in vivo evidence of hexarelin-induced improvements in cardiac function have been reported after bolus injection in humans (2), and in vitro data from isolated rat heart preparations suggest that ghrelin may be protective against ischemia-reperfusion injury, at least partially through reducing myocyte lactate dehydrogenase and myoglobin release (4) and/or via PKC-related mechanisms (7).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, GHS-R populations have been detected in the heart, and these are thought to mediate the coronary vasoconstrictor actions of the synthetic GH-releasing hexapeptide hexarelin in isolated heart preparations (3). Hexarelin improves cardiac function and decreases peripheral resistance in rats with myocardial infarction (35) and also protects the isolated heart from ventricular dysfunction associated with Ca 2ϩ depletion (29). Ghrelin may also have a role in the cardiovascular system, because it is expressed in the heart at both the RNA (14) and peptide (10) levels and it decreases mean arterial pressures and increases cardiac index and stroke volume index without any effect on heart rate in humans (21).…”

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confidence: 99%

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Ghrelin induces vasoconstriction in the rat coronary vasculature without altering cardiac peptide secretion

Pemberton¹,

Tokola²,

Bagi³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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We administered ghrelin, a novel growth hormone-releasing hormone, to isolated perfused rat hearts, coronary arterioles, and cultured neonatal cardiomyocytes to determine its effects on coronary vascular tone, contractility, and natriuretic peptide secretion and gene expression. We also determined cardiac levels of ghrelin and whether the heart is a source of the circulating peptide. Ghrelin dose dependently increased coronary perfusion pressure (44 +/- 9%, P < 0.01), constricted isolated coronary arterioles (12 +/- 2%, P < 0.05), and significantly enhanced the pressure-induced myogenic tone of arterioles. These effects were blocked by diltiazem, an L-type Ca(2+) channel blocker, and bisindolylmaleimide (Bis), a protein kinase C (PKC) inhibitor. Interestingly, coinfusion of ghrelin with diltiazem completely restored myocardial contractile function that was decreased 30 +/- 3% (P < 0.01) by diltiazem alone. In contrast, combination of ghrelin with diltiazem or Bis did not significantly alter atrial natriuretic peptide (ANP) secretion, which was decreased 40% (P < 0.01) and 50% (P < 0.05) by these agents alone, respectively. Administration of ghrelin to cultured cardiomyocytes had no effect on ANP or B-type natriuretic peptide secretion or gene expression. Detectable amounts of low-molecular-weight ghrelin were present in cardiac tissue extracts but not in isolated heart perfusate. Thus we provide the first evidence that ghrelin has a coronary vasoconstrictor action that is dependent on Ca(2+) and PKC. Furthermore, the data obtained from diltiazem infusion suggest that ghrelin has a role in regulation of contractility when L-type Ca(2+) channels are blocked. Finally, the observation that immunoreactive ghrelin is found in cardiac tissue suggests the presence of a local cardiac ghrelin system.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Ghrelin induces vasoconstriction in the rat coronary vasculature without altering cardiac peptide secretion

Pemberton¹,

Tokola²,

Bagi³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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“…Recent evidence has indicated that GHSs improve LV dysfunction, diminish LV pathological remodeling (10,21,39), and alleviate infarction-enhanced and workload-induced heart failure (15,26). Our previous study (38) has shown that hexarelin significantly suppressed ANG II-and transforming growth factor (TGF)-␤-induced cardiac fibroblast proliferation and collagen synthesis in cultured rat cardiac fibroblasts, despite that fact that ANG II and TGF-␤ are two potent and key profibrotic factors.…”

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confidence: 99%

Chronic administration of hexarelin attenuates cardiac fibrosis in the spontaneously hypertensive rat

Fan

Pang

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Cardiac fibrosis is a hallmark of heart disease and plays a vital role in cardiac remodeling during heart diseases, including hypertensive heart disease. Hexarelin is one of a series of synthetic growth hormone secretagogues (GHSs) possessing a variety of cardiovascular effects via action on GHS receptors (GHS-Rs). However, the role of hexarelin in cardiac fibrosis in vivo has not yet been investigated. In the present study, spontaneously hypertensive rats (SHRs) were treated with hexarelin alone or in combination with a GHS-R antagonist for 5 wk from an age of 16 wk. Hexarelin treatment significantly reduced cardiac fibrosis in SHRs by decreasing interstitial and perivascular myocardial collagen deposition and myocardial hydroxyproline content and reducing mRNA and protein expression of collagen I and III in SHR hearts. Hexarelin treatment also increased matrix metalloproteinase (MMP)-2 and MMP-9 activities and decreased myocardial mRNA expression of tissue inhibitor of metalloproteinase (TIMP)-1 in SHRs. In addition, hexarelin treatment significantly attenuated left ventricular (LV) hypertrophy, LV diastolic dysfunction, and high blood pressure in SHRs. The effect of hexarelin on cardiac fibrosis, blood pressure, and cardiac function was mediated by its receptor, GHS-R, since a selective GHS-R antagonist abolished these effects and expression of GHS-Rs was upregulated by hexarelin treatment. In summary, our data demonstrate that hexarelin reduces cardiac fibrosis in SHRs, perhaps by decreasing collagen synthesis and accelerating collagen degradation via regulation of MMPs/TIMP. Hexarelin-reduced systolic blood pressure may also contribute to this reduced cardiac fibrosis in SHRs. The present findings provided novel insights and underscore the therapeutic potential of hexarelin as an antifibrotic agent for the treatment of cardiac fibrosis.

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“…Recent evidence indicates that GHSs feature a variety of cardiovascular activities, including an increase in myocardial contractility (6 -8), improvement of left ventricular dysfunction and left ventricular pathological remodeling (9 -12), protection of cardiomyocytes from angiotensin II-induced apoptosis (2), amelioration of myocardial infarction-induced or pressure overload-induced heart failure in vivo (13)(14)(15), inhibition of collagen synthesis, and proliferation of cardiac fibroblasts (16). However, the cellular and molecular mechanisms underlying the immediate effect of GHSs on cardiomyocytes have not been fully established (16,17).…”

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confidence: 99%

Effects of GH Secretagogues on Contractility and Ca²⁺Homeostasis of Isolated Adult Rat Ventricular Myocytes

Sun¹,

Ma²,

Zhang³

et al. 2010

Endocrinology

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Ghrelin and its synthetic analogue hexarelin are specific ligands of GH secretagogue receptor (GHS-R) and induce a variety of cardiovascular protective and cardiac positive inotropic effects. The signaling system underlying immediate effects of both GHSs in cardiomyocytes remains undefined. In the present study, we investigated the immediate effects of GHSs on isolated ventricular myocyte shortening, intracellular Ca(2+) ([Ca(2+)](i)) transients, and the L-type Ca(2+) current (I(Ca,L)). Putative intracellular signalling cascades were studied with specific receptor and signalling blockers. In fresh isolated adult Wistar rat ventricular myocytes, GHSs produced a positive inotropic effect in a concentration-dependent manner and increased the amplitude of [Ca(2+)](i) transients and the I(Ca,L). The positive inotropic response was abolished by the GHS-R1a antagonist [D-Lys(3)]-GH-releasing peptide-6 (10 microm). GHS-induced increase in the I(Ca,L) was abolished by [D-Lys(3)]-GH-releasing peptide-6 and protein kinase C inhibitor, chelerythrine chloride (5 microm), but not by protein kinase A inhibitor, KT 5720 (10 microm). We conclude that hexarelin and ghrelin increase the I(Ca,L), through GHS-R1a receptor and protein kinase C signalling cascade, which contribute to its direct positive inotropic effect on cardiomyocytes.

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Hexarelin, a growth hormone secretagogue, protects the isolated rat heart from ventricular dysfunction produced by exposure to calcium-free medium

Cited by 11 publications

References 16 publications

Ghrelin induces vasoconstriction in the rat coronary vasculature without altering cardiac peptide secretion

Ghrelin induces vasoconstriction in the rat coronary vasculature without altering cardiac peptide secretion

Chronic administration of hexarelin attenuates cardiac fibrosis in the spontaneously hypertensive rat

Effects of GH Secretagogues on Contractility and Ca²⁺Homeostasis of Isolated Adult Rat Ventricular Myocytes

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Hexarelin, a growth hormone secretagogue, protects the isolated rat heart from ventricular dysfunction produced by exposure to calcium-free medium

Cited by 11 publications

References 16 publications

Ghrelin induces vasoconstriction in the rat coronary vasculature without altering cardiac peptide secretion

Ghrelin induces vasoconstriction in the rat coronary vasculature without altering cardiac peptide secretion

Chronic administration of hexarelin attenuates cardiac fibrosis in the spontaneously hypertensive rat

Effects of GH Secretagogues on Contractility and Ca2+Homeostasis of Isolated Adult Rat Ventricular Myocytes

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Effects of GH Secretagogues on Contractility and Ca²⁺Homeostasis of Isolated Adult Rat Ventricular Myocytes