Copyright © 2005, European Society of Cardiology
Ghrelin improves tissue perfusion in severe sepsis via downregulation of endothelin-1
Center for Immunology and Inflammation, Institute for Medical Research, North Shore-Long Island Jewish (LIJ) Health System, USA
Division of Surgical Research, North Shore University Hospital and LIJ Medical Center, Manhasset, NY 11030, USA
* Corresponding author. Division of Surgical Research, North Shore University Hospital and LIJ Medical Center, Manhasset, NY 11030, USA. Tel.: +1 516 562-9445; fax: +1 516 562-2396. Email address: pwang{at}nshs.edu
Objectives: Severe sepsis is associated with increased total peripheral resistance (TPR) and decreased organ blood flow, in which endothelin-1 (ET-1) plays an important role. Plasma levels of ghrelin, a newly-identified endogenous ligand for growth hormone secretagogue receptor and a potent vasodilatory peptide, are significantly reduced in sepsis. Ghrelin downregulation heralds the hypodynamic response in severe sepsis. Therefore, we hypothesized that the administration of exogenous ghrelin improves organ blood flow by downregulation of ET-1 under such conditions.
Methods: Male adult Sprague–Dawley rats were subjected to sepsis by cecal ligation and puncture (CLP). At 5 h post-CLP, a bolus intravenous injection of 2 nmol ghrelin was followed by a continuous infusion of 12 nmol ghrelin via a primed mini-pump over 15 h. At 20 h post-CLP (i.e., severe sepsis), cardiac output (CO), stroke volume (SV), TPR, and organ blood flow were measured using 141Ce-microspheres. Plasma ET-1 levels and preproET-1 gene expression in the liver, small intestine, and kidneys were measured by ELISA and RT-PCR, respectively. The direct effect of ghrelin on ET-1 production was studied using cultured human umbilical vein endothelial cells (HUVECs) treated with tumor necrosis factor-
(TNF-).
Results: Ghrelin administration reduced TPR, increased CO, SV, and organ blood flow, downregulated preproET-1 gene expression, and decreased plasma levels of ET-1 in sepsis. Ghrelin inhibited TNF--induced ET-1 release from HUVECs in a dose-dependent manner. Moreover, ghrelin inhibited TNF--induced activation of nuclear factor-
B (NF-B) in HUVECs.
Conclusions: The improvement of tissue perfusion by ghrelin in severe sepsis appears to be mediated by downregulation of ET-1 involving a NF-B-dependent pathway.
KEYWORDS Peptide hormones; Sepsis; Blood flow; Endothelin-1; Nuclear factor-B
1 Current address: Department of Surgery, Albert Einstein Medical Center, Philadelphia, PA 19141, USA.
Time for primary review 21 days
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