Urocortin-1 Infusion in Normal Humans

Davis, Mark E.; Pemberton, Chris J.; Yandle, Timothy G.; Lainchbury, John G.; Rademaker, Miriam T.; Nicholls, M. Gary; Frampton, Christopher M.; Richards, A. Mark

doi:10.1210/jc.2003-031231

Cited by 88 publications

(78 citation statements)

References 59 publications

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“…All CRFpeptide family members improve cardiac function via binding to cardiac CRF 2 receptors when administered intravenously. In addition, consistent with CRF-mediated responses, Ucn I has been shown to stimulate ACTH release in healthy rats (63) and humans (12), as well as in sheep (49) and humans (11) with HF via binding to the CRF 1 receptor in the PVN. Although the influence of HF on endogenous Ucn-1 production is unknown, it is possible that Ucn-1 concomitantly with CRF may contribute to the neural-humoral activation characteristic of HF as the CRF 1 and CRF 2 receptor subtypes (11) for Ucn-1 and CRF are expressed in PVN tissue (26).…”

Section: Discussionmentioning

confidence: 68%

Increased interleukin-6 receptor expression in the paraventricular nucleus of rats with heart failure

Helwig¹,

Musch²,

Craig³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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Helwig BG, Musch TI, Craig RA, Kenney MJ. Increased interleukin-6 receptor expression in the paraventricular nucleus of rats with heart failure. Am J Physiol Regul Integr Comp Physiol 292: R1165-R1173, 2007. First published November 9, 2006; doi:10.1152/ajpregu.00507.2006.-Activation of the hypothalamicpituitary-adrenal (HPA) axis and augmented plasma and tissue levels of IL-6 are hallmarks of heart failure (HF). Within the forebrain, cardiovascular homeostasis is mediated in part by the paraventricular nucleus (PVN) of the hypothalamus. IL-6, via binding to the IL-6 receptor (IL-6R)/glycoprotein 130 (gp130) complex influences cellular and physiological responses. Thus, in the current study, we hypothesized that PVN IL-6R protein and gene expression are upregulated in HF vs. sham-operated rats, whereas gp130 levels in the same tissues remain stable. Six weeks after coronary ligation surgery, hemodynamic measurements were obtained, and HF rats were divided into moderate noncongestive and severe chronic congestive groups based on cardiac indices. Plasma IL-6 levels were determined and changes in gene and protein expression of IL-6R and gp130 between sham-operated and HF rats were determined via real-time PCR and Western blot analyses, respectively. Plasma levels of IL-6 were elevated in rats with severe, but not moderate, HF compared with sham-operated controls. In both moderate and severe HF rats, protein but not gene expression of IL-6R was significantly increased in PVN tissue but not in non-PVN tissue, compared with sham-operated controls. Gene and protein levels of the gp130 subunit were not altered by HF in either tissue analyzed. Collectively, these data suggest that within the brain of HF rats, IL-6R expression is not a global change. Rather the increased IL-6 levels characteristic of HF may alter PVN-mediated physiological responses via enhanced expression of the IL-6R. signal transduction; gp130; hypothalamic-pituitary axis THE PARAVENTRICULAR NUCLEUS (PVN) of the hypothalamus is a forebrain nucleus with projections to brainstem and spinal cord regions regulating cardiovascular homeostasis (10). The PVN is also a key component of the hypothalamic-pituitary-adrenal (HPA) axis. Using cytokines as messengers, bidirectional communication between the nervous and immune systems occurs along the HPA axis (16,17,39,41,54,59). Among the cytokines, IL-6 plays a significant role in HPA activation by stimulating the release of negative feedback hormones, which inhibit cytokine gene expression, resulting in attenuation of immune responses and accompanying inflammation (38,44,51).The initial step in IL-6-mediated responses is interaction of the cytokine with the interleukin-6 receptor (IL-6R), the nonsignaling subunit of the receptor complex. Binding of ligand to the alpha subunit (e.g., IL-6R) results in homodimerization of the signal transducing ␤-subunit, glycoprotein130 (gp130), at the plasma membrane (25,43,55). This recruitment allows the binding of IL-6/IL-6R to gp130, resulting in a functional receptor compl...

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Section: Discussionmentioning

confidence: 68%

Increased interleukin-6 receptor expression in the paraventricular nucleus of rats with heart failure

Helwig¹,

Musch²,

Craig³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Exogenous treatment with somatostatin and its analogs, such as octreotide, as well as infusion of urocortin-1, a potent anorexigenic peptide, suppress plasma ghrelin concentration (17,60,100,177,231). However, administration of leptin does not modify ghrelin levels (36).…”

Section: A Regulation Of Ghrelin Secretionmentioning

confidence: 99%

Ghrelin: Structure and Function

Kojima

Kangawa²

2005

Physiological Reviews

1,595

1,176

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Small synthetic molecules called growth hormone secretagogues (GHSs) stimulate the release of growth hormone (GH) from the pituitary. They act through the GHS-R, a G protein-coupled receptor whose ligand has only been discovered recently. Using a reverse pharmacology paradigm with a stable cell line expressing GHS-R, we purified an endogenous ligand for GHS-R from rat stomach and named it “ghrelin,” after a word root (“ghre”) in Proto-Indo-European languages meaning “grow.” Ghrelin is a peptide hormone in which the third amino acid, usually a serine but in some species a threonine, is modified by a fatty acid; this modification is essential for ghrelin's activity. The discovery of ghrelin indicates that the release of GH from the pituitary might be regulated not only by hypothalamic GH-releasing hormone, but also by ghrelin derived from the stomach. In addition, ghrelin stimulates appetite by acting on the hypothalamic arcuate nucleus, a region known to control food intake. Ghrelin is orexigenic; it is secreted from the stomach and circulates in the bloodstream under fasting conditions, indicating that it transmits a hunger signal from the periphery to the central nervous system. Taking into account all these activities, ghrelin plays important roles for maintaining GH release and energy homeostasis in vertebrates.

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“…Urocortin 1 radioimmunoassay was performed on plasma samples, as described previously. 31 Sample preparation included steps previously used to extract total CRF (boundϩfree) from human plasma. One milliliter of plasma was mixed with 2 mL methanol and centrifuged.…”

Section: Patientsmentioning

confidence: 99%

Plasma Urocortin 1 in Human Heart Failure

Wright

Doughty

Frampton

et al. 2009

Circ: Heart Failure

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Background-The urocortins are emerging as potentially important contributors to neurohumoral regulation of the circulation with recent reports attributing a powerful array of hemodynamic, renal, and neurohumoral effects to the urocortins in cardiac failure. These peptides also seem to have cardioprotective effects in the setting of ischemiareperfusion. Little is known concerning the plasma concentrations of the urocortins in health and disease. We have investigated plasma urocortin 1 as a potential diagnostic marker of heart failure and documented its relationships to symptoms, measures of cardiac function, and concurrent levels of other circulating neurohormones. Methods and Results-In 299 patients with recent onset dyspnea or peripheral edema presenting to primary care, plasma urocortin 1 and other vasoactive hormones were assayed, and echocardiography was performed. Heart failure was present in 74 patients (25%) according to predefined diagnostic criteria. Urocortin 1 levels were increased in patients with heart failure and were related to functional class, clinical signs of heart failure, echocardiographic indicators of left ventricular dimensions and function, plasma creatinine, and concurrent circulating levels of plasma natriuretic peptides, adrenomedullin, and endothelin 1. Conclusions-Plasma urocortin 1 is elevated in heart failure (in proportion to the degree of cardiac dysfunction) in concert with the generalized neurohormonal activation seen in this condition. Urocortin levels predict heart failure independent of age, history of previous myocardial infarction, diabetes, hypertension, fractional shortening, and N-terminal prohormone brain natriuretic peptide levels. (Circ Heart Fail. 2009;2:465-471.)

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Urocortin-1 Infusion in Normal Humans

Cited by 88 publications

References 59 publications

Increased interleukin-6 receptor expression in the paraventricular nucleus of rats with heart failure

Increased interleukin-6 receptor expression in the paraventricular nucleus of rats with heart failure

Ghrelin: Structure and Function

Plasma Urocortin 1 in Human Heart Failure

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