Regulatory Peptides[JOURNAL]
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200 papers
Reg IV is differently expressed in enteroendocrine cells of human small intestine and colon.
Heiskala K, Andersson LC
Regul Pept · 2013 May · PMID 23499801 · Publisher ↗
Reg IV is a 17 kD secreted C-type lectin physiologically found in selected enteroendocrine cells (EEC). It is thought be involved in the regulation of normal and pathological intestinal and/or neuroendocrine differentiat...
Reg IV is a 17 kD secreted C-type lectin physiologically found in selected enteroendocrine cells (EEC). It is thought be involved in the regulation of normal and pathological intestinal and/or neuroendocrine differentiation and proliferation but its ultimate functional role(s) is still unclear. We used immunostaining and compared the cellular expression of Reg IV with a panel of neuroendocrine markers in human GI-tract tissue samples. Reg IV showed cellular co-distribution with serotonin and chromogranin A in all parts of GI-tract. Co-localization of Reg IV with somatostatin was seen in colon and with substance P in ileum. Subpopulations of cells expressing Reg IV overlapped with EECs containing GLP-1, GLP-2, secretin, PYY, and ghrelin, depending on the anatomical localization of the samples. The results further underscore the high degree of diversity among EECs and suggest that Reg IV may be involved in the finetuning of functions exerted by the neuroendocrine cells in the GI-tract.
The effects of unilateral truncal vagotomy on gastric carcinogenesis in hypergastrinemic Japanese female cotton rats.
Fossmark R, Sørdal ØF, Bakkelund KE … +2 more , Nordrum IS, Waldum H
Regul Pept · 2013 Jun · PMID 23499800 · Publisher ↗
The stomach is innervated by the vagal nerve. Several studies have demonstrated that the vagal nerve has a trophic effect on the rat oxyntic mucosa and that the trophic effect of hypergastrinemia is dependent on intact v...
The stomach is innervated by the vagal nerve. Several studies have demonstrated that the vagal nerve has a trophic effect on the rat oxyntic mucosa and that the trophic effect of hypergastrinemia is dependent on intact vagal innervation. The effect of vagal denervation on gastric carcinogenesis has been examined in Mastomys natalensis and hypergastrinemic transgenic INS-GAS mice, with no effect of unilateral vagotomy in Mastomys but an anti-carcinogenic effect in INS-GAS mice. A proportion of female Japanese cotton rats develop spontaneous hypergastrinemia and ECL cell derived gastric carcinomas. In the current study we have examined the effects of unilateral anterior subdiaphragmatic vagotomy on gastric carcinogenesis. Female Japanese cotton rats were operated with unilateral anterior vagotomy or sham-operation at age 2 months and were terminated at age 10 months. Ten of fifteen animals operated by anterior vagotomy and 11 of 16 sham-operated developed hypergastrinemia. Vagotomy did not affect intragastric pH or serum gastrin. When comparing the anterior and posterior sides of the stomachs, vagotomy did not affect the occurrence of dysplasia or carcinoma development in the oxyntic mucosa. However, vagotomy resulted in lower stomach weight and reduced oxyntic mucosal thickness on the anterior side. Vagotomy also resulted in a reduction in volume density of chromogranin A positive cells in the oxyntic mucosa. In conclusion, vagotomy reduced the trophic effects of hypergastrinemia on the ECL cell and oxyntic mucosa, but did not prevent gastric carcinogenesis in female Japanese cotton rats. The effects of vagotomy on gastric carcinogenesis in animal models are conflicting and further studies in patients should be done to clarify the clinically significant effects of vagotomy.
Tachykinin (NK1, NK2 and NK3) receptor, transient receptor potential vanilloid 1 (TRPV1) and early transcription factor, cFOS, mRNA expression in rat tissues following systemic capsaicin treatment.
Kunde DA, Crawford A, Geraghty DP
Regul Pept · 2013 May · PMID 23499799 · Publisher ↗
Capsaicin, the pungent component of chilli pepper, stimulates TRPV1-expressing cells which are followed by desensitisation to subsequent exposure to capsaicin and other TRPV1 activators. At high systemic doses (>125 mg/k...
Capsaicin, the pungent component of chilli pepper, stimulates TRPV1-expressing cells which are followed by desensitisation to subsequent exposure to capsaicin and other TRPV1 activators. At high systemic doses (>125 mg/kg), capsaicin produces long-term changes in both tachykinin receptor and TRPV1 expression and function in rats. However, whether desensitising (low) doses of capsaicin (~50 mg/kg) affect tachykinin receptor and TRPV1 gene expression in the short term has yet to be investigated. The aim of the present study was to compare tachykinin receptor (NK1, NK2 and NK3) and TRPV1 mRNA expression 24h after administration of capsaicin (50 mg/kgs.c.). Tachykinin receptor and TRPV1 mRNA were detected in all tissues studied with expression levels differing by up to 2500-fold between tissues. The highest expression of TRPV1 and NK1 mRNA was observed in the salivary gland, whereas NK2 mRNA expression was highest in the urinary bladder and NK3 mRNA expression in the frontal cortex. In the cervical spinal cord of rats treated with capsaicin, NK1 and NK3 mRNA expression were reduced by 56% and 80%, respectively (P<0.05), whereas NK2 and TRPV1 mRNA expression were increased 2.2- and 1.4-fold, respectively (P<0.05). NK1 and NK2 mRNA expression were decreased (P<0.05) in the urinary bladder and gastric fundus, respectively, following capsaicin treatment. There was a marked 100-fold increase in cFOS mRNA expression and 100-fold decrease in NK2 mRNA expression in the whole blood of capsaicin-treated rats. In conclusion, these studies show that tachykinin receptor and TRPV1 mRNA expression undergo significant changes within 24h of systemic low-dose capsaicin administration.
Novel biological effects of alloferon and its selected analogues: structure-activity study.
Kuczer M, Czarniewska E, Rosiński G
Regul Pept · 2013 May · PMID 23499798 · Publisher ↗
The subject of this paper is a search for new biological properties of alloferon (H-His-Gly-Val-Ser-Gly-His-Gly-Gln-His-Gly-Val-His-Gly-OH) and a series of its analogues. The studies on structure/activity relationship in...
The subject of this paper is a search for new biological properties of alloferon (H-His-Gly-Val-Ser-Gly-His-Gly-Gln-His-Gly-Val-His-Gly-OH) and a series of its analogues. The studies on structure/activity relationship in alloferon, the synthesis of a series of 28 analogues were performed. The analogues were modified at position 1 or 6, and other were oligopeptides with a shortened peptide sequence. Biological effects of the peptides were evaluated by the pro-apoptotic action in vivo on haemocytes of Tenebrio molitor and in the cardiotropic test in vitro on the heart of T. molitor and Zophobas atratus. In the in vivo bioassays, new biological activities of alloferon and its analogues were discovered. In haemocytotoxic bioassay, alloferon strongly induces T. molitor haemocytes to undergo apoptosis at a dose of 10 nM. Moreover, [Phe(p-NH2)(1)]-, [Tyr(6)]- and [1-10]-alloferon exhibit a two-fold increase of caspases activation in comparison with the alloferon. However, alloferon and its analogues show a weak cardiostimulatory activity in Z. atratus but the heart of T. molitor is not sensitive to these peptides. The results obtained here suggest that alloferon plays pleiotropic functions in insects.
Reevaluation of sst₁ somatostatin receptor expression in human normal and neoplastic tissues using the novel rabbit monoclonal antibody UMB-7.
Lupp A, Nagel F, Schulz S
Regul Pept · 2013 May · PMID 23466804 · Publisher ↗
BACKGROUND: The somatostatin receptor 1 (sst1) is widely distributed throughout the body and is also present in neoplastic tissues. However, little is known about its precise tissue distribution, regulation and function,...
BACKGROUND: The somatostatin receptor 1 (sst1) is widely distributed throughout the body and is also present in neoplastic tissues. However, little is known about its precise tissue distribution, regulation and function, which may in part be due to the lack of specific monoclonal anti-sst1 antibodies. METHODS: We have characterized the novel rabbit monoclonal anti-human sst1 antibody UMB-7 using sst1-expressing cells and human pituitary samples. The antibody was then used for immunohistochemical staining of a large panel of formalin-fixed, paraffin-embedded human tissues. RESULTS: Western blot analyses of BON-1 cells and human pituitary revealed a broad band migrating at a molecular weight of 45,000-60,000. After enzymatic deglycosylation the size of this band decreased to a molecular weight of 45,000. UMB-7 yielded an efficient immunostaining of distinct cell populations in the human tissue samples with a predominance of plasma membrane staining, which was completely abolished by preadsorption of UMB-7 with its immunizing peptide. The sst1 receptor was detected in anterior pituitary, pancreatic islets, distal tubules, enteric ganglion cells and nerve fibers, chief cells of the gastric mucosa, macrophages and mast cells. In addition, sst1 was observed in pituitary adenomas, gastrointestinal neuroendocrine tumors and pheochromocytoma as well as in pancreatic adenocarcinomas, gastric carcinomas, urinary bladder carcinomas and sarcomas. CONCLUSIONS: UMB-7 may prove of great value in the identification of sst1-expressing tumors during routine histopathological examinations. This may open up new routes for diagnostic and therapeutic intervention.
Urotensin II-induced collagen synthesis in cultured smooth muscle cells from rat aortic media and a possible involvement of transforming growth factor-β1/Smad2/3 signaling pathway.
Zhao J, Ding W, Song N … +4 more , Dong X, Di B, Peng F, Tang C
Regul Pept · 2013 Mar · PMID 23403244 · Publisher ↗
BACKGROUND: Recent studies suggest that urotensin II (UII) and transforming growth factor-β1 (TGF-β1) both have critical roles in vascular remodeling. UII is a recently discovered vasoconstrictive peptide that is involve...
BACKGROUND: Recent studies suggest that urotensin II (UII) and transforming growth factor-β1 (TGF-β1) both have critical roles in vascular remodeling. UII is a recently discovered vasoconstrictive peptide that is involved in the pathogenesis of atherosclerosis, restenosis and hypertension. TGF-β1 is an important factor that has a pivotal role in vascular fibrosis. This study aimed to explore whether TGF-β1 is involved in UII-induced collagen synthesis in rat aortic vascular smooth muscle cells (VSMCs) and examined the effects and mechanisms of UII on collagen synthesis and secretion in VSMCs. METHODS: VSMCs were prepared by the explant culture method. TGF-β1 and collagen I secretions from the cells were determined by enzyme-linked immunosorbent assay (ELISA). The mRNA and protein expressions of TGF-β1, collagen I, Smad2 and Smad3 were determined using Real-time RT-PCR and Western blotting. RESULTS: UII dose-dependently promoted TGF-β1 protein expression and secretion from VSMCs, with maximal effect at 10(-8) mol/l at 24 h for protein expression and 10(-7) mol/l at 24 h for protein secretion (both P<0.01). Moreover, UII dose-dependently promoted Smad2 and Smad3 mRNA expression in VSMCs, with maximal effect at 10(-8) mol/l for 12 h (both P<0.01). The effects of UII were significantly inhibited by its receptor antagonists urantide (10(-6) mol/l) or SB-710411 (10(-6) mol/l), and by the mitogen-activated protein kinase (MAPK/ERK) inhibitor PD98059 (10(-6) mol/l). UII dose-dependently promoted collagen I mRNA expression and protein secretion in VSMCs, with maximal effect at 10(-8) mol/l at 12h for mRNA expression and 10(-6) mol/l at 24 h for protein secretion (both P<0.01). Collagen synthesis and secretion from VSMCs induced by UII were inhibited significantly by a TGF-β1-specific neutralizing antibody, SB-431542 (an antagonist of the TGF-β1 type II receptor) and PD98059 (all P<0.01). CONCLUSIONS: This study suggests that UII could induce collagen synthesis and secretion through upregulation of TGF-β1 expression and secretion in VSMCs, and that TGF-β1/Smad2/3 signaling might be one of the important pathways by which UII is involved in vascular fibrosis.
Immunocytochemical distribution of EM66 within the hypothalamic parvocellular paraventricular nucleus: colocalization with CRH and TRH but no plasticity related to acute stress and thyroidectomy in the rat.
El Yamani FZ, Yon L, Guérin M … +5 more , El Ouezzani S, Alaoui A, Chartrel N, Anouar Y, Magoul R
Regul Pept · 2013 Mar · PMID 23333484 · Publisher ↗
EM66 is a secretogranin II-derived peptide strongly expressed within hypothalamic neuroendocrine areas such as the parvocellular aspect of the paraventricular nucleus (pPVN) as well as the median eminence (ME), suggestin...
EM66 is a secretogranin II-derived peptide strongly expressed within hypothalamic neuroendocrine areas such as the parvocellular aspect of the paraventricular nucleus (pPVN) as well as the median eminence (ME), suggesting a hypophysiotropic role for this neuropeptide. The aim of the present study was to explore such a role in the corticotrope and thyrotrope axes. We analyzed EM66 occurrence respectively in CRH and TRH neurosecretory cells of the rat pPVN by double immunohistochemistry. Functionally, we studied the effect of acute stress (immobilization for 2 h or cold exposure at 5°C for 4 h) and hypothyroidism (induced by 1-week thyroidectomy) on EM66 immunoreactivity (IR) within the pPVN. Double immunohistochemical labeling revealed that EM66-IR colocalized with CRH or TRH labelings within pPVN hypophysiotropic neurons as well as the axon terminals of the external layer of the ME. Because TRH neuronal population of the pPVN is completely distinct from the CRH neurosecretory system, our data demonstrate the existence of at least two distinct EM66 neuronal populations in the rat pPVN. Acute immobilization or cold exposure stresses did not affect EM66 expression as evaluated by the number of EM66-IR neurons within the pPVN. These results suggest that EM66 does not participate to the phenotypic plasticity of hypothalamic parvocellular neurons in response to acute stress. In addition, short-term hypothyroidism did not provoke any significant variation of the number of intraparaventricular EM66 neurons, indicating that EM66 expression would be insensitive to short-term hypothyroidism despite its occurrence within TRH neurons. Thus, the present data show the occurrence of EM66 in distinct areas of the rat PVN but its expression is not coregulated with those of CRH and TRH during acute stress and hypothyroidism.
Chemerin gene expression is regulated by food restriction and food restriction-refeeding in rat adipose tissue but not in liver.
Stelmanska E, Sledzinski T, Turyn J … +3 more , Presler M, Korczynska J, Swierczynski J
Regul Pept · 2013 Feb · PMID 23328001 · Publisher ↗
Chemerin is an adipokine that regulates adipocyte development and metabolism as well as inflammatory and immune function of some cells. Although chemerin may be linked to obesity and related diseases, little is known abo...
Chemerin is an adipokine that regulates adipocyte development and metabolism as well as inflammatory and immune function of some cells. Although chemerin may be linked to obesity and related diseases, little is known about the nutritional regulation of chemerin gene expression. We investigated the effect of prolonged food restriction, a common approach in treating obesity and related diseases, and prolonged food restriction-refeeding on chemerin gene expression in rat white adipose tissue and liver. The prolonged food restriction was accompanied by an approximately 2-fold decrease in chemerin mRNA level in rat white adipose tissue. Upon refeeding, an increase (approximately 8-fold as compared to rats maintained on restricted diet and 4-fold as compared to control) in chemerin mRNA level in white adipose tissue was found. Surprisingly, no effect of food restriction and food restriction-refeeding on chemerin mRNA level in the liver was found. Chemerin mRNA level in adipose tissue was positively correlated with serum insulin concentration. Moreover insulin increased significantly chemerin gene expression in primary rat adipocytes. The changes in chemerin mRNA level in adipose tissue and serum chemerin concentrations were associated with changes in serum leptin and free fatty acid concentrations. Collectively, the data presented here indicate that chemerin gene expression is regulated by nutritional status in rat adipose tissue but not in liver. It seems that insulin plays important role in stimulation of chemerin gene expression in adipose tissue. However, changes in serum leptin and free fatty acids concentrations after food restriction-refeeding suggest that the role of these factors in the regulation of chemerin gene expression in adipose tissue cannot be excluded. Lack of the effect of food restriction and food restriction-refeeding on liver chemerin gene expression suggests that adipose tissue is the dietary modifiable source of serum chemerin concentration.
Comparative effects of metformin and pioglitazone on omentin and leptin concentrations in patients with newly diagnosed diabetes: a randomized clinical trial.
Esteghamati A, Noshad S, Rabizadeh S … +3 more , Ghavami M, Zandieh A, Nakhjavani M
Regul Pept · 2013 Mar · PMID 23328000 · Publisher ↗
AIMS: To assess the effects of two commonly used oral hypoglycemic medications metformin and pioglitazone on serum concentrations of omentin and leptin in patients with newly diagnosed type 2 diabetes. METHODS: In a clin...
AIMS: To assess the effects of two commonly used oral hypoglycemic medications metformin and pioglitazone on serum concentrations of omentin and leptin in patients with newly diagnosed type 2 diabetes. METHODS: In a clinical trial setting (NCT01593371), patients were randomly allocated to either metformin 1000mg daily (n=41), or pioglitazone 30mg daily (n=50). Serum concentrations of omentin and leptin were measured at baseline and after 12weeks. Patients' weight, waist circumference, blood pressure, fasting plasma glucose, fasting insulin, HbA1c, highly sensitive C-reactive protein, and serum lipids were also measured at the two visits. RESULTS: Baseline concentrations of omentin and leptin were not different between the two arms of the trial. After three months, metformin decreased both omentin and leptin concentrations in women, and leptin concentrations only in men. On the other hand, pioglitazone reduced both adipokines only in women, but not men. Univariate and multivariate ANCOVA models revealed that both interventions are equally effective in reducing omentin concentration (p=0.497 for women and 0.344 for men in multivariate models controlling for the effects of confounding variables). Similarly, neither medication was more effective in reducing leptin concentrations after three months (p=0.822 for women and 0.441 for men in multivariate models). CONCLUSIONS: Metformin and pioglitazone at pharmacologic doses are equally effective in alteration of serum omentin and leptin concentrations in patients with diabetes, albeit sex differences in response to medications exist. Implication of these findings on long term management and complication prevention of diabetes needs to be elucidated.
Tolerance to hypophagia induced by prolonged treatment with a CB1 antagonist is related to the reversion of anorexigenic neuropeptide gene expression in the hypothalamus.
Rorato R, Miyahara C, Antunes-Rodrigues J … +1 more , Elias LL
Regul Pept · 2013 Mar · PMID 23327999 · Publisher ↗
It is well established that treatment with rimonabant, a CB1 antagonist, decreases food intake and body weight gain. In part, these responses are mediated by increased activity of hypothalamic neurons related with energy...
It is well established that treatment with rimonabant, a CB1 antagonist, decreases food intake and body weight gain. In part, these responses are mediated by increased activity of hypothalamic neurons related with energy homeostasis. However, food consumption is reversed to basal level during prolonged CB1 antagonist treatment, suggesting tolerance to its anorexigenic effect. This study investigated the effects of acute or prolonged CB1 receptor blockade on the expression of hypothalamic neuropeptides involved with energy homeostasis. Male Wistar rats received vehicle, a single dose or daily doses of rimonabant (10 mg/kg by gavage) over 7 days. Food intake, body weight, CRF and CART immunoreactivity, as well as, mRNA expression of hypothalamic neuropeptides were evaluated. In comparison with vehicle treatment, single dose of rimonabant decreased food intake and body weight. Acute rimonabant treatment also increased Fos-CRF and Fos-CART double labeled neurons in the PVN and Fos immunoreactivity in the ARC. We also observed that acute rimonabant treatment increased CRF, CART and TRH mRNA expression in the PVN, while it decreased POMC and NPY mRNA expression in the ARC with no changes in the CART mRNA expression in this nucleus. There was an increase in CB1 mRNA expression in the PVN of rats that received both acute and prolonged-rimonabant treatment. Interestingly, rats subjected to prolonged rimonabant treatment had no changes in food intake, body weight gain, hypothalamic mRNA expression, Fos expression and CRF and CART neuron activation. These data indicate that tolerance to hypophagic effects of CB1 antagonist, rimonabant, is associated with reversion of hypothalamic neuropeptide gene expression related to regulation of energy homeostasis.
Atrial natriuretic peptide suppresses Th17 development through regulation of cGMP-dependent protein kinase and PI3K-Akt signaling pathways.
Ma L, Li J, Wang G … +7 more , Gong S, Zhang L, Li K, Ji X, Liu Y, Chen P, Xiang X
Regul Pept · 2013 Feb · PMID 23327998 · Publisher ↗
In recent years, accumulating evidence suggests that atrial natriuretic peptide (ANP), a hormone widely known as a result of its significant effects on the cardiovascular system mediated by natriuretic peptide receptor A...
In recent years, accumulating evidence suggests that atrial natriuretic peptide (ANP), a hormone widely known as a result of its significant effects on the cardiovascular system mediated by natriuretic peptide receptor A (NPRA), may play a nonnegligible role in the regulation of immune responses. In this study, we firstly investigated whether ANP signaling could regulate the differentiation and capacity of Th17 cells and discovered ANP-dose (10(-8)-10(-6)M) dependently indeed suppressed the differentiation of Th17 cells along with the reduced IL-17 production by polarizing naïve CD4(+) T cells isolated from splenocytes to Th17 phenotype in vitro. Moreover, ANP primarily signals through NPRA and cGMP-dependent protein kinase (PKG) which could be antagonized when pretreated with either ANP/NPRA signaling antagonist or PKG inhibitor. In addition, we also found that ANP signaling could upregulate the levels of phosphorylation of Akt which was hypothesized to be implicated in ANP-induced inhibition of Th17 development in our studies, and the effect of ANP on the development of murine Th17 cells seemed to be partially reversed when an inhibitor of phosphatidylinositol 3'-kinase (PI3K)/Akt had been performed in advance. Briefly, we showed for the first time that ANP signaling could suppress murine Th17 cell development from naïve CD4(+) T cells in vitro through NPRA/PKG pathway and the PI3K-Akt signal was implicated in the ANP-mediated suppression of Th17 development.
Mortal hyperkalemia disturbances in rats are NO-system related. The life saving effect of pentadecapeptide BPC 157.
Barisic I, Balenovic D, Klicek R … +15 more , Radic B, Nikitovic B, Drmic D, Udovicic M, Strinic D, Bardak D, Berkopic L, Djuzel V, Sever M, Cvjetko I, Romic Z, Sindic A, Bencic ML, Seiwerth S, Sikiric P
Regul Pept · 2013 Feb · PMID 23327997 · Publisher ↗
We demonstrate the full counteracting ability of stable gastric pentadecapeptide BPC 157 against KCl-overdose (intraperitoneal (i), intragastric (ii), in vitro (iii)), NO-system related. (i) We demonstrated potential (/k...
We demonstrate the full counteracting ability of stable gastric pentadecapeptide BPC 157 against KCl-overdose (intraperitoneal (i), intragastric (ii), in vitro (iii)), NO-system related. (i) We demonstrated potential (/kg) of: BPC 157 (10ng, 10μg ip, complete counteraction), l-arginine (100mg ip, attenuation) vs. L-NAME (5mg ip, deadly aggravation), given alone and/or combined, before or after intraperitoneal KCl-solution application (9mEq/kg). Therapy was confronted with promptly unrelenting hyperkalemia (>12mmol/L), arrhythmias (and muscular weakness, hypertension, low pressure in lower esophageal and pyloric sphincter) with an ultimate and a regularly inevitable lethal outcome within 30min. Previously, we established BPC 157-NO-system interaction; now, a huge life-saving potential. Given 30min before KCl, all BPC 157 regimens regained sinus rhythm, had less prolongation of QRS, and had no asystolic pause. BPC 157 therapy, given 10min after KCl-application, starts the rescue within 5-10min, completely restoring normal sinus rhythm at 1h. Likewise, other hyperkalemia-disturbances (muscular weakness, hypertension, low sphincteric pressure) were also counteracted. Accordingly with NO-system relation, deadly aggravation by L-NAME: l-arginine brings the values to the control levels while BPC 157 always completely nullified lesions, markedly below those of controls. Combined with l-arginine, BPC 157 exhibited no additive effect. (ii) Intragastric KCl-solution application (27mEq/kg) - (hyperkalemia 7mmol/L): severe stomach mucosal lesions, sphincter failure and peaked T waves were fully counteracted by intragastric BPC 157 (10ng, 10μg) application, given 30min before or 10min after KCl. (iii). In HEK293 cells, hyperkalemic conditions (18.6mM potassium concentrations), BPC 157 directly affects potassium conductance, counteracting the effect on membrane potential and depolarizations caused by hyperkalemic conditions.
Genetic and pharmacological mouse models of chronic melanocortin activation show enhanced baroreflex control of heart rate.
Rinne P, Harjunpää J, Mäkelä S … +1 more , Savontaus E
Regul Pept · 2013 Mar · PMID 23327996 · Publisher ↗
The central melanocortin system is an important regulator of energy homeostasis and cardiovascular functions. Although the acute effects of melanocortins on central blood pressure regulation are well-established, their l...
The central melanocortin system is an important regulator of energy homeostasis and cardiovascular functions. Although the acute effects of melanocortins on central blood pressure regulation are well-established, their long-term effects on autonomic balance and baroreflex function remain largely unexplored. Here we investigated the impact of chronic melanocortin activation on cardiovascular and autonomic nervous system functions by studying α- and γ-MSH overexpressing (MSH-OE) mice and, as pharmacological model, mice treated with the stable α-MSH analogue melonotan-II (MT-II, 0.3 mg/kg/day for 7 days, i.p.). Mean arterial pressure (MAP) and heart rate (HR) were measured in conscious mice by radiotelemetry. MSH-OE mice did not differ from their wild-type littermates in terms of MAP, but displayed reduced HR under physiological baseline conditions. To evaluate the relative activities of sympathetic and parasympathetic nervous systems, we applied autonomic receptor blockers and found an enhanced HR response to atropine in MSH-OE mice, indicating increased cardiac vagal activity. The compensatory increase in HR after drug-evoked vasodilatation was also augmented in MSH-OE mice. Exposure to a high-sodium diet (8% NaCl) markedly reduced HR in MSH-OE mice without concomitant changes in blood pressure, suggesting improved reflex regulation of HR. Chronic treatment with MT-II did not change 24-h MAP or HR regardless of the acute pressor and tachycardic actions of MT-II. Consistent with the finding in MSH-OE mice, MT-II-treated mice showed an enhanced HR response to vasodilatation. These observations suggest that chronic melanocortin activation may provide cardioprotective regulation by enhancing vagal nerve activity and baroreflex control of heart rate.
The C-terminal extension of exendin-4 provides additional metabolic stability when added to GLP-1, while there is minimal effect of truncating exendin-4 in anaesthetized pigs.
Simonsen L, Holst JJ, Madsen K … +1 more , Deacon CF
Regul Pept · 2013 Feb · PMID 23318502 · Publisher ↗
The most striking sequence difference between glucagon-like peptide-1 (GLP-1)(2) and the longer-acting GLP-1 receptor agonist, exendin-4 (Ex-4),(3) is the nine-amino acid COOH-terminal extension of Ex-4. We investigated...
The most striking sequence difference between glucagon-like peptide-1 (GLP-1)(2) and the longer-acting GLP-1 receptor agonist, exendin-4 (Ex-4),(3) is the nine-amino acid COOH-terminal extension of Ex-4. We investigated the contribution of this extension to the survival time of Ex-4. We assessed the overall metabolism of GLP-1, Ex-4, a COOH-terminally extended GLP-1 peptide (GLP-1+Ex(31-39); GLP-Ex),(4) and a COOH-terminally truncated exendin peptide (Ex(1-30)) in anaesthetized, catheterized pigs, with focus on the extraction across the kidneys and a peripheral tissue (a hindleg, representing muscle, adipose- and connective tissue). Peptide analysis was carried out with assays against the mid-region of the peptides, whereby the role of dipeptidyl peptidase-4 (DPP-4)(5) mediated NH(2)-terminal degradation could be disregarded. The half-life of GLP-1 was significantly increased when the COOH-terminal extension of Ex-4 was added (GLP-1 4.8±3.3min; GLP-Ex 19.5±3.3min). In contrast, there was no effect of truncating Ex-4 (Ex-4 32.4±4.1min; Ex(1-30) 28.4±1.7min). Ex-4 and Ex(1-30) were cleared solely by the kidneys at rates corresponding to the glomerular filtration rate (GFR),(6) while GLP-1 and GLP-Ex were cleared by both the kidneys and peripheral tissues. Both extraction rates were, however, significantly reduced with GLP-Ex compared to GLP-1. The renal clearance rate of GLP-1 greatly exceeded GFR, while GLP-Ex was cleared at a rate resembling GFR. In conclusion, the COOH-terminal extension of Ex-4 contributes minimally to the increased survival time of Ex-4, while addition of this sequence to GLP-1 significantly reduces its clearance.
Cardiovascular and electrocardiographic parameters after tonin administration in Wistar rats.
Damasceno DD, Lima MP, Motta DF … +6 more , Ferreira AJ, Quintão-Junior JF, Drummond LR, Natali AJ, Almeida AP, Pesquero JL
Regul Pept · 2013 Feb · PMID 23318501 · Publisher ↗
In order to understand the mechanisms of interaction between tonin-angiotensin and renin-angiotensin systems (RAS) we evaluated, "in vivo" and "in vitro", in Wistar rats, cardiovascular and electrocardiographic parameter...
In order to understand the mechanisms of interaction between tonin-angiotensin and renin-angiotensin systems (RAS) we evaluated, "in vivo" and "in vitro", in Wistar rats, cardiovascular and electrocardiographic parameters after tonin administration. Arterial pressure (AP) and electrocardiogram (ECG) were recorded in awake animals before and after tonin administration. Langendorff technique was used to analyze cardiac function in isolated heart in the presence of tonin and video motion edge detection system was used to evaluate the effect of tonin upon contractile function of isolated rat ventricular cardiomyocytes. After tonin infusion rats presented significantly higher diastolic and mean arterial pressure (MAP) and heart rate (HR) as compared with control. The ECG analysis revealed shorter RR interval, increase in the low-frequency (LF) range of the heart rate variability (HRV) power (%) and decrease in the high-frequency (HF) of HRV power (%). Isolated hearts perfused with tonin presented an increase in the arterial coronary pressure (ACP) and decline in the ventricular systolic tension (ST), maximal (dT/dt+) and minimal (dT/dt) contractility. The rates of contraction and relaxation of isolated ventricular cardiomyocytes were significantly increased due to the presence of tonin. The angiotensin II (Ang II) levels in the coronary sinus effluent increased in the presence of tonin in a dose-dependent manner and the effect of tonin upon ACP was completely blocked by candesartan. Tonin is able to generate the vasoconstrictor peptide Ang II in the isolated heart of the rat and the cardiovascular response induced by tonin was completely blocked by candesartan, an indication that the action of Ang II on Ang II type 1 (AT1) receptors is the major mechanism of the heart effects. Tonin affects cardiomyocyte contractile function which may be due to interference with Ca(2+) handling.
Binding affinities and activation of Asp712Ala and Cys100Ser mutated kinin B1 receptor forms suggest a bimodal scheme for the molecule of bound-DABK.
Rodrigues ES, Martin RP, Silva RF … +3 more , Nakaie CR, Oliveira L, Shimuta SI
Regul Pept · 2013 Feb · PMID 23318500 · Publisher ↗
Mutant forms of kinin B(1) receptor (B(1)R) and analogs of the full agonist des-Arg(9)-bradykinin (DABK) were investigated aiming to verify the importance of selected receptor residues and of each agonist-peptide residue...
Mutant forms of kinin B(1) receptor (B(1)R) and analogs of the full agonist des-Arg(9)-bradykinin (DABK) were investigated aiming to verify the importance of selected receptor residues and of each agonist-peptide residue in the specific binding and activation. Linked by a specific disulfide bond (Cys(100)-Cys(650)), the N-terminal (N(t)) and the EC3 loop C-terminal (C(t)) segments of angiotensin II (AngII) receptor 1 (AT(1)R) have been identified to form an extracellular site for binding the agonist N(t) segment (Asp(1) and Arg(2) residues). Asp(712) residue at the receptor EC3 loop binds the peptide Arg(2) residue. By homology, a similar site might be considered for DABK binding to B(1)R since this receptor contains the same structural elements for composing the site in AT(1)R, namely the disulfide bond and the EC3 loop Asp(712) residue. DABK, Ala(n)-DABK analogs (n=Ala(1)-, Ala(2)-, Ala(3)-, Ala(4)-, Ala(5)-, Ala(6)-, Ala(7)-, Ala(8)-DABK), and other analogs were selected to binding wild-type, Asp712Ala and Cys100Ser mutated B(1)R receptors. The results obtained suggested that the same bimodal scheme adopted for AngII-AT(1)R system may be applied to DABK binding to B(1)R. The most crucial similarity in the two cases is that the N(t) segments of peptides equally bind to the homologous Asp(712) residue of both AT(1)R and B(1)R extracellular sites. Confirming this preliminary supposition, mutation of residues located at the B(1)R extracellular site as EC3 loop Asp(712) and Cys(100) caused the same modifications in biological assays observed in AT(1)R submitted to homologous mutations, such as significant weakening of agonist binding and reduction of post-receptor-activation processes. These findings provided enough support for defining a site that determines the specific binding of DABK to B(1)R receptors.
Serum levels of growth arrest specific protein 6 are increased in preeclampsia.
Stepan H, Richter J, Kley K … +10 more , Kralisch S, Jank A, Schaarschmidt W, Ebert T, Lössner U, Jessnitzer B, Kratzsch J, Blüher M, Stumvoll M, Fasshauer M
Regul Pept · 2013 Mar · PMID 23318499 · Publisher ↗
Preeclampsia (PE) contributes to maternal and fetal morbidity and mortality worldwide. Moreover, it is associated with an increased future metabolic and cardiovascular risk for mother and newborn. Recently, growth arrest...
Preeclampsia (PE) contributes to maternal and fetal morbidity and mortality worldwide. Moreover, it is associated with an increased future metabolic and cardiovascular risk for mother and newborn. Recently, growth arrest specific protein (Gas) 6 has been introduced as a novel metabolic risk factor with anti-angiogenic, pro-atherogenic, and pro-adipogenic properties. In the current study, we investigated serum concentrations of Gas6 in patients with PE (n=51) as compared to healthy, age-matched controls (n=51) during and 6 months after pregnancy. Furthermore, association of Gas6 with markers of renal function, glucose and lipid metabolism, as well as inflammation, was assessed in all individuals. Median maternal Gas6 serum levels adjusted for body mass index and gestational age at blood sampling were significantly increased in PE patients (5.7 μg/l) as compared to healthy, age-matched pregnant women (4.6 μg/l) (p<0.05). Furthermore, Gas6 concentrations positively correlated with blood pressure, creatinine, free fatty acids, C-reactive protein, leptin, and adiponectin during pregnancy. Moreover, leptin and adiponectin remained independently associated with Gas6 levels in multivariate analysis. Gas6 serum levels 6 months after pregnancy were not significantly different between former PE and control patients. Taken together, maternal Gas6 serum concentrations are significantly increased in PE during pregnancy. Furthermore, the adipokines leptin and adiponectin are independent predictors of circulating Gas6 in pregnant women.
Intracellular renin alters the electrical properties of the intact heart ventricle of adult Sprague Dawley rats.
De Mello WC
Regul Pept · 2013 Feb · PMID 23318498 · Publisher ↗
UNLABELLED: The influence of intracellular renin injection on the electrical properties of the intact left ventricle from adult Sprague Dawley rat heart was investigated. Intracellular renin injection was performed using...
UNLABELLED: The influence of intracellular renin injection on the electrical properties of the intact left ventricle from adult Sprague Dawley rat heart was investigated. Intracellular renin injection was performed using intracellular microelectrodes filled with solution containing renin (120pM). Pressure pulses (40-70psi) for short periods of time (20ms), were applied to the micropipette while recording the action potential simultaneously from the same fiber. The results indicated that intracellular renin caused a depolarization of ventricular fibers of 7.3±2±mV (n=38) (4 animals) (P<0.05) and a decrease of the action potential duration at 50% and at 90% repolarization, respectively. Moreover, the refractoriness was significantly decreased with consequent generation of triggered activity. The effect of intracellular renin was seen within 3min of enzyme injection. The shortening of the action potential was related to an increase of potassium current which was measured in isolated ventricular myocytes before and after intracellular dialysis of renin (10(-9)M) using a voltage whole cell clamp configuration. Valsartan (10(-8)M) dialyzed together with renin (120pM) into the cell decreased drastically the effect of renin on potassium current. An increment of potassium current was also found when intracellular renin was dialyzed into cardiomyocytes exposed to Krebs solution containing valsartan (10(-8)M) for 10min prior to renin administration. Bis-1 which is a specific inhibitor of PKC, abolished the effect of intracellular renin on potassium current. IN CONCLUSION: intracellular renin decreases the action potential duration and cardiac refractoriness in the intact left ventricle of adult Sprague Dawley rats. The shortening of the action potential was related to an increase in total potassium current. The effect of renin on total potassium currents was inhibited by valsartan and by Bis-1. Implication for cardiac arrhythmias was discussed.
Short-term exercise combined with Acipimox administration induces an increase in plasma ACTH and its subsequent fall in the recovery phase in bulimic women.
Smitka K, Papezova H, Vondra K … +3 more , Hill M, Hainer V, Nedvidkova J
Regul Pept · 2013 Mar · PMID 23318497 · Publisher ↗
OBJECTIVE: Free fatty acids (FFA)-adrenocorticotropin (ACTH) feedback loop between adipose tissue and the hypothalamic-pituitary centers in the brain has been suggested to be affected by the exercise and by administratio...
OBJECTIVE: Free fatty acids (FFA)-adrenocorticotropin (ACTH) feedback loop between adipose tissue and the hypothalamic-pituitary centers in the brain has been suggested to be affected by the exercise and by administration of anti-lipolytic drugs. Also leptin may be affected by exercise. Dysfunction of FFA-leptin-ACTH secretion might be involved in binge eating and subsequent purging as is the case in bulimia nervosa (BN). METHODS: In the present single-blind, randomized study, we explored responses of plasma ACTH, leptin and FFA concentrations to exercise (45 min, 2 W/kg of lean body mass [LBM]) with Acipimox (Aci), an anti-lipolytic nicotinic acid analog, or placebo randomly received in nine women with BN and nine healthy women. RESULTS: The exercise with Aci administration resulted in plasma ACTH (p<0.001) and leptin increase higher in BN patients and a decrease in the plasma FFA levels in both groups. The falling of plasma ACTH (p<0.01) levels in the post-exercise recovering phase (90-minute) with Aci administration is more expressed in BN patients. The exercise induced an increase in plasma ACTH (p<0.05) and FFA levels and a decrease in the plasma leptin level in both groups. CONCLUSIONS: We demonstrated that the Aci-induced elevation in plasma ACTH (p<0.001) levels after the exercise higher in BN patients and that the falling of plasma ACTH (p<0.01) levels in the post-exercise recovering phase (90-minute) with Aci administration is suppressed only in BN patients, while Aci increased plasma leptin levels in this recovering phase more in BN patients. Therefore, these observations led us to suggesting that FFA-leptin-ACTH are involved in the dysregulation of neuroendocrine profile in this syndrome and that Aci affects a FFA-independent mechanism. In conclusion, Aci can be considered acceptable in the treatment of eating disorders, and it may also serve as an alternative low-dose dexamethasone suppression test (LDDST) in these patients. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12612000309886.
Cocaine- and amphetamine-regulated transcript is expressed in adipocytes and regulate lipid- and glucose homeostasis.
Banke E, Riva M, Shcherbina L … +2 more , Wierup N, Degerman E
Regul Pept · 2013 Mar · PMID 23318496 · Publisher ↗
Cocaine- and amphetamine-regulated transcript (CART) is a regulatory peptide expressed in the nervous system and in endocrine cells, e.g. in pancreatic islets. CART deficient mice exhibit islet dysfunction, impaired insu...
Cocaine- and amphetamine-regulated transcript (CART) is a regulatory peptide expressed in the nervous system and in endocrine cells, e.g. in pancreatic islets. CART deficient mice exhibit islet dysfunction, impaired insulin secretion and increased body weight. A mutation in the CART gene in humans is associated with reduced metabolic rate, obesity and diabetes. Furthermore, CART is upregulated in islets of type-2 diabetic rats and regulates islet hormone secretion in vitro. While the function of CART in the nervous system has been extensively studied, there is no information on its expression or function in white adipose tissue. CART mRNA and protein were found to be expressed in both subcutaneous and visceral white adipose tissue from rat and man. Stimulating rat primary adipocytes with CART significantly potentiated isoprenaline-induced lipolysis, and hormone sensitive lipase activation (phosphorylation of Ser 563). On the other hand, CART significantly potentiated the inhibitory effect of insulin on isoprenaline-induced lipolysis. CART inhibited insulin-induced glucose uptake and lipogenesis, which was associated with inhibition of PKB phosphorylation. In conclusion, CART is a novel constituent of human and rat adipocytes and affects several biological processes central in both lipid- and glucose homeostasis. Depending on the surrounding conditions, the effects of CART are insulin-like or insulin-antagonistic.
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