Plecanatide Is Effective and Safe in the Treatment for Chronic Idiopathic Constipation: Results of a Phase II Trial.

BACKGROUND: Many patients with chronic idiopathic constipation (CIC) remain unsatisfied with their treatment options. Plecanatide is a pH-sensitive uroguanylin analog that increases fluid and ion movement into the gastrointestinal lumen, softening stools and encouraging motility, while limiting the risk of diarrhea. AIMS: The objective of this phase 2 study is to evaluate the safety and efficacy of once-daily oral plecanatide in patients with CIC and identify the most effective dose. METHODS: A 12-week, multicenter, randomized, double-blind, placebo-controlled, dose-ranging study was conducted in patients aged 18-75 years and diagnosed with CIC based on modified Rome III criteria (< 3 complete spontaneous bowel movements [CSBMs] per week and infrequent loose stools without the use of laxatives). Participants were randomized to placebo or plecanatide 0.3, 1.0, or 3.0 mg. The primary efficacy endpoint was the proportion of overall CSBM responders. Key secondary endpoints included time to first CSBM, change in CSBM and spontaneous bowel movement (SBM) frequency rates, patient-reported outcomes, safety, and tolerability. RESULTS: Of 951 randomized participants, 946 were included in the modified intent-to-treat population. Plecanatide 0.3 and 3.0 mg significantly increased overall CSBM responder rates compared with placebo (0.3 mg, P = 0.016; 3.0 mg, P = 0.009). Plecanatide was associated with decreased time to first CSBM, significant increases in CSBM and SBM frequency, and decreased patient-reported constipation severity compared with placebo. Diarrhea was the most frequently reported treatment-emergent adverse event. CONCLUSIONS: Plecanatide is a well-tolerated treatment that relieved the symptoms of CIC with a relatively low incidence of diarrhea.

The endogenous ligand for guanylate cyclase-C activation reliefs intestinal inflammation in the DSS colitis model.

Ulcerative colitis (UC) is a major type of inflammatory bowel disease (IBD) and significantly impacts patient quality of life. Previous research revealed that the guanylate cyclase-C (GC-C) signaling pathway is associated with the severity of UC. We aimed to investigate the effect of the GC-C agonist, guanylin (Gn), on inflammatory injury in mice with colitis. An experimental UC model was established in Balb/c mice. Mesalamine served as a positive control. The Gn overexpression vector was administered once per day for 1 week. Intestinal permeability of the mice was measured using fluorescein isothiocyanate-dextran after the treatment. Histopathologic grading was estimated to assess the inflammatory injury of the colon. The expression level of crucial mediators of the GC-C signaling pathway (Gn, Ugn and GC-C) and tight junction proteins (occludin, claudin-1 and ZO-1) was measured in the colon. Additionally, the level of pro-inflammatory cytokines (IL-8 and TNF-α) in serum was measured. After injecting the UC mice with the Gn overexpression vector, the body weight increased, and the frequency of loose stools and bloody stools was decreased. Intestinal permeability and histopathologic score were significantly reduced (P<0.05). The expression level of GC-C, Gn, Ugn, claudin-1 and ZO-1 was significantly increased (P<0.05). The level of IL-8 and TNF-α in the serum was significantly decreased (P<0.01). Therefore, the application of Gn overexpression vector can ameliorate the intestinal inflammatory injury and repair the mucosal barrier in colitis mice, which further suggests the clinical therapeutic potential of GC-C agonists in IBD.

Long-term treatment with plecanatide was safe and tolerable in patients with irritable bowel syndrome with constipation.

Objective: This open-label, multi-center, fixed-dose study (NCT02706483) evaluated the long-term safety and tolerability of plecanatide for the treatment of adults with irritable bowel syndrome with constipation (IBS-C).Methods: Safety and tolerability of once-daily plecanatide 6 mg for up to 53 weeks was assessed in patients with IBS-C who either had been enrolled in one of the phase 3 studies or were study-naïve but met eligibility criteria of the double-blind studies. Safety was assessed by treatment-emergent adverse events (AEs). Patient-reported questionnaires assessed overall IBS symptoms, treatment satisfaction, and desire for treatment continuation. No dose adjustments or treatment interruptions were permitted during the study.Results: Of the 2272 patients enrolled, 1842 (81.1%) completed the study. AEs were experienced by 27.3%, and 4.3% discontinued due to an AE. Most AEs were mild or moderate (90.3%). The incidence of diarrhea, the most commonly reported AE, was low (6.7%), and declined in frequency over time. Diarrhea was the most common cause of AE-related withdrawals (2.7% of patients). At week 53 or end of treatment, 88.2% of patients reported "significant" or "moderate" relief, 72.4% were "very" or "quite" satisfied with treatment, and 76.6% were "very" or "quite" likely to continue treatment.Conclusions: Plecanatide 6 mg was safe and well tolerated in patients with IBS-C treated for up to 53 weeks, with an overall safety profile similar to the 12-week IBS-C studies. Patients reported high rates of relief and satisfaction with treatment, and interest in continuing therapy.Trial registration: ClinicalTrials.gov identifier: NCT02706483.

Peptídeos natriuréticos tipo B (BNP e NT-ProBNP) para o diagnóstico de insuficiência cardíaca / Natriuretic peptides type B (BNP and NT-ProBNP) for the diagnosis of heart failure

CONTEXTO: A insuficiência cardíaca (IC) é uma síndrome clínica frequente que representa a etapa final de diferentes cardiopatias e constitui um grave problema de saúde pública. Sua prevalência em adultos é estimada entre 1 e 2%, chegando a 10% nas pessoas com idade acima de 75 anos. No Brasil, estima-se que a prevalência de IC supere os 6 milhões de pessoas afetadas. Segundo dados do DATASUS, a IC resulta em mais de 300.000 internações por ano, o que corresponde a um terço das internações por doenças cardíacas. Estima-se que a taxa de mortalidade hospitalar por IC seja de aproximadamente 8%. Tecnologia: Peptídeo Natriurético Tipo B (Bnp) e Fragmento N-Terminal Do Peptídeo Natriurético Atrial (NT-ProBNP). PERGUNTA: Qual a acurácia diagnóstica e qual o impacto orçamentário do BNP/NT-ProBNP para o diagnóstico de insuficiência cardíaca na atenção primária à saúde do SUS. EVIDÊNCIAS CIENTÍFICAS: Foi realizada uma atualização da revisão sistemática e metanálise de Booth e colaboradores (2014). Existe extensa documentação em estudos científicos publicados de que os testes BNP/NT-ProBNP apresentam boa acurácia diagnóstica para o diagnóstico de IC na atenção primária (acurácia global de aproximadamente 80%). A qualidade da evidência para os dados de sensibilidade é moderada, enquanto que para os dados de especificidade é baixa, de acordo com o GRADE. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: O presente estudo de impacto orçamentário aplica como caso base um cenário bastante conservador de custo na incorporação do BNP/NT-ProBNP, estimando impacto orçamentário total de R$ 39.054.323,64 no primeiro ano, e de R$ 206.242.756,48 para um período de 5 anos. Importante considerar que esse custo é conservador, pois: (a) foi utilizada toda a população brasileira como base, incluindo a população atendida na saúde suplementar; (b) os parâmetros de custos foram bastante conservadores, sendo utilizado o custo de BNP vinculado a pequenas licitações e o valor de custo de ecocardiograma de acordo com o SIGTAP, não considerando o custo de encaminhamento para especialista e retorno à unidade de saúde, prática comum em diversos municípios para a solicitação do exame; (c) foi considerado também que toda a população suspeita seria avaliada, contudo esperamos que, devido a problemas de acesso, os números reais sejam inferiores; (d) foi considerada adoção plena a 100% desde a incorporação, cenário que dificilmente seria observado. Análise complementar, utilizando os mesmos parâmetros conservadores acima apresentados, definiu como o BNP/NT-ProBNP promovendo economia para o SUS caso possua um valor igual ou inferior a R$ 13,64. Considerando o custo da ecografia equivalente a R$ 79,20, resultaria em impacto orçamentário de R$ 130.147.691,10 em cinco anos; nesse cenário, a incorporação do BNP/NT-ProBNP promoveria economia para o SUS caso possua valor igual ou inferior a R$ 27,00. DISCUSSÃO: O teste diagnóstico é de fácil implementação e apresenta menos restrições logísticas do que o referenciamento ao cardiologista e a realização de ecocardiografia, os quais são atualmente os métodos majoritariamente utilizados para o diagnóstico de IC na atenção primária. A logística da realização da ecocardiografia é mais complexa comparada à realização do teste proposto, demandando também estrutura diferenciada e longo período de formação de ecocardiografistas; a dosagem de BNP ou de NT-PróBNP pode ser realizada em pequenos municípios, onde não se dispõe de estrutura para a realização de exames mais complexos, ajudando a reduzir inequidades em saúde. É provável que o valor de reembolso de R$ 39,94 por ecocardiografia potencialmente esteja subestimando o custo do exame para o sistema; adicionalmente o custo de R$ 50,00 pelo exame de BNP ou NT-ProBNP realizado deve diminuir com aumento de escala. Não estão também computadas potenciais economias e ganho em saúde com o diagnóstico mais precoce da IC e do uso da ecocardiografia em um espectro de pacientes no qual o uso do exame seria mais benéfico. A estimativa do impacto orçamentário no cenário base é extremamente conservadora. A disponibilização do BNP/NT-ProBNP tem potencial de auxiliar a suprir a demanda reprimida no diagnóstico da IC e de diminuir inequidades em saúde, uma vez que está facilitando o acesso às estratégias diagnósticas, diminuindo a necessidade de ecocardiografia e oferecendo alternativa de mais fácil implantação para pequenos municípios. Contudo, é importante salientar que o BNP/NT-ProBNP não substitui plenamente a ecocardiografia, sendo essa última necessária para confirmação diagnóstica nos casos em que o BNP/NTProBNP for positivo. Nesse caso, a cada 2,93 exames de BNP ou NT-ProBNP, espera-se que uma ecocardiografia será poupada. As estimativas de impacto orçamentário poderão ser aprimoradas a partir de registro do consumo do BNP/NT-ProBNP e dos custos efetivos de aquisição do teste quando da sua implementação inicial. RECOMENDAÇÃO INICIAL DA CONITEC: Os membros do Plenário da CONITEC, em sua 65ª reunião ordinária, recomendaram que a matéria fosse enviada à Consulta Pública com manifestação preliminar favorável à incorporação. CONSULTA PÚBLICA: A consulta pública nº 31/2018 foi realizada entre os dias 06/07/2018 e 25/07/2018. Foram recebidas 43 contribuições, sendo 30 pelo formulário para contribuições técnico-científicas e 13 pelo formulário para contribuições sobre experiência ou opinião de pacientes, familiares, amigos ou cuidadores de pacientes, profissionais de saúde ou pessoas interessadas no tema. A participação na consulta pública foi majoritariamente de profissionais da saúde e interessados no tema. Das 43 contribuições recebidas, 41 concordaram totalmente com a recomendação preliminar, uma concordou parcialmente e uma discordou totalmente. Todas as contribuições da consulta pública foram analisadas, discutidas e respondidas. Após apreciação das contribuições encaminhadas, pela consulta pública, o plenário da CONITEC entendeu que o resultado da consulta pública esteve em linha com a decisão preliminar realizada, mantendo-se assim a recomendação favorável à incorporação da tecnologia. RECOMENDAÇÃO FINAL DA CONITEC: Os membros da CONITEC presentes na 70ª reunião ordinária, no dia 30 de agosto de 2018, deliberaram, por recomendar a incorporação ao SUS do teste BNP/NT-ProBNP. Foi assinado o registro de deliberação Nº 372/2018. DECISÃO: Incorporar os peptídeos natriuréticos tipo B (BNP e NT-ProBNP) para diagnóstico de insuficiência cardíaca, para uso conforme diretrizes do Ministério da Saúde, no âmbito do Sistema Único de Saúde - SUS. Dada pela Portaria nº 62, publicada no DOU nº 218, pág. 56, seção 1, em 13 de novembro de 2018.

Current treatment paradigm and landscape for the management of chronic idiopathic constipation in adults: Focus on plecanatide.

BACKGROUND AND PURPOSE: Chronic idiopathic constipation (CIC) is a prevalent disorder affecting productivity, quality of life, and health care resource utilization. Nurse practitioners (NPs) play a critical function in managing patients presenting with CIC, with roles including evaluation, diagnosis, treatment decisions, and patient education. For adults with inadequate response or tolerability issues using over-the-counter treatments, three prescription agents (plecanatide, linaclotide, and lubiprostone) are available in the United States to treat CIC, of which plecanatide was mostly recently approved. This review provides NPs with a current overview and summary of plecanatide in the current treatment landscape for CIC. METHODS: PubMed was searched for the literature regarding clinical practice guidelines and published trial data for lubiprostone, linaclotide, and plecanatide in CIC. CONCLUSIONS: Efficacy and safety comparisons between prescription agents are limited beacause of the differences in trial duration and primary end points (all different). Generally, plecanatide and linaclotide demonstrated similar efficacy, with plecanatide demonstrating lower rates of adverse events. IMPLICATIONS FOR PRACTICE: The success of CIC treatment can be affected by patient adherence to the regimen, which is dependent on the efficacy and tolerability of treatment. Plecanatide is a promising option for patients whose CIC symptoms are not adequately controlled using their current treatment approach.

Efficacy, safety, and tolerability of plecanatide in patients with irritable bowel syndrome with constipation: results of two phase 3 randomized clinical trials.

OBJECTIVES: Two identical, phase 3, randomized, double-blind, placebo-controlled trials evaluated the efficacy and safety of plecanatide in patients with irritable bowel syndrome with constipation (IBS-C). METHODS: Adults meeting Rome III criteria for IBS-C were randomized (1:1:1) to placebo or plecanatide (3 or 6 mg) for 12 weeks. The primary efficacy end point was the percentage of overall responders (patients reporting ≥30% reduction from baseline in worst abdominal pain plus an increase of ≥1 complete spontaneous bowel movement (CSBM)/week from baseline in the same week for ≥6 of 12 treatment weeks). Safety was assessed by adverse events (AEs). RESULTS: Overall, 2189 individuals were randomized across the two studies and 1879 completed the studies. Demographic and baseline characteristics were similar across treatment groups and between studies. The percentage of overall responders in Study 1 was 30.2% and 29.5% for plecanatide 3 and 6 mg, respectively, vs. 17.8% placebo (P < 0.001 for each dose vs. placebo), and in Study 2 was 21.5% (P = 0.009) and 24.0% (P < 0.001) for plecanatide 3 and 6 mg, respectively, compared to 14.2% for placebo. The percentage of sustained efficacy responders (overall responders plus weekly responders for ≥2 of last 4 weeks of the 12-week treatment period) was significantly greater for both doses of plecanatide vs. placebo across both studies. All secondary end points (stool frequency/consistency, straining, abdominal symptoms) showed statistically significant improvements compared with placebo. The most common AE was diarrhea (3 mg, 4.3%; 6 mg, 4.0%; placebo, 1.0%). Discontinuation due to diarrhea was infrequent (3 mg, 1.2%; 6 mg, 1.4%; placebo, 0). CONCLUSIONS: Plecanatide significantly improved both abdominal pain and constipation symptoms of IBS-C with minimal associated side effects and high levels of tolerability.

Uroguanylin: a new actor in the energy balance movie.

Uroguanylin (UGN) is a potential target in the fight against obesity. The mature protein is released after enzymatic cleavage from its natural precursor, proUGN. UGN is mostly produced in the gut, and its production is regulated by nutritional status. However, UGN is also produced in other tissues such as the kidneys. In the past, UGN has been widely studied as a natriuretic peptide owing to its involvement in several different pathologies such as heart failure, cancer and gastrointestinal diseases. However, recent studies have suggested that UGN also acts as a regulator of body weight homeostasis because it modulates both food intake and energy expenditure. This ultimately results in a decrease in body weight. This action is mediated by the sympathetic nervous system. Future studies should be directed at the potential effects of UGN agonists in regulating body weight in human obesity.

Plecanatide: First Global Approval.

Plecanatide (TrulanceTM) is an oral guanylate cyclase-C agonist that is being developed by Synergy Pharmaceuticals for the treatment of gastrointestinal disorders, such as chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C). It is a synthetic analogue of human uroguanylin, a 16 amino acid peptide that regulates ion and fluid transport in the gastrointestinal tract. In January 2017, plecanatide received its first global approval in the USA for the treatment of adult patients with CIC. Plecanatide is undergoing phase III investigation in IBS-C. This article summarizes the milestones in the development of plecanatide leading to this first approval in CIC.

Uroguanylin Action in the Brain Reduces Weight Gain in Obese Mice via Different Efferent Autonomic Pathways.

The gut-brain axis is of great importance in the control of energy homeostasis. The identification of uroguanylin (UGN), a peptide released in the intestines that is regulated by nutritional status and anorectic actions, as the endogenous ligand for the guanylyl cyclase 2C receptor has revealed a new system in the regulation of energy balance. We show that chronic central infusion of UGN reduces weight gain and adiposity in diet-induced obese mice. These effects were independent of food intake and involved specific efferent autonomic pathways. On one hand, brain UGN induces brown adipose tissue thermogenesis, as well as browning and lipid mobilization in white adipose tissue through stimulation of the sympathetic nervous system. On the other hand, brain UGN augments fecal output through the vagus nerve. These findings are of relevance as they suggest that the beneficial metabolic actions of UGN through the sympathetic nervous system do not involve nondesirable gastrointestinal adverse effects, such as diarrhea. The present work provides mechanistic insights into how UGN influences energy homeostasis and suggests that UGN action in the brain represents a feasible pharmacological target in the treatment of obesity.

New medical therapies for heart failure.

Heart failure (HF) can rightfully be called the epidemic of the 21(st) century. Historically, the only available medical treatment options for HF have been diuretics and digoxin, but the capacity of these agents to alter outcomes has been brought into question by the scrutiny of modern clinical trials. In the past 4 decades, neurohormonal blockers have been introduced into clinical practice, leading to marked reductions in morbidity and mortality in chronic HF with reduced left ventricular ejection fraction (LVEF). Despite these major advances in pharmacotherapy, our understanding of the underlying disease mechanisms of HF from epidemiological, clinical, pathophysiological, molecular, and genetic standpoints remains incomplete. This knowledge gap is particularly evident with respect to acute decompensated HF and HF with normal (preserved) LVEF. For these clinical phenotypes, no drug has been shown to reduce long-term clinical event rates substantially. Ongoing developments in the pharmacotherapy of HF are likely to challenge our current best-practice algorithms. Novel agents for HF therapy include dual-acting neurohormonal modulators, contractility-enhancing agents, vasoactive and anti-inflammatory peptides, and myocardial protectants. These novel compounds have the potential to enhance our armamentarium of HF therapeutics.

In vitro evaluation of cenderitide-eluting stent I -an antirestenosis and proendothelization approach.

Despite the success that drug-eluting stents (DESs) have achieved for minimizing in-stent restenosis (ISR), the antirestenotic agents used in DES have been implicated in delayed endothelial healing and impairment of endothelial functions. Cenderitide (CD-NP) is a novel antiproliferation chimeric peptide of semiendothelial origin; thus, this paper aims to demonstrate the selectivity aspect of this new peptide via in vitro evaluation on key players in ISR-smooth muscle cells (SMCs) and endothelial cells. The microbicinchoninic acid protein assay was used to investigate the CD-NP release from films and stents. Cenderitide-containing films blended with poly(ethylene glycol) and its copolymer exhibited higher release kinetics compared with neat poly(ε-caprolactone) (PCL) formulation. Cenderitide-eluting stents (CES) was produced by coating bare metallic stents with CD-NP entrapped PCL using an ultrasonic spray coater. The investigation of CD-NP on in vitro cells revealed that CD-NP inhibits human coronary smooth muscle cells (HCaSMCs) proliferation but exhibits no effects on human umbilical vein endothelial cells (HUVECs) proliferation. Moreover, CD-NP released up to 7 days displayed inhibitory effects on SMCs proliferation. The CES produced in this work shows that the released CD-NP inhibits HCaSMCs proliferation but did not hamper HUVECs proliferation in vitro, suggesting that it has potential to reduce ISR without retarding the endothelialization healing in vivo.

Update on clinical trials for the prevention of acute kidney injury in patients undergoing cardiac surgery.

BACKGROUND: Effective therapeutic agents for the prevention and treatment of acute kidney injury (AKI) after cardiac surgery remain elusive despite the tremendous advances in surgical techniques, technology, and understanding of disease processes. Recent developments and their effect on the incidence of AKI after cardiac surgery are discussed. DATA SOURCES: Published clinical trials in PubMed, strength of evidence assessed by the guidelines of the American Family Physicians. CONCLUSIONS: The definition of AKI has changed, and the focus of interventions has shifted from treatment to prevention to recovery from AKI. Antioxidants and biological agents have been added to classic armaments of hydration and diuretics in addition to tighter metabolic control to prevent AKI. Although the treatment options remain unsatisfactory, a lot of progress nevertheless continues to be made in the prevention and treatment of AKI.

Diabetes-induced loss of gastric ICC accompanied by up-regulation of natriuretic peptide signaling pathways in STZ-induced diabetic mice.

Our previous study demonstrated that natriuretic peptides (NPs) play an inhibitory role in regulation of gastric smooth muscle motility. However, it is not clear whether NPs are involved in diabetics-induced loss of gastric interstitial cell of Cajal (ICC). The present study was designed to investigate the relationship between diabetics-induced loss of gastric ICC and natriuretic peptide signaling pathway in streptozotocin (STZ)-induced diabetic mice. The results showed that the protein expression levels of c-Kit and membrane-bound stem cell factor (mSCF) in gastric smooth muscle layers were decreased in STZ-induced diabetic mice. However, both mRNA and protein expression levels of natriuretic peptide receptor (NPR)-A, B and C were increased in the same place of the diabetic mice. The amplitude of spontaneous contraction in gastric antral smooth muscles was inhibited by C-type natriuretic peptide (CNP) dose-dependently and the inhibitory effect was potentiated in diabetic mice. Pretreatment of the cultured gastric smooth muscle cells (GSMCs) with different concentration of CNP can significantly decrease the mSCF expression level. 8-Bromoguanosine-3',5'-cyclomo-nophosphate (8-Br-cGMP), a membrane permeable cGMP analog, mimicked the effect of CNP but not cANF (a specific NPR-C agonist). Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay showed that high concentration of cANF (10(-6) mol/L) inhibited cell proliferation in cultured GSMCs. These findings suggest that up-regulation of NPs/NPR-A, B/cGMP and NPs/NPR-C signaling pathways may be involved in diabetes-induced loss of gastric ICC.

Novel natriuretic peptides: new compounds and new approaches.

The natriuretic peptides (NPs) are a group of structurally similar yet genetically distinct peptides that have diverse actions in cardiovascular, renal, and endocrine homeostasis. Since the discovery of atrial natriuretic peptide in 1981, the diagnostic, prognostic, and therapeutic significance of NPs have been studied extensively in relation to heart failure. Indeed, it now is understood that a hallmark of heart failure is the activation of the cardiac endocrine system, in particular the natriuretic peptide family including atrial natriuretic peptide and B-type natriuretic peptide. Currently, the only approved therapeutic application for NPs is the intravenous treatment of acute decompensated heart failure. However, in recent years there has been considerable research aimed at creating novel NPs and administering them via novel routes. This review focuses on the novel NPs that have been created and on novel approaches for their administration.

Natriuretic and antikaliuretic effects of uroguanylin and prouroguanylin in the rat.

The peptide uroguanylin (Ugn) is stored and released as a propeptide (proUgn) by enterochromaffin cells in the intestine, and converted to Ugn and other metabolites in the renal tubules. Both proUgn and Ugn are natriuretic, although the response to proUgn is thought to depend on its conversion to Ugn within nephrons. To assess the efficiency of intrarenal conversion of proUgn to Ugn, we measured urinary Ugn excretion in rats following intravenous infusions of proUgn or Ugn. Infusion of 2 and 10 nmol proUgn/kg body wt increased plasma proUgn concentration from 2.2 ± 0.3 to 5.6 ± 1.3 pmol/ml and to 37 ± 9.6 pmol/ml, respectively. No proUgn was detected in urine before, during, or after proUgn infusions. These two proUgn infusion doses resulted in total Ugn recovery in urine of 162 ± 64 and 206 ± 39 pmol/kg body wt (9 and 2% of the infused amount, respectively). By contrast, the same molar amounts of Ugn resulted in 1,009 ± 477 and 5,352 ± 2,133 pmol/kg body wt of Ugn in urine (recoveries of ∼50%). Unexpectedly, comparisons of natriuretic dose-response curves for each peptide showed proUgn to be about five times more potent than Ugn, despite the relatively modest amount of Ugn generated from infused proUgn. In addition, both peptides were antikaliuretic at low doses, but in this case Ugn showed greater potency than proUgn. These data do not support Ugn as the primary active principle of proUgn for regulation of renal sodium excretion. Instead, an alternative peptide fragment produced from proUgn may be responsible for natriuretic activity in the kidney, whereas Ugn itself may play an antikaliuretic role.

The role of natriuretic peptides in inflammation and immunity.

The natriuretic peptides (NPs) are a family of widely distributed, but evolutionarily conserved, polypeptide mediators that exert a range of effects throughout the body. There is growing realization that NP actions go far beyond volume and blood pressure homeostasis. Their pleiotropic effects include a significant role in regulating the immune system. Localization of NP receptors in various immune organs as well as in modulation of inflammation in vascular disease supports this hypothesis. Immune cells, including macrophages, dendritic cells, and T lymphocytes, express receptors for NPs. NPs are also involved in polarizing the immune response to allergens. NPs play an important role in shaping the early immune response to environmental antigens and appear to play a critical role in the interaction between cells of the innate and adaptive immune systems. The recent explosion of basic and clinical research has resulted in improved understanding of their molecular structure. This has facilitated development of chimeric forms of NPs as well as more convenient routes of administration. Thus, the NPs and their receptors could be exploited to develop therapeutics for the inflammatory and immune responses in wide range of diseases. Also discussed are several patents regarding NPs in the present review.

Effects of short-term food deprivation on orexin-A-induced intestinal bicarbonate secretion in comparison with related secretagogues.

Studies of gastrointestinal physiology in humans and intact animals are usually conducted after overnight fast. We compared the effects of orexin-A, vasoactive intestinal polypeptide (VIP), melatonin, serotonin, uroguanylin, ghrelin and prostaglandin E(2) (PGE(2)) on duodenal bicarbonate secretion in fed and overnight fasted animals. This review is a summary of our findings. Secretagogues were administered by intra-arterial infusion or luminally (PGE(2)). Enterocyte intracellular calcium ([Ca(2+)](i)) signalling was studied by fluorescence imaging. Total RNA was extracted, reverse transcripted to cDNA and expression of orexin receptors measured by quantitative real-time PCR. Orexin-A stimulates the duodenal secretion in continuously fed animals but not in food-deprived animals. Similarly, short-term fasting causes a 100-fold decrease in the amount of the muscarinic agonist bethanechol required for stimulation of secretion. In contrast, fasting does not affect secretory responses to intra-arterial VIP, melatonin, serotonin, uroguanylin and ghrelin, or that to luminal PGE(2). Orexin-A induces [Ca(2+)](i) signalling in enterocytes from fed rats but no significant [Ca(2+)](i) responses occur in enterocytes from fasted animals. In addition, overnight fasting decreases the expression of mucosal orexin receptors. Short-term food deprivation thus decreases duodenal expression of orexin receptors and abolishes the secretory response to orexin-A as well as orexin-A-induced [Ca(2+)](i) signalling. Fasting, furthermore, decreases mucosal sensitivity to bethanechol. The absence of declines in secretory responses to other secretagogues tested strongly suggests that short-term fasting does not affect the secretory capacity of the duodenal mucosa in general. Studies of intestinal secretion require particular evaluation with respect to feeding status.

Can colorectal cancer be prevented or treated by oral hormone replacement therapy?

Guanylyl cyclase C (GCC) is the receptor specifically expressed by intestinal cells for the paracrine hormones guanylin and uroguanylin and diarrheagenic bacterial heat-stable enterotoxins. This tissue-specific receptor coordinates lineage-dependent regulation of epithelial homeostasis, and its disruption contributes to intestinal tumorigenesis. It coordinates regenerative and metabolic circuits by restricting the cell cycle and proliferation and programming metabolic transitions central to organizing the dynamic crypt-surface axis. Further, mice deficient in GCC signaling are more susceptible to colon cancer induced by Apc mutations or the carcinogen azoxymethane. Moreover, guanylin and uroguanylin are gene products most commonly lost, early, in colon cancer in animals and humans. The role of GCC as a tumor suppressing receptor regulating proliferation and metabolism, together with the universal loss of guanylin and uroguanylin in tumorigenesis, suggests a model in which colorectal cancer is a paracrine hormone deficiency syndrome. In that context, activation of GCC reverses the tumorigenic phenotype by limiting growth of colorectal cancer cells by restricting progression through the G1/S transition and reprogramming metabolic circuits from glycolysis to oxidative phosphorylation, limiting bioenergetic support for rapid proliferation. These observations suggest a pathophysiological hypothesis in which GCC is a lineage-dependent tumor suppressing receptor coordinating proliferative homeostasis whose dysregulation through hormone loss contributes to neoplasia. The correlative therapeutic hypothesis suggests that colorectal cancer is a disease of hormone insufficiency that can be prevented or treated by oral supplementation with GCC ligands.

High-salt intake primes the rat kidney to respond to a subthreshold uroguanylin dose during ex vivo renal perfusion.

In a variety of animal models, uroguanylin causes diuresis, natriuresis and kaliuresis and is found in larger concentrations in the urine compared to controls after oral salt intake or in conditions of excess salt and fluid retention. It has been proposed that uroguanylin functions as an intestinal natriuretic hormone following intake of meals high in salt content. In the present work, we examined if 10 days of salt ingestion resulted in an enhanced response to uroguanylin in the isolated perfused rat kidney. Rats were given normal water, 1% NaCl (HS1%), or 2% NaCl (HS2%) for 10 days, at which time the right kidneys were surgically removed and perfused with a modified Krebs-Henseleit solution for 30 min. After a 30-min control period, the kidneys were perfused with a modified Krebs-Henseleit solution containing 0.06 microM uroguanylin for an additional 90 min. Compared to vehicle-matched time controls, 0.06 microM uroguanylin perfusion of kidneys from rats maintained on HS2% resulted in a significantly increased urine flow (UF; from 0.17+/-0.01 to 0.23+/-0.01, after 60 min, n=6, P<0.05), fractional Na(+) excretion (%E(Na+); from 16.6+/-0.7 to 30+/-2, after 60 min, n=6, P<0.05), fractional K(+) excretion (%E(K+); from 20.5+/-0.58 to 37.4+/-2.1, after 60 min, n=6, P<0.05), and fractional Cl(-) excretion increased from 18.16+/-0.52 to 35.2+/-2.0 at 60 min, n=6, P<0.05. With the exception of a significant increase in the %E(K)(+), no other effect was observed in the kidneys from the rats maintained on HS1%, and no significant effects were seen in those that were maintained on normal water. The effect of a higher dose (0.6 microM) of uroguanylin on urinary flow, sodium or potassium excretion was also significantly increased by 2% NaCl (HS2%) treatment (P<0.05). We also observed an expressive upregulation of the GC-C and a slight downregulation of the GC-A receptor in high-salt treated rats. These data demonstrate that prolonged salt ingestion primes the kidney to enhanced renal responses to uroguanylin.