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      Review article: the pathophysiological roles of the renin–angiotensin system in the gastrointestinal tract

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          Summary

          Background

          The renin‐angiotensin system ( RAS) is a homeostatic pathway widely known to regulate cardiovascular and renal physiology; however, little is known about its influence in gastrointestinal tissues.

          Aim

          To elicit the anatomical distribution and physiological significance of the components of the RAS in the gastrointestinal tract.

          Methods

          An extensive online literature review including Pubmed and Medline.

          Results

          There is evidence for RAS involvement in gastrointestinal physiology and pathophysiology, with all the components required for autonomous regulation identified throughout the gastrointestinal tract. The RAS is implicated in the regulation of glucose, amino acid, fluid and electrolyte absorption and secretion, motility, inflammation, blood flow and possibly malignant disease within the gastrointestinal tract. Animal studies investigating the effects of RAS blockade in a range of conditions including inflammatory bowel disease, functional gut disorders, gastrointestinal malignancy and even intestinal ischaemia have been encouraging to date. Given the ready availability of drugs that modify the RAS and their excellent safety profile, an opportunity exists for investigation of their possible therapeutic role in a variety of human gastrointestinal diseases.

          Conclusions

          The gastrointestinal renin‐angiotensin system appears to be intricately involved in a number of physiological processes, and provides a possible target for novel investigative and therapeutic approaches.

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          Most cited references163

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          The renin-angiotensin system and cancer: old dog, new tricks.

          For cancers to develop, sustain and spread, the appropriation of key homeostatic physiological systems that influence cell growth, migration and death, as well as inflammation and the expansion of vascular networks are required. There is accumulating molecular and in vivo evidence to indicate that the expression and actions of the renin-angiotensin system (RAS) influence malignancy and also predict that RAS inhibitors, which are currently used to treat hypertension and cardiovascular disease, might augment cancer therapies. To appreciate this potential hegemony of the RAS in cancer, an expanded comprehension of the cellular actions of this system is needed, as well as a greater focus on translational and in vivo research.
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            Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomised controlled trials.

            Angiotensin-receptor blockers (ARBs) are a widely used drug class approved for treatment of hypertension, heart failure, diabetic nephropathy, and, recently, for cardiovascular risk reduction. Experimental studies implicate the renin-angiotensin system, particularly angiotensin II type-1 and type-2 receptors, in the regulation of cell proliferation, angiogenesis, and tumour progression. We assessed whether ARBs affect cancer occurrence with a meta-analysis of randomised controlled trials of these drugs. We searched Medline, Scopus (including Embase), Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and the US Food and Drug Administration website for studies published before November, 2009, that included any of the seven currently available ARBs. Randomised controlled trials with an ARB given in at least one group, with a follow-up of at least 1 year, and that enrolled at least 100 patients were included. New-cancer data were available for 61,590 patients from five trials. Data on common types of solid organ cancers were available for 68,402 patients from five trials, and data on cancer deaths were available for 93,515 patients from eight trials. Telmisartan was the study drug in 30,014 (85.7%) patients who received ARBs as part of the trials with new cancer data. Patients randomly assigned to receive ARBs had a significantly increased risk of new cancer occurrence compared with patients in control groups (7.2%vs 6.0%, risk ratio [RR] 1.08, 95% CI 1.01-1.15; p=0.016). When analysis was limited to trials where cancer was a prespecified endpoint, the RR was 1.11 (95% CI 1.04-1.18, p=0.001). Among specific solid organ cancers examined, only new lung-cancer occurrence was significantly higher in patients randomly assigned to receive ARBs than in those assigned to receive control (0.9%vs 0.7%, RR 1.25, 1.05-1.49; p=0.01). No statistically significant difference in cancer deaths was observed (1.8%vs 1.6%, RR 1.07, 0.97-1.18; p=0.183). This meta-analysis of randomised controlled trials suggests that ARBs are associated with a modestly increased risk of new cancer diagnosis. Given the limited data, it is not possible to draw conclusions about the exact risk of cancer associated with each particular drug. These findings warrant further investigation. 2010 Elsevier Ltd. All rights reserved.
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              Minireview: overview of the renin-angiotensin system--an endocrine and paracrine system.

              Since the discovery of renin as a pressor substance in 1898, the renin-angiotensin (RAS) system has been extensively studied because it remains a prime candidate as a causative factor in the development and maintenance of hypertension. Indeed, some of the properties of the physiologically active component of the RAS, angiotensin II, include vasoconstriction, regulation of renal sodium and water absorption, and increasing thirst. Initially, its affect on blood pressure was thought to be mediated primarily through the classical endocrine pathway; that is, the generation of blood-borne angiotensin with actions in target tissues. More recently, however, it has become appreciated that a local autocrine or paracrine RAS may exist in a number of tissues, and that these may also play a significant role in regulating blood pressure. Some of the difficulties in studying tissue RAS stem from the limitations of pharmacology in not differentiating between RAS products made systemically from those synthesized locally. However, the development of transgenic animals with highly specific promoters to target the RAS to specific tissues provided important tools to dissect these systems. Thus, this minireview will discuss recent advances in understanding the relationship between endocrine and paracrine (tissue) RAS using transgenic models.
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                Author and article information

                Journal
                Aliment Pharmacol Ther
                Aliment. Pharmacol. Ther
                10.1111/(ISSN)1365-2036
                APT
                Alimentary Pharmacology & Therapeutics
                John Wiley and Sons Inc. (Hoboken )
                0269-2813
                1365-2036
                February 2012
                05 January 2012
                : 35
                : 4 ( doiID: 10.1111/apt.2012.35.issue-4 )
                : 414-428
                Affiliations
                [ 1 ] Department of Gastroenterology & Hepatology Eastern Health Vic., Australia
                [ 2 ] Department of Medicine Melbourne University Vic., Australia
                [ 3 ] Gastroenterology and Liver Transplant Unit Austin Hospital Vic., Australia
                [ 4 ] Eastern Health Clinical School Monash University Vic., Australia
                Author notes
                [*] [* ] Correspondence to:

                Dr M. Garg, Department of Gastroenterology & Hepatology, Eastern Health, Level 2, 5 Arnold St, Box Hill 3128, Vic., Australia.

                E‐mail: mayur.garg@ 123456monash.edu

                Article
                APT4971
                10.1111/j.1365-2036.2011.04971.x
                7159631
                22221317
                805e5307-9af9-4ea9-b86e-f482ba7232a7
                © 2012 Blackwell Publishing Ltd

                This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.

                History
                : 24 October 2011
                : 29 November 2011
                : 12 December 2011
                : 13 December 2011
                Page count
                Pages: 15
                Categories
                Review Article
                Review Articles
                Custom metadata
                2.0
                February 2012
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.0 mode:remove_FC converted:15.04.2020

                Pharmacology & Pharmaceutical medicine
                Pharmacology & Pharmaceutical medicine

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