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      How Do Antihypertensive Drugs Work? Insights from Studies of the Renal Regulation of Arterial Blood Pressure

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          Abstract

          Though antihypertensive drugs have been in use for many decades, the mechanisms by which they act chronically to reduce blood pressure remain unclear. Over long periods, mean arterial blood pressure must match the perfusion pressure necessary for the kidney to achieve its role in eliminating the daily intake of salt and water. It follows that the kidney is the most likely target for the action of most effective antihypertensive agents used chronically in clinical practice today. Here we review the long-term renal actions of antihypertensive agents in human studies and find three different mechanisms of action for the drugs investigated. (i) Selective vasodilatation of the renal afferent arteriole (prazosin, indoramin, clonidine, moxonidine, α-methyldopa, some Ca ++-channel blockers, angiotensin-receptor blockers, atenolol, metoprolol, bisoprolol, labetolol, hydrochlorothiazide, and furosemide). (ii) Inhibition of tubular solute reabsorption (propranolol, nadolol, oxprenolol, and indapamide). (iii) A combination of these first two mechanisms (amlodipine, nifedipine and ACE-inhibitors). These findings provide insights into the actions of antihypertensive drugs, and challenge misconceptions about the mechanisms underlying the therapeutic efficacy of many of the agents.

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          Limitations of the usual blood-pressure hypothesis and importance of variability, instability, and episodic hypertension.

          Although hypertension is the most prevalent treatable vascular risk factor, how it causes end-organ damage and vascular events is poorly understood. Yet, a widespread belief exists that underlying usual blood pressure can alone account for all blood-pressure-related risk of vascular events and for the benefits of antihypertensive drugs, and this notion has come to underpin all major clinical guidelines on diagnosis and treatment of hypertension. Other potentially informative measures, such as variability in clinic blood pressure or maximum blood pressure reached, have been neglected, and effects of antihypertensive drugs on such measures are largely unknown. Clinical guidelines recommend that episodic hypertension is not treated, and the potential risks of residual variability in blood pressure in treated hypertensive patients have been ignored. This Review discusses shortcomings of the usual blood-pressure hypothesis, provides background to accompanying reports on the importance of blood-pressure variability in prediction of risk of vascular events and in accounting for benefits of antihypertensive drugs, and draws attention to clinical implications and directions for future research. Copyright 2010 Elsevier Ltd. All rights reserved.
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            Hypertension prevalence, awareness, treatment and control in national surveys from England, the USA and Canada, and correlation with stroke and ischaemic heart disease mortality: a cross-sectional study

            Objective Comparison of recent national survey data on prevalence, awareness, treatment and control of hypertension in England, the USA and Canada, and correlation of these parameters with each country stroke and ischaemic heart disease (IHD) mortality. Design Non-institutionalised population surveys. Setting and participants England (2006 n=6873), the USA (2007–2010 n=10 003) and Canada (2007–2009 n=3485) aged 20–79 years. Outcomes Stroke and IHD mortality rates were plotted against countries’ specific prevalence data. Results Mean systolic blood pressure (SBP) was higher in England than in the USA and Canada in all age–gender groups. Mean diastolic blood pressure (DBP) was similar in the three countries before age 50 and then fell more rapidly in the USA, being the lowest in the USA. Only 34% had a BP under 140/90 mm Hg in England, compared with 50% in the USA and 66% in Canada. Prehypertension and stages 1 and 2 hypertension prevalence figures were the highest in England. Hypertension prevalence (≥140 mm Hg SBP and/or ≥90 mm Hg DBP) was lower in Canada (19·5%) than in the USA (29%) and England (30%). Hypertension awareness was higher in the USA (81%) and Canada (83%) than in England (65%). England also had lower levels of hypertension treatment (51%; USA 74%; Canada 80%) and control (<140/90 mm Hg; 27%; the USA 53%; Canada 66%). Canada had the lowest stroke and IHD mortality rates, England the highest and the rates were inversely related to the mean SBP in each country and strongly related to the blood pressure indicators, the strongest relationship being between low hypertension awareness and stroke mortality. Conclusions While the current prevention efforts in England should result in future-improved figures, especially at younger ages, these data still show important gaps in the management of hypertension in these countries, with consequences on stroke and IHD mortality.
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              Incident dementia and blood pressure lowering in the Hypertension in the Very Elderly Trial cognitive function assessment (HYVET-COG): a double-blind, placebo controlled trial.

              Observational epidemiological studies have shown a positive association between hypertension and risk of incident dementia; however, the effects of antihypertensive therapy on cognitive function in controlled trials have been conflicting, and meta-analyses of the trials have not provided clear evidence of whether antihypertensive treatment reduces dementia incidence. The Hypertension in the Very Elderly trial (HYVET) was designed to assess the risks and benefits of treatment of hypertension in elderly patients and included an assessment of cognitive function. Patients with hypertension (systolic pressure 160-200 mm Hg; diastolic pressure <110 mm Hg) who were aged 80 years or older were enrolled in this double-blind, placebo-controlled trial. Participants were randomly assigned to receive 1.5 mg slow release indapamide, with the option of 2-4 mg perindopril, or placebo. The target systolic blood pressure was 150 mm Hg; the target diastolic blood pressure was 80 mm Hg. Participants had no clinical diagnosis of dementia at baseline, and cognitive function was assessed at baseline and annually with the mini-mental state examination (MMSE). Possible cases of incident dementia (a fall in the MMSE score to <24 points or a drop of three points in 1 year) were assessed by standard diagnostic criteria and expert review. The trial was stopped in 2007 at the second interim analysis after treatment resulted in a reduction in stroke and total mortality. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00122811. 3336 HYVET participants had at least one follow-up assessment (mean 2.2 years) and were included: 1687 participants were randomly assigned to the treatment group and 1649 to the placebo group. Only five reports of adverse effects were attributed to the medication: three in the placebo group and two in the treatment group. The mean decrease in systolic blood pressure between the treatment and placebo groups at 2 years was systolic -15 mm Hg, p<0.0001; and diastolic -5.9 mm Hg, p<0.0001. There were 263 incident cases of dementia. The rates of incident dementia were 38 per 1000 patient-years in the placebo group and 33 per 1000 patient-years in the treatment group. There was no significant difference between treatment and placebo groups (hazard ratio [HR] 0.86, 95% CI 0.67-1.09); however, when these data were combined in a meta-analysis with other placebo-controlled trials of antihypertensive treatment, the combined risk ratio favoured treatment (HR 0.87, 0.76-1.00, p=0.045). Antihypertensive treatment in elderly patients does not statistically reduce incidence of dementia. This negative finding might have been due to the short follow-up, owing to the early termination of the trial, or the modest effect of treatment. Nevertheless, the HYVET findings, when included in a meta-analysis, might support antihypertensive treatment to reduce incident dementia.
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                Author and article information

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                29 July 2016
                2016
                : 7
                : 320
                Affiliations
                [1] 1Medical Sciences Division, University of Oxford Oxford, UK
                [2] 2Department of Physiology, Anatomy and Genetics, University of Oxford Oxford, UK
                [3] 3Nuffield Department of Anaesthetics, John Radcliffe Hospital Oxford, UK
                Author notes

                Edited by: Alexander Staruschenko, Medical College of Wisconsin, USA

                Reviewed by: Roger Evans, Monash University, Australia; Zhen Wang, University of Mississippi Medical Center, USA

                *Correspondence: Keith L. Dorrington keith.dorrington@ 123456dpag.ox.ac.uk

                This article was submitted to Renal and Epithelial Physiology, a section of the journal Frontiers in Physiology

                Article
                10.3389/fphys.2016.00320
                4965470
                27524972
                4a74620b-ffd5-4af6-a02a-cb4077a6abf4
                Copyright © 2016 Digne-Malcolm, Frise and Dorrington.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 27 May 2016
                : 13 July 2016
                Page count
                Figures: 7, Tables: 4, Equations: 9, References: 150, Pages: 19, Words: 15607
                Funding
                Funded by: Dunhill Medical Trust 10.13039/501100000377
                Categories
                Physiology
                Review

                Anatomy & Physiology
                antihypertensive drugs,renal circulation,hypertension,diuretics,vasodilator agents

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