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Renin
Kinds of Renin Terms modified by Renin Selected AbstractsINHIBITION OF BRAIN RENIN,ANGIOTENSIN SYSTEM IMPROVES DIASTOLIC CARDIAC FUNCTION FOLLOWING MYOCARDIAL INFARCTION IN RATSCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 8 2009IG Araujo SUMMARY 1Recently, we demonstrated that oral captopril treatment improved diastolic function and attenuated cardiac remodelling after myocardial infarction (MI) in rats. Considering the feasible role of the brain renin,angiotensin system (RAS) in heart failure, in the present study we investigated the role of the captopril injected intracerebroventricularly (i.c.v.) on the progression of cardiac dysfunction. 2Male Wistar rats underwent experimental MI or sham operation. Infarcted animals received daily i.c.v. injections of captopril (approximately 200 mg/kg; MI + Cap) or saline (MI) from 11 to 18 days after infarction. Electro- and echocardiogram assessments were performed before and after i.c.v. treatment (10 and 18 days after MI, respectively). Water and hypertonic saline ingestion were determined daily between 12 and 16 days after MI. 3Electrocardiograms from the MI and MI + Cap groups showed signs that resembled large MI before and after i.c.v. treatment. However, despite similar systolic dysfunction observed in both groups, only captopril-treated rats exhibited reduced left ventricular (LV) dilatation and improved LV filling, as assessed by echocardiograms, and low levels of water ingestion compared with the saline-treated control group. 4The results of the present study suggest that the brain RAS may participate in the development of cardiac dysfunction induced by ischaemia and that inhibition of the brain RAS may provide a new strategy for the prevention of diastolic dysfunction. [source] THE ,BODY FLUID PRESSURE CONTROL SYSTEM' RELIES ON THE RENIN,ANGIOTENSIN,ALDOSTERONE SYSTEM: BALANCE STUDIES IN FREELY MOVING DOGSCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 5-6 2005Erdmann Seeliger SUMMARY 1.,The physiological role of the ,renal body fluid pressure control system', including the intrarenal mechanism of ,pressure natriuresis', is uncertain. 2.,Balance studies in freely moving dogs address the following questions: (i) what is the physiological contribution of pressure natriuresis to the control of total body sodium (TBS); (ii) to what extent is long-term mean arterial blood pressure (MABP) determined by TBS and total body water (TBW); and (iii) during Na accumulation, is Na stored in an osmotically inactive form? 3.,Diurnal time-courses of Na excretion (UNaV) and MABP reveal no correlation. Spontaneous MABP changes do not affect UNaV. The long-term 20% reduction of renal perfusion pressure (RPP) results in Na retention via pressure-dependent stimulation of the renin,angiotensin,aldosterone system (RAAS), not via a pressure natriuresis mechanism. Prevention of pressure natriuresis does not result in ongoing Na retention when the RAAS is operative. The long-term 20% elevation of RPP induced by sustained TBS elevation facilitates Na excretion via pressure natriuresis, but does not restore TBS to normal. 4.,Changes in TBW correlate well with changes in TBS (r2 = 0.79). This correlation is even closer when concomitant changes in total body potassium are also considered (r2 = 0.91). 5.,With normal or elevated TBW, long-term MABP changes correlate well with TBW changes (r2 = 0.69). At lowered TBW, no correlation is found. 6.,In conclusion, the physiological role of pressure natriuresis is limited. Pressure natriuresis does not appear to be operative when RPP is changed from ,20 to +10% and neurohumoral control of UNaV is unimpeded. Within this range, pressure-dependent changes in the RAAS mediate the effects of changes in RPP on UNaV. Pressure natriuresis may constitute a compensating mechanism under pathophysiological conditions of substantial elevation of RPP. A large portion of the long-term changes in MABP are attributable to changes in TBW. The notion of osmotically inactive Na storage during Na accumulation appears to be invalid. [source] Pharmacogenetics of antihypertensive treatmentDRUG DEVELOPMENT RESEARCH, Issue 3 2004Donna K. Arnett Abstract Hypertension is a common disorder associated with increased cardiovascular morbidity and mortality. Unfortunately, in the United States, only about one third of those who are aware of their hypertensive status successfully control their blood pressure. One reason for this is the variable and unpredictable response individuals have to pharmacologic treatment. Clinicians often resort to a trial-and-error approach to match patients with effective drug treatment. It is the goal of hypertension pharmacogenetics to apply knowledge of genetic predictors of treatment response to drugs that lower blood pressure and to translate this knowledge into clinical practice. To date, more than 30 studies have investigated associations between specific genetic polymorphisms and response to particular antihypertensive drugs. Angiotensin-converting enzyme inhibitors have been most frequently studied, followed by diuretics, beta-blockers, angiotensin II blockers, adrenergic alpha-agonists, and calcium channel blockers. Renin,angiotensin,aldosterone system genes have been the most widely studied, with the angiotensin-converting enzyme I/D variant being typed in about one third of all hypertension pharmacogenetic studies to date. In a number of cases, significant and potentially promising associations between genes and drug treatments have been reported. However, taken in sum, the literature suggests that the path from gene-drug-outcome association studies to clinically useful knowledge may be neither short nor direct. In the future, carefully designed studies must acknowledge that hypertension is caused by multiple genes and environmental factors that act in concert. These considerations, along with a better understanding of the complexities of the biology of hypertension, open the next set of opportunities for hypertension pharmacogenetics research. Drug Dev. Res. 62:191,199, 2004. © 2004 Wiley-Liss, Inc. [source] The Renin-Angiotensin System in the Bovine Utero-Placental UnitREPRODUCTION IN DOMESTIC ANIMALS, Issue 3-4 2000AH Nielsen Contents Renin, angiotensin converting enzyme, and angiotensin II receptors are expressed in the bovine utero-placental unit, indicating the presence of a local renin-angiotensin system (RAS). Angiotensin II receptors of type AT1 and AT2 as well as non-AT1/non-AT2 binding sites were identified. The expression of both renin and the angiotensin II receptor types in the bovine utero-placental unit differs from that in humans. This fact is probably related to differences in placental architecture. The RAS in the bovine utero-placental unit might be important for growth processes in the endometrium and for placentation. It might also participate in the regulation of the utero-placental blood flow and secretion of hormones. Disturbances in the utero-placental RAS might cause a reduced utero-placental blood flow, intrauterine growth retarda_tion and intrauterine death. [source] TNF Alpha,308 Genotype and Renin,Angiotensin System in Hemodialysis Patients: An Effect on Inflammatory Cytokine Levels?ARTIFICIAL ORGANS, Issue 2 2005Gultekin Genctoy Abstract:, Background: Renin,angiotensin system (RAS) was suggested to modulate inflammatory cytokine production. Angiotensin II was consistently shown to increase production of tumor necrosis factor alpha (TNF-,). However, inflammatory cytokines and RAS were modulated by genetic polymorphisms such as TNF-,,308 G > A and angiotensin-converting enzyme (ACE) I/D gene polymorphisms. The aim of this study was to investigate the effects of ACE and TNF-, genotypes on inflammatory cytokines in hemodialysis (HD) patients. Methods: ACE I/D and TNF-,,308 G > A genotypes, pre- and postdialysis plasma renin activity (PRA), serum ACE, interleukin-1 beta (IL-1,), and TNF-, levels were determined in 22 HD patients. Results: Predialysis serum ACE activity is correlated with TNF-, (r = 0.63; P = 0.01), and PRA was correlated with IL-1, levels (r = 0.49; P = 0.02). Pre/postdialysis IL-1, and TNF-, were similar in DD and II/ID ACE genotypes. Predialysis TNF-, and IL-1, (32.4 ± 5; 35.1 ± 4.2 vs. 28.1 ± 3.7; 26.5 ± 6.2 pg/mL; P < 0.05) and postdialysis TNF-, levels (30.4 ± 1.4 vs. 28.4 ± 0.82 pg/mL; P < 0.05) were significantly higher in TNF1/2 than TNF1/1 patients. Conclusion: ACE and TNF-,,308 G > A (1/2) gene polymorphisms may contribute to modulation of proinflammatory cytokine production and hence chronic inflammation in HD patients. [source] Renin: from ,pro' to promoterBIOESSAYS, Issue 5 2003Brian J. Morris Renin is the rate-limiting enzyme in a cascade that leads to production of angiotensin II, which is perhaps our most important regulator of salt and water balance and blood pressure. In this personal perspective, I describe how I entered the renin field 33 years ago by discovering that proteases increased the level of renin activity in biological fluids, so revealing the existence of a ,pro' form of the molecule. This led me on a journey that encapsulated all of the major milestones in molecular discovery for renin. These included (1) the elucidation of the steps in renin biosynthesis, (2) the cloning of renin cDNA and its gene, (3) demonstration of the structure of the renin protein, (4) using the renin gene in the first genetic studies in hypertension, (5) finding the mechanism by which the major controller, cyclic AMP, regulates the promoter, (6) showing that a strong enhancer and its weak promoter control this physiologically regulatable gene in accord with the variegation (on/off switching) model, and (7) being the first to identify molecules involved in posttranscriptional control. The renin molecule, its gene and molecular control are now very well understood, but more fine details on the topic of renin continue to emerge to delight ,reninologists' and others. BioEssays 25:520,527, 2003. © 2003 Wiley Periodicals, Inc. [source] Association between renin,angiotensin,aldosterone system genotypes and haplotypes and risk of ischemic stroke of atherosclerotic etiologyACTA NEUROLOGICA SCANDINAVICA, Issue 6 2009S. Saidi Objective,,, The association of renin C-4063T and angiotensinogen (AGT) T174M, AGT M235T and AGT A-6G polymorphisms with ischemic stroke of atherosclerotic etiology was investigated in 329 Tunisian patients with stroke and 444 controls. Materials and methods,,, Genotyping was performed using PCR-RFLP and the contributions of polymorphisms to the risk of stroke were analyzed using haplotype and multivariate regression analysis. Results,,, AGT 235T and AGT-6G allele and AGT 235T/T, AGT-6A/G and AGT-6G/G genotype frequencies were higher in patients. Linkage disequilibrium (LD) was noted for AGT174T with AGT235M and AGT(-6)A in patients, while AGT235M was in LD with AGT(-6)A in controls and AGT235T was in LD with AGT(-6)G in both groups. The AGT 174T/235T/-6A and AGT 174T/235M/-6G haplotypes were positively and negatively associated with stroke respectively. Multivariate regression analysis identified AGT 174T/235M/-6A, AGT 174T/235T/-6G, AGT 174T/235T/-6A and AGT 174M/235T/-6A haplotypes to be significantly associated with an increased risk of stroke. Conclusions,,, Renin,angiotensin,aldosterone system polymorphisms influence the risk of atherosclerotic stroke in Tunisians. [source] Hypertension, vascular cognitive disorders and neuroprotectionACTA NEUROPSYCHIATRICA, Issue 5 2007Dimiter Hadjiev Objective:, The role of the antihypertensive therapy in preventing vascular cognitive disorders in elderly persons without a history of stroke is a matter of debate. This review focuses on cognitive disorders in elderly hypertensive patients. Methods:, Relevant papers were identified by searches in PubMed from 1946 until February 2007 using the keywords ,cerebral blood flow autoregulation', ,vascular cognitive disorders', ,neuroimaging in hypertension', ,antihypertensive treatment' and ,neuroprotection in cerebral ischemia'. Results:, Excessive blood pressure lowering in patients with long-standing hypertension may increase the risk of cerebral hypoperfusion, white matter lesions and consequent cognitive decline. White matter lesions have been found in the majority of patients with long-standing hypertension. They correlate with vascular cognitive disorders, particularly impairments of attention and executive function, while memory is relatively preserved. Cerebral small vessel disease in elderly patients should be taken into account when antihypertensive treatment is considered. Renin,angiotensin blockade, some calcium channel blockers and statins are thought to possess neuroprotective action. Conclusion:, For prevention of cerebral hypoperfusion in elderly hypertensives blood pressure lowering should be cautiously controlled. The increased risk of white matter lesions is an indication for early neuroprotection. The combination of renin,angiotensin blockade or calcium channel blockers with statins may become a promising preventive strategy against cognitive decline in elderly hypertensives. Cerebral white matter protection is a future challenge. [source] Role of aldosterone and angiotensin II in insulin resistance: an updateCLINICAL ENDOCRINOLOGY, Issue 1 2009Guido Lastra-Lastra Summary The role of the Renin,Angiotensin,Aldosterone system (RAAS) on the development of insulin resistance and cardiovascular disease is an area of growing interest. Most of the deleterious actions of the RAAS on insulin sensitivity appear to be mediated through activation of the Angiotensin II (Ang II) Receptor type 1 (AT1R) and increased production of mineralocorticoids. The underlying mechanisms leading to impaired insulin sensitivity remain to be fully elucidated, but involve increased production of reactive oxygen species and oxidative stress. Both experimental and clinical studies also implicate aldosterone in the development of insulin resistance, hypertension, endothelial dysfunction, cardiovascular tissue fibrosis, remodelling, inflammation and oxidative stress. There is abundant evidence linking aldosterone, through non-genomic actions, to defective intracellular insulin signalling, impaired glucose homeostasis and systemic insulin resistance not only in skeletal muscle and liver but also in cardiovascular tissue. Blockade of the different components of the RAAS, in particular Ang II and AT1R, results in attenuation of insulin resistance, glucose homeostasis, as well as decreased cardiovascular disease morbidity and mortality. These beneficial effects go beyond to those expected with isolated control of hypertension. This review focuses on the role of Ang II and aldosterone in the pathogenesis of insulin resistance, as well as in clinical relevance of RAAS blockade in the prevention and treatment of the metabolic syndrome and cardiovascular disease. [source] Systemic nitric oxide clamping in normal humans guided by total peripheral resistanceACTA PHYSIOLOGICA, Issue 2 2010J. A. Simonsen Abstract Aim:, We wanted to stabilize the availability of nitric oxide (NO) at levels compatible with normal systemic haemodynamics to provide a model for studies of complex regulations in the absence of changes in NO levels. Methods:, Normal volunteers (23,28 years) were infused i.v. with the nitric oxide synthase (NOS) inhibitor NG -nitro- l -arginine methyl ester (l -NAME) at 0.5 mg kg,1 h,1. One hour later, the NO donor sodium nitroprusside (SNP) was co-infused in doses eliminating the haemodynamic effects of l -NAME. Haemodynamic measurements included blood pressure (MABP) and cardiac output (CO) by impedance cardiography. Results:,l -NAME increased MABP and total peripheral resistance (TPR, 1.02 ± 0.05 to 1.36 ± 0.07 mmHg s mL,1, mean ± SEM, P < 0.001). With SNP, TPR fell to a stable value slightly below control (0.92 ± 0.05 mmHg s mL,1, P < 0.05). CO decreased with l -NAME (5.8 ± 0.3 to 4.7 ± 0.3 L min,1, P < 0.01) and returned to control when SNP was added (6.0 ± 0.3 L min,1). A decrease in plasma noradrenaline (42%, P < 0.01) during l -NAME administration was completely reversed by SNP. Plasma renin activity decreased during l -NAME administration and returned towards normal after addition of SNP. In contrast, plasma aldosterone was increased by l -NAME and remained elevated. Conclusions:, Concomitant NOS inhibition and NO donor administration can be adjusted to maintain TPR at control level for hours. This approach may be useful in protocols in which stabilization of the peripheral supply of NO is required. However, the dissociation between renin and aldosterone secretion needs further investigation. [source] Blood volume, blood pressure and total body sodium: internal signalling and output controlACTA PHYSIOLOGICA, Issue 1 2009P. Bie Abstract Total body sodium and arterial blood pressure (ABP) are mutually dependent variables regulated by complex control systems. This review addresses the role of ABP in the normal control of sodium excretion (NaEx), and the physiological control of renin secretion. NaEx is a pivotal determinant of ABP, and under experimental conditions, ABP is a powerful, independent controller of NaEx. Blood volume is a function of dietary salt intake; however, ABP is not, at least not in steady states. A transient increase in ABP after a step-up in sodium intake could provide a causal relationship between ABP and the regulation of NaEx via a hypothetical integrative control system. However, recent data show that subtle sodium loading (simulating salty meals) causes robust natriuresis without changes in ABP. Changes in ABP are not necessary for natriuresis. Normal sodium excretion is not regulated by pressure. Plasma renin is log-linearly related to salt intake, and normally, decreases in renin secretion are a precondition of natriuresis after increases in total body sodium. Renin secretion is controlled by renal ABP, renal nerve activity and the tubular chloride concentrations at the macula densa (MD). Renal nerve activity is related to blood volume, also at constant ABP, and elevates renin secretion by means of ,1 -adrenoceptors. Recent results indicate that renal denervation reduces ABP and renin activity, and that sodium loading may decrease renin without changes in ABP, glomerular filtration rate or ,1 -mediated nerve activity. The latter indicates an essential role of the MD mechanism and/or a fourth mediator of the physiological control of renin secretion. [source] Acute exercise causes an enhancement of tissue renin,angiotensin system in the kidney in ratsACTA PHYSIOLOGICA, Issue 1 2005S. Maeda Abstract Aims:, Initially, the renin,angiotensin system (RAS) produced through the classical endocrine pathway was well known for its regulation of blood pressure. However, it was revealed that a local autocrine and/or paracrine RAS may exist in a number of tissues (such as kidney). Exercise causes a redistribution of tissue blood flow, by which the blood flow is greatly increased in active muscles, whereas it is decreased in the splanchnic circulation (such as in the kidney). We hypothesized that exercise causes an enhancement of tissue RAS in the kidney. Methods:, We studied whether exercise affects expression of angiotensinogen and angiotensin-converting enzyme (ACE) and tissue angiotensin II level in the kidney. The rats performed treadmill running for 30-min. Immediately after this exercise, kidney was quickly removed. Control rats remained at rest during this 30-min period. Results:, The expression of angiotensinogen mRNA in the kidney was markedly higher in the exercise rats than in the control rats. ACE mRNA in the kidney was significantly higher in the exercise rats than in the control rats. Western blot analysis confirmed significant upregulation of ACE protein in the kidney after exercise. Tissue angiotensin II level was also increased by exercise. Conclusion:, The present study suggests that the exercise-induced enhancement of tissue RAS in the kidney causes vasoconstriction and hence decreases blood flow in the kidney, which are helpful in increasing blood flow in active muscles, thereby contributing to the redistribution of blood flow during exercise. [source] Plasma renin in mice with one or two renin genesACTA PHYSIOLOGICA, Issue 4 2004P. B. Hansen Abstract Aim:, In the present study we have investigated whether the presence of a second renin gene exerts an overriding influence on plasma renin such that mice with two renin genes have consistently higher renin levels than mice with only one renin gene. Methods:, Plasma renin was determined as the rate of angiotensin I generation using a radioimmunoassay (RIA) kit with (plasma renin concentration, PRC) or without (plasma renin activity, PRA) the addition of purified rat angiotensinogen as substrate. Results:, In male 129SvJ, DBA/2 and Swiss Webster mice, strains possessing both Ren-1 and Ren-2, PRC (ng Ang I mL,1 h,1) averaged 178 ± 36, 563 ± 57 and 550 ± 43 while PRA was 2.9 ± 0.5, 3.6 ± 0.8 and 7.8 ± 1.2. In male C57BL/6, C3H and BALB/c mice that express only Ren-1, PRC averaged 426 ± 133, 917 ± 105 and 315 ± 72, and PRA was 3.4 ± 1.0, 6.9 ± 1.7 and 4.5 ± 1.2. In the two renin gene A1AR,/, mice compared with the one renin gene A1AR+/+, PRC averaged 538 ± 321 and 415 ± 159 while PRA averaged 3.2 ± 1.1 and 4.4 ± 1.4 ng Ang I mL,1 h,1. Aldosterone levels showed no significant differences between one renin (C57BL/6, C3H and BALB/c) and two renin (129SvJ, DBA/2 and Swiss Webster) gene mice. Furthermore, by quantitative real-time polymerase chain reaction (RT-PCR) we found no correlation between the number of renin genes and whole kidney renin mRNA levels from one and two renin gene mice. Conclusion:, Our data show that baseline plasma renin is not systematically higher in mice with two renin genes than in one renin gene mice. Thus, the presence of a second renin gene does not seem to be a major determinant of differences in PRC between different mouse strains. [source] Volume natriuresis vs. pressure natriuresisACTA PHYSIOLOGICA, Issue 4 2004P. Bie Abstract Body fluid regulation depends on regulation of renal excretion. This includes a fast vasopressin-mediated water-retaining mechanism, and slower, complex sodium-retaining systems dominated by the renin,angiotensin aldosterone cascade. The sensory mechanisms of sodium control are not identified; effectors may include renal arterial pressure, renal reflexes, extrarenal hormones and other regulatory factors. Since the pioneering work of Guyton more than three decades ago, pressure natriuresis has been in focus. Dissociations between sodium excretion and blood pressure are explained as conditions where regulatory performance exceeds the precision of the measurements. It is inherent to the concept, however, that sudden transition from low to high sodium intake elicits an arterial pressure increase, which is reversed by the pressure natriuresis mechanism. However, such transitions elicit parallel changes in extracellular fluid volume thereby activating volume receptors. Recently we studied the orchestration of sodium homeostasis by chronic and acute sodium loading in normal humans and trained dogs. Small increases in arterial blood pressure are easily generated by acute sodium loading, and dogs appear more sensitive than humans. However, with suitable loading procedures it is possible , also acutely , to augment renal sodium excretion by at least one order of magnitude without any change in arterial pressure whatsoever. Although pressure natriuresis is a powerful mechanism capable of overriding any other controller, it seems possible that it is not operative under normal conditions. Consequently, it is suggested that physiological control of sodium excretion is neurohumoral based on extracellular volume with neural control of renin system activity as an essential component. [source] Transgenic mice for studies of the renin,angiotensin system in hypertensionACTA PHYSIOLOGICA, Issue 4 2004J. L. Lavoie Abstract Hypertension is a polygenic and multi-factorial disorder that is extremely prevalent in western societies, and thus has received a great deal of attention by the research community. The renin,angiotensin system has a strong impact on the control of blood pressure both in the short- and long-term, making it one of the most extensively studied physiological systems. Nevertheless, despite decades of research, the specific mechanisms implicated in its action on blood pressure and electrolyte balance, as well as its integration with other cardiovascular pathways remains incomplete. The production of transgenic models either over-expressing or knocking-out specific components of the renin,angiotensin system has given us a better understanding of its role in the pathogenesis of hypertension. Moreover, our attention has recently been refocused on local tissue renin,angiotensin systems and their physiological effect on blood pressure and end-organ damage. Herein, we will review studies using genetic manipulation of animals to determine the role of the endocrine and tissue renin,angiotensin system in hypertension. We will also discuss some untraditional approaches to target the renin,angiotensin system in the kidney. [source] Ontogeny of urine preference and its relationship to NH4Cl preference and sodium hunger in suckling rat pupsDEVELOPMENTAL PSYCHOBIOLOGY, Issue 2 2005Micah Leshem Abstract We chart the postnatal ontogeny of urine preference in the suckling rat. Twelve-day-old sucklings, when offered urine, NH4Cl, or NaCl, ingest more urine and NH4Cl than NaCl. When rendered sodium hungry by ivc renin or by sodium depletion, these sucklings prefer urine and NH4Cl to NaCl, dilute urine, or an NaCl and KCl mineral mix equimolar to urine; however, by 18 days of age, urine and NH4Cl are no longer preferred to NaCl. Hence, urine preference in the suckling may be specific and preparatory for the variety of purposes urine preference serves in the adult rat, and it might guide the pup to urinary sodium in the nest. Since preference for urine and NH4Cl covary during postnatal development, the high preference for NH4Cl in midterm sucklings might be because its ammonium flavor is similar to urine. © 2005 Wiley Periodicals, Inc. Dev Psychobiol 46: 111,117, 2005. [source] Treatment of diabetic hypertensionDIABETES OBESITY & METABOLISM, Issue 5 2009David S. H. Bell Insulin resistance and hyperglycaemia combine to make hypertension more prevalent in the type 2 diabetic patient. Blood pressure goals below those for the non-diabetic subject have been shown to be more effective in lowering mortality and cardiovascular events in the diabetic patient. To achieve these goals in most cases, three to five antihypertensives from different therapeutic groups need to be utilized. Suppression of the renin,angiotensin system (RAS) with angiotensin-converting enzyme inhibitors, angiotensin 2 receptor blockers or a renin inhibitor should be the primary therapy. A second goal should be suppression of the sympathetic nervous system utilizing a beta-blocker that does not increase insulin resistance. The addition of a diuretic, calcium channel blocker or a vasodilator to suppressors of the RAS and sympathetic nervous system aid in achieving hypertensive goals in the diabetic patient. Achieving hypertensive goals with suppression of the RAS and sympathetic nervous system should result in a decrease in mortality and cardiovascular events in the diabetic hypertensive patient. In this review article, the benefits and disadvantages of the different antihypertensive therapies in the diabetic patient are discussed. [source] The role of renin,angiotensin,aldosterone system-based therapy in diabetes prevention and cardiovascular and renal protectionDIABETES OBESITY & METABOLISM, Issue 12 2008Hussam Abuissa Hypertension increases the risk of type 2 diabetes mellitus (T2DM) and cardiovascular disease. In addition to lowering blood pressure, blockade of the renin,angiotensin,aldosterone system (RAAS) reduces the risk of new-onset T2DM and offers renal protection. Using a MEDLINE search, we identified multiple trials that reported the incidence of T2DM in patients taking inhibitors of RAAS. In this review, we will discuss the RAAS as a potential target in diabetes prevention and the mechanisms through which inhibitors of this system achieve such an important effect. We will also shed light on the beneficial cardiovascular and renal effects of RAAS blockade. Although multiple studies have demonstrated that inhibitors of RAAS, especially angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, can reduce the incidence of T2DM, randomized controlled studies are still needed to further elucidate their exact role in diabetes prevention. [source] Effects of insulin resistance on endothelial function: possible mechanisms and clinical implicationsDIABETES OBESITY & METABOLISM, Issue 10 2008D Tousoulis Insulin resistance (IR) is defined as a reduced responsiveness of peripheral tissues to the effects of the hormone, referring to abated ability of insulin in stimulating glucose uptake in peripheral tissues and in inhibiting hepatic glucose output. Insulin has both a vasodilatory effect, which is largely endothelium dependent through the release of nitric oxide, and a vasoconstrictory effect through the stimulation of the sympathetic nervous system and the release of endothelin-1. IR and endothelial dysfunction (ED) are not only linked by common pathogenetic mechanisms, involving deranged insulin signalling pathways, but also by other, indirect to the hormone's actions, mechanisms. Different treatment modalities have been proposed to affect positively both the metabolic effects of insulin and ED. Weight loss has been shown to improve sensitivity to insulin as a result of either altered diet or exercise. Exercise has favourable effects on endothelial function in normal states and in states of disease, in men and women, and throughout the age spectrum and, hence, in IR states. Metformin improves sensitivity to insulin and most likely affects positively ED. Studies have shown that inhibitors of the renin,angiotensin system alter IR favourably, while Angiotensin converting enzyme (ACE) inhibitors and Angiotensin receptor type II (ATII) inhibitors improve ED. Ongoing studies are expected to shed more light on the issue of whether treatment with the thiazolidinediones results in improvement of endothelial function, along with the accepted function of improving insulin sensitivity. Finally, improved endothelial function by such treatments is not in itself proof of reduced risk for atherosclerosis; this remains to be directly tested in clinical trials. [source] Cardiovascular drugs as antidiabetic agents: evidence for the prevention of type 2 diabetesDIABETES OBESITY & METABOLISM, Issue 7 2008D. P. Macfarlane Given the long-term health consequences and increasing incidence of type 2 diabetes, there is great interest to potentially prevent or delay its onset. Primary prevention studies have demonstrated that intensive exercise and weight reduction, and to a lesser extent certain antidiabetic agents, can reduce new onset diabetes in at-risk individuals. Results from post hoc analyses and secondary end-point outcomes of large randomized controlled trials of cardiovascular drugs suggest that these may also have beneficial effects, reducing the incidence of new onset diabetes in addition to their proven cardiovascular benefits. Multiple meta-analyses confirm that drugs primarily acting on the renin,angiotensin system (RAS) reduce the incidence of diabetes in the populations studied, perhaps via improved insulin sensitivity and/or effects on pancreatic beta cells. However, results from the recent Diabetes REduction Approaches with Medication study specifically failed to show a significant reduction in the incidence of diabetes with ramipril in individuals with abnormal glucose tolerance at baseline. There is only limited evidence that statins improve glucose tolerance, and although beta-blockers tend to have detrimental effects on glucose tolerance, newer agents with vasodilatory properties may confer benefits. With current guidelines, the use of cardiovascular drugs modifying the RAS will increase in at-risk individuals, but at present, they cannot be recommended to prevent diabetes. [source] ,-Blocker use and diabetes symptom score: results from the GEMINI studyDIABETES OBESITY & METABOLISM, Issue 3 2007J. B. McGill Aim:, The Glycemic Effect in Diabetes Mellitus: Carvedilol,Metoprolol Comparison in Hypertensives (GEMINI) trial compared the metabolic effects of two ,-blockers in people with type 2 diabetes and hypertension treated with renin,angiotensin system (RAS) blockade and found differences in metabolic outcomes. In this paper, we report the results of a prespecified secondary analysis of GEMINI that sought to determine the effect of these two ,-blockers on commonly reported symptoms. Methods:, The Diabetes Symptom Checklist (DSC), a self-report questionnaire measuring the occurrence and perceived burden of diabetes-related symptoms, was completed by GEMINI participants at baseline and at the end of the study (maintenance month 5). The DSC assessed symptoms in eight domains: psychology (fatigue), psychology (cognitive), neuropathy (pain), neuropathy (sensory), cardiology, ophthalmology, hyperglycaemia and hypoglycaemia. Results:, Comparison of the mean change in self-reported diabetes-related symptoms indicated a significant treatment difference favouring carvedilol over metoprolol tartrate in overall symptom score (,0.08; 95% CI ,0.15, ,0.01; p = 0.02) and in the domains for hypoglycaemia symptoms (,0.12; 95% CI ,0.23, ,0.02; p = 0.02) and hyperglycaemia symptoms (,0.16; 95% CI ,0.27, ,0.05; p = 0.005). Carvedilol resulted in fewer perceived diabetes-related symptoms in patients with diabetes and hypertension. Conclusion:, Carvedilol resulted in a lower perceived burden of diabetes-related symptoms in patients with type 2 diabetes and hypertension. The addition of a well-tolerated ,-blocker to RAS blockade may improve hypertension treatment and quality of life in patients with diabetes. [source] Serum angiotensin-converting enzyme and frequency of severe hypoglycaemia in Type 1 diabetes: does a relationship exist?DIABETIC MEDICINE, Issue 12 2007N. N. Zammitt Abstract Aims An association has been described between elevated serum angiotensin-converting enzyme (ACE) and an increased risk of severe hypoglycaemia (SH). To ascertain whether this reported association could be replicated in a different country, it was re-examined in 300 individuals with Type 1 diabetes. Methods People with Type 1 diabetes, none of whom was taking renin,angiotensin system blocking drugs, were recruited. Participants recorded the frequency with which they had experienced SH. Glycated haemoglobin (HbA1c) and serum ACE were measured. The difference in the incidence of SH between different quartiles of ACE activity and the relationship between serum ACE and SH were examined using non-parametric statistical tests and a negative binomial model. Results Data were obtained from 300 patients [158 male; HbA1c median (range) 8.2% (5.2,12.8%), median age 36 years (16,88); duration of diabetes 14.5 years (2,49)]. The incidence of SH was 0.93 episodes per patient year. The mean incidence of SH in the top and bottom quartiles of ACE activity was 0.5 and 1.7 episodes per patient year, respectively, but this difference was not statistically significant (P = 0.075). Spearman's test showed a very weak, although statistically significant, association between serum ACE level and SH incidence (r = 0.115, P = 0.047). The binomial model also showed a statistically significant (P = 0.002), but clinically weak, relationship between serum ACE and SH. Conclusions The present survey showed a weak relationship between serum ACE and the frequency of SH, the clinical relevance of which is unclear. This limits the proposed role for serum ACE as an index of risk for SH. [source] Inhibition of the renin,angiotensin system: added value in reducing cardiovascular and renal risk?DIABETIC MEDICINE, Issue 1 2004S. M. Marshall No abstract is available for this article. [source] The renin,angiotensin system and the long-term complications of diabetes: pathophysiological and therapeutic considerationsDIABETIC MEDICINE, Issue 8 2003R. E. Gilbert Abstract The relationship between the renin,angiotensin system (RAS) and the progression of diabetic renal disease has been a major focus of investigation over the past 20 years. More recently, experimental and clinical studies have also suggested that the RAS may have a pathogenetic role at other sites of micro- and macrovascular injury in diabetes. Complementing major advances into the understanding of the local, as distinct from the systemic RAS, a number of large clinical trials have examined whether blockade of the RAS might provide protection from the long-term complications of diabetes, beyond that due to blood pressure reduction alone. While some controversy remains, these studies have, in general, suggested that angiotensin converting enzyme (ACE) inhibition and more recently, angiotensin receptor blockade reduce the development and progression of diabetic nephropathy, cardiovascular disease and possibly retinopathy. This review will focus on recent developments in our understanding of the tissue-based RAS and its role in end-organ injury in diabetes, the results of recent clinical trials and newer strategies for the pharmacological manipulation of the RAS. [source] ACE and angiotensinogen gene genotypes and left ventricular mass in athletesEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 10 2001F. Diet Background Genetic factors may be important in modifying heart size due to long-term athletic training. The significance of polymorphisms of genes of the renin,angiotensin system in myocardial mass in a population of athletes participating in different disciplines is not known. Methods The angiotensin I-converting enzyme gene insertion/deletion (I/D) polymorphism, angiotensinogen gene M235T polymorphism and angiotensin II type 1 receptor gene A1166C polymorphism were determined in 83 male Caucasian endurance athletes and associated with left ventricular mass. Results No association with left ventricular mass was found for the polymorphisms of angiotensin I-converting enzyme gene I/D, angiotensinogen gene M235T and angiotensin II type 1 gene A1166C when studied separately. However, combined analysis of the angiotensin I-converting enzyme gene I/D polymorphism and angiotensinogen gene M235T polymorphism genotypes suggested an association with left ventricular mass (g m,2) (P = 0·023). Athletes with the angiotensin I-converting enzyme gene DD/angiotensinogen gene TT genotype combination had greater left ventricular mass compared with all other genotype combinations (179·8 ± 26·1 g m,2 vs. 145·2 ± 27·3 g m,2, P = 0·003). Conclusions These results suggest an association of combined angiotensin I-converting enzyme gene I/D polymorphism genotypes, and angiotensinogen gene M235T polymorphism genotypes with left ventricular hypertrophy due to long-term athletic training. A synergistic effect of angiotensin I-converting enzyme gene DD genotype and angiotensinogen gene TT genotype on left ventricular mass in endurance athletes appears to occur. [source] Angiotensin-converting enzyme genotype and encephalopathy in Chernobyl cleanup workersEUROPEAN JOURNAL OF NEUROLOGY, Issue 1 2009A. D. Kehoe Background and purpose:, To identify, using a genetic model, a key role for the renin,angiotensin system (RAS) in the development of dyscirculatory encephalopathy (DE) in Chernobyl cleanup workers (CCW). The insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE) gene denotes a substantial individual variation in RAS activity with the D-allele being associated with higher ACE activity. Methods:, Ninety-three male, Caucasian CCW were recruited from those under regular review at the All-Russia Centre of Emergency and Radiation Medicine, St. Petersburg. The presence or absence of DE was determined using existing institutional guidelines. ACE genotype was determined using internationally accepted methodologies. Results:, Angiotensin-converting enzyme genotype distribution in 59 subjects with DE was II: 10 (17%), ID: 31 (53%), DD: 18 (30%), D-allele frequency 56.8%. Whereas in those without the condition the distribution was II: 12 (35%), ID: 19 (56%), DD 3 (9%) and D-allele frequency 35.9% (P = 0.02). Conclusions:, These data are the first to identify an association between the ACE D-allele and DE in CCW. They provide evidence of a significant role for the RAS in the development of DE and suggest that clinical trials of ACE inhibition would be profitable in this group. [source] N -methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (MBDB): its properties and possible risksADDICTION BIOLOGY, Issue 3 2000L. A. G. J. M. Van Aerts MBDB (N -methyl-1-(1,3-benzodioxol-5-yl)-2-aminobutane) is the ,-ethyl homologue of MDMA (3,4-methylenedioxy-N-methylamphetamine). MBDB is metabolized and excreted similarly to MDMA: presumably, the majority of oral MBDB is excreted in urine unmetabolized. The main metabolic routes in man are thought to be O-dealkylation and subsequent methylation, sulphation and glucuronidation of the newly formed hydroxy groups. The major acute neuropharmacological effects of MBDB in the rat are an increase in serotonin release in the brain and an inhibition of serotonin and noradrenaline re-uptake. These effects compare well with those of MDMA, although the latter is more potent. MBDB may also slightly increase dopamine release and inhibit dopamine re-uptake, but to a lesser extent than MDMA. This is important, as dopamine release has been implicated in the reinforcing qualities of substances such as cocaine and amphetamine. The neuroendocrine effects of MBDB resemble those of MDMA. Both substances increase plasma ACTH, corticosterone, prolactin and renin. The neurophysiological effects of MBDB are characterized by a decrease in electrical activity throughout the brain, most notably in the alpha 2 and delta frequency bands. In contrast, hallucinogens increase the activity in the alpha 1 band, especially in the corpus striatum. In drug discrimination tests in the rat, MBDB, like MDMA, can be distinguished clearly from both stimulants and hallucinogens. The class of substances to which MBDB belongs may be named entactogens. MBDB dose-dependently increases locomotor activity and decreases exploratory behaviour in the rat and causes distress vocalization and wing extension in the newly hatched chicken. The rewarding properties of MBDB appear to be smaller than those of MDMA, as suggested by a 2.5 times weaker potency in the conditioned place preference test in rats. The main subjective effects of MBDB in man are a pleasant state of introspection, with greatly facilitated interpersonal communication and a pronounced sense of empathy and compassion between subjects. In this respect, MBDB again resembles MDMA. However, there are also differences. MBDB has a slower and more gentle onset of action than MDMA, produces less euphoria and has less stimulant properties. The few toxicological data available suggest that MBDB may cause serotonergic deficits in the brain, although the potency of MBDB to cause this neurotoxic effect is smaller than that of MDMA. Severe acute reactions in man as have been reported for MDMA have not been published for MBDB. The dependence potential of MBDB appears to be small, probably even smaller than that of MDMA. MBDB has been available at least since 1994 but its position on the synthetic drugs market is marginal. Subjective reports indicate that MBDB is less popular among users than MDMA. The reason may be that MBDB produces less euphoria than MDMA. Another possible explanation is that MBDB largely lacks the stimulant properties of MDMA. We calculated a margin of safety with a method similar to one used in the risk assessment of pharmaceuticals. The results suggest that MBDB is three times less likely to cause serotonergic brain deficits than MDMA. However, it should be noted that for both substances the margin of safety is less than one, indicating that the risk of neurotoxicity is not negligible. In animals, serotonergic brain deficits after exposure to MDMA have been linked to the degeneration of serotonergic nerve terminals. [source] Human skin: source of and target organ for angiotensin IIEXPERIMENTAL DERMATOLOGY, Issue 3 2004U. Muscha Steckelings Abstract:, The present study examined the expression of angiotensin receptors in human skin, the potential synthesis of angiotensin II (Ang II) in this location and looked for a first insight into physiological functions. AT1 and AT2 receptors were found within the epidermis and in dermal vessel walls. The same expression pattern was found for angiotensinogen, renin and angiotensin-converting enzyme (ACE). All components could additionally be demonstrated at mRNA level in cultured primary keratinocytes, melanocytes, dermal fibroblasts and dermal microvascular endothelial cells, except for AT2 receptors in melanocytes. The ability of cutaneous cells to synthesize Ang II was proved by identifying the molecule in cultured keratinocytes. Furthermore, in artificially wounded keratinocyte monolayers, ACE-mRNA expression was rapidly increased, and enhanced ACE expression was still found in cutaneous human scars 3 months after wounding. These findings suggest that the complete renin,angiotensin system is present in human skin and plays a role in normal cutaneous homeostasis as well as in human cutaneous wound healing. [source] Candesartan pretreatment is cerebroprotective in a rat model of endothelin-1-induced middle cerebral artery occlusionEXPERIMENTAL PHYSIOLOGY, Issue 8 2009Adam P. Mecca Endogenous levels of angiotensin II (Ang II) are increased in the cortex and hypothalamus following stroke, and Ang II type 1 receptor blockers (ARBs) have been shown to attenuate the deleterious effects in animal stroke models using middle cerebral artery (MCA) intraluminal occlusion procedures. However, the endothelin-1 (ET-1)-induced middle cerebral artery occlusion (MCAO) model of cerebral ischaemia is thought to more closely mimic the temporal events of an embolic stroke. This method provides rapid occlusion of the MCA and a gradual reperfusion that lasts for 16,22 h. The aim of the present study was to evaluate whether systemic administration of an ARB prior to ET-1-induced MCAO would provide cerebroprotection during this model of ischaemic stroke. Injection of 3 ,l of 80 ,m ET-1 adjacent to the MCA resulted in complete occlusion of the vessel that resolved over a period of 30,40 min. Following ET-1-induced MCAO, rats had significant neurological impairment, as well as an infarct that consisted of 30% of the ipsilateral grey matter. Systemic pretreatment with 0.2 mg kg,1 day,1 candesartan for 7 days attenuated both the infarct size and the neurological deficits caused by ET-1-induced MCAO without altering blood pressure. This study confirms the cerebroprotective properties of ARBs during ischaemic stroke and validates the ET-1-induced MCAO model for examination of the role of the brain renin,angiotensin system in ischaemic stroke. [source] Recent advances in the renin,angiotensin system: angiotensin-converting enzyme 2 and (pro)renin receptorEXPERIMENTAL PHYSIOLOGY, Issue 5 2008Mohan K. Raizada No abstract is available for this article. [source] | |||||||||||||||||||||||||||||||||||||