UMLS:C0020538 - FACTA Search

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Query: UMLS:C0020538 (hypertension)
170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin II (AII), acting via its G-protein linked receptor, is an important regulator of cardiac, vascular, and renal function. Following injection of AII into rats, we find that there is also a rapid tyrosine phosphorylation of the major insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) in the heart. This phenomenon appears to involve JAK2 tyrosine kinase, which associates with the AT1 receptor and IRS-1/IRS-2 after AII stimulation. AII-induced phosphorylation leads to binding of phosphatidylinositol 3-kinase (PI 3-kinase) to IRS-1 and IRS-2; however, in contrast to other ligands, AII injection results in an acute inhibition of both basal and insulin-stimulated PI 3-kinase activity. The latter occurs without any reduction in insulin receptor or IRS phosphorylation or in the interaction of the p85 and p110 subunits of PI 3-kinase with each other or with IRS-1/IRS-2. These effects of AII are inhibited by AT1 receptor antagonists. Thus, there is direct cross-talk between insulin and AII signaling pathways at the level of both tyrosine phosphorylation and PI 3-kinase activation. These interactions may play an important role in the association of insulin resistance, hypertension, and cardiovascular disease.
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PMID:Cross-talk between the insulin and angiotensin signaling systems. 890 9

The associations between insulin resistance, hyperinsulinaemia, and hypertension are well recognized. Hyperinsulinaemia induces hypertension through increased renal tubular reabsorption of sodium and water, increased sympathetic nervous system activity, proliferation of vascular smooth muscle cells, and alterations of transmembrane cation transport. At physiological concentrations, insulin decreases urinary sodium excretion, an action mediated by binding to specific high-affinity receptors. Insulin resistance is present also in strains of rats with genetic hypertension (spontaneously hypertensive and Dahl salt-sensitive rats) that can be utilized as models to study the molecular mechanisms of this abnormality. In normal rats, the number and mRNA levels of insulin receptors in the kidney are inversely related with dietary sodium content, suggesting the existence of a feedback mechanism that limits insulin-induced sodium retention when extracellular fluid volume is expanded. We have investigated the relationships between dietary sodium intake and renal insulin receptors in spontaneously hypertensive rats and have found that in this strain the feedback mechanism is abolished. In addition, spontaneously hypertensive rats have decreased expression of the insulin receptor gene in the liver and decreased receptor autophosphorylation and phosphorylation of an endogenous substrate (IRS-1) in liver and muscle. These observations provide a potential explanation for the decreased sensitivity to insulin present in spontaneously hypertensive rats. In these rats, the loss of the capability to down-regulate insulin receptor in the kidney when extracellular fluid volume is expanded can lead to further sodium retention and might play a role in the development and maintenance of hypertension.
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PMID:Molecular mechanisms of insulin resistance in arterial hypertension. 916 38

Clustering of risk factors for cardiovascular disease related to insulin resistance may account for the increased incidence of vascular disease in these conditions and in non-diabetic subjects. To investigate the relationship between a coding polymorphism in the insulin receptor substrate-1 gene and the presence of cardiovascular risk factors, 209 patients with NIDDM and 452 subjects investigated for coronary artery disease (CAD) were studied. In the NIDDM subjects 22 (10.5%) were heterozygous at codon 972 for a polymorphism which codes for a glycine to arginine substitution and 187 (89.5%) were homozygous for the wild type. Patients with the mutation had lower levels of cholesterol compared with wild type (mean, 95% confidence intervals), 5.3 (4.9-5.8) vs 6.0 (5.9-6.2) mmol/l, respectively (P = 0.002), triglyceride 1.7 (1.4-2.1) vs 2.2 (2.0-2.4) mmol/l (P = 0.051), factor VII:C activity 109.5 (85.5-133.5) vs 133.5 (127-140)% (P = 0.057) and PAI-1 antigen, 16.0 (10.5-24.3) vs 22.2 (20.0-24.6) ng/ml (P = 0.054). There were no differences in body mass index, indices of glycaemic control, fasting insulin or the prevalence of hypertension. In patients with CAD, 55 (12.7%) were carriers of the mutation (including three homozygotes) (NIDDM vs CAD, NS). Although similar trends in cholesterol, factor VII, PAI-1 antigen and triglyceride existed between carriers of the mutation and the wild type, none reached statistical significance. The results indicate that the IRS-1 gene is not implicated in the pathogenesis of NIDDM or CAD.
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PMID:Insulin receptor substrate-1 gene polymorphism and cardiovascular risk in non-insulin dependent diabetes mellitus and patients undergoing coronary angiography. 921 52

Insulin stimulates the tyrosine kinase activity of its receptor, resulting in the phosphorylation of its cytosolic substrate, insulin receptor substrate 1 (IRS-1). Previous studies have demonstrated a tissue-specific regulation of IRS-1. In the present study we investigated the levels and phosphorylation state of IRS-1 after insulin stimulation in the rat aorta in vivo, and the modulation of this protein after 72 h of fasting, using immunoprecipitation and immunoblotting with anti-insulin receptor, anti-IRS-1 and antiphosphotyrosine antibodies. We show that IRS-1 is present in rat aorta, and is tyrosine phosphorylated after insulin stimulation. After insulin stimulation, rats fasted for 72 h showed an increase in insulin receptor (100 +/- 45%, P < 0.05) and IRS-1 phosphorylation (68 +/- 24%, P < 0.05) in aorta, compared to fed rats. There was no change in insulin receptor of IRS-1 protein levels in fasted rats. In summary, the present study demonstrated that proteins involved in the early steps of insulin signal transduction are present in the rat aorta and can be modulated by fasting. It will be of interest to study the regulation of these proteins in the aorta of animal models of hypertension and/or atherosclerosis.
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PMID:Effect of fasting on insulin signaling in the aorta of intact rats. 922 20

Insulin resistance is associated with both obesity and hypertension. However, the cellular mechanisms of insulin resistance in genetic models of obese-hypertension have not been identified. The objective of the present study was to investigate the effects of genetic obesity on a background of inherited hypertension on initial components of the insulin signal transduction pathway and glucose transport in skeletal muscle and liver. Oral glucose tolerance testing in SHROB demonstrated a sustained postchallenge elevation in plasma glucose at 180 and 240 min compared with lean spontaneously hypertensive rat (SHR) littermates, which is suggestive of glucose intolerance. Fasting plasma insulin levels were elevated 18-fold in SHROB. The rate of insulin-stimulated 3-O-methylglucose transport was reduced 68% in isolated epitrochlearis muscles from the SHROB compared with SHR. Insulin-stimulated tyrosine phosphorylation of the insulin receptor beta-subunit and insulin receptor substrate-1 (IRS-1) in intact skeletal muscle of SHROB was reduced by 36 and 23%, respectively, compared with SHR, due primarily to 32 and 60% decreases in insulin receptor and IRS-1 protein expression, respectively. The amounts of p85 alpha regulatory subunit of phosphatidylinositol-3-kinase and GLUT-4 protein were reduced by 28 and 25% in SHROB muscle compared with SHR. In the liver of SHROB, the effect of insulin on tyrosine phosphorylation of IRS-1 was not changed, but insulin receptor phosphorylation was decreased by 41%, compared with SHR, due to a 30% reduction in insulin receptor levels. Our observations suggest that the leptin receptor mutation fak imposed on a hypertensive background results in extreme hyperinsulinemia, glucose intolerance, and decreased expression of postreceptor insulin signaling proteins in skeletal muscle. Despite these changes, hypertension is not exacerbated in SHROB compared with SHR, suggesting these metabolic abnormalities may not contribute to hypertension in this model of Syndrome X.
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PMID:Reduced insulin receptor signaling in the obese spontaneously hypertensive Koletsky rat. 937 89

Insulin action starts with binding to a membrane receptor (insulin receptor-tyrosine kinase) and with activating an insulin receptor substrate 1 (IRS-1) and substrate 2 (IRS-2). Insulin receptors interact at least with three cascade reactions, phosphorylating G proteins and IRS-1, that activate PLC "ras" and PI-3-K. NIDDM can be defined as a disease caused by defective transduction of insulin signals and IR as a complex phenotype manifesting itself, emphasized by individual and environmental factors, in the cellular systems of signal transduction. IRS is a syndrome characterized by NIDDM, hypertension, visceral obesity, CHD: the X syndrome. Up to day the described mutations of the insulin-receptor gene are rare (e.g. the leprechaunism): genetic IR. Obesity is the principal cause of IR by receptorial and post-receptorial defects: metabolic IR. The obese skeletal muscle shows a reduction of insulin receptor and IRS-1 phosphorylation and of PI-3-K activation; the scarce expression of these proteins would determine the muscular IR. IR is a pattern of essential hypertension. Hypertension, dyslipidemia and abnormality of glucose metabolism are linked by IR. The so called high erythrocyte Na(+)-Li+ counter-transport is a new biochemical marker for IR and hypertension. These drugs can reduce IR: metformin, sulphonilureas, fibrats, dexfenfluramine, troglitazone, doxazosin, ACE-inhibitors.
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PMID:[Insulin resistance. Receptor and post-receptor abnormalities]. 984 54

Increased activity of the sympathetic nervous system may be a critical factor in the development of impaired insulin secretion and insulin resistance. We studied the chronic effects of sympathetic inhibition with moxonidine on glucose metabolism in the spontaneously hypertensive genetically obese rat (SHROB). This unique animal model closely resembles human syndrome X, expressing insulin resistance, genetic obesity, spontaneous hypertension, and hyperlipoproteinemia. Moxonidine, a selective imidazoline receptor agonist, was administered to lean spontaneous hypertensive rats (SHR) and SHROBs for 90 days in food at 8 mg/kg/day and significantly reduced mean blood pressure. Moxonidine treatment reduced fasting insulin levels by 71% in SHROB and lowered plasma free fatty acids by 25%. In SHR, moxonidine treatment decreased free fatty acids by 17% compared with controls. During an oral glucose tolerance test, blood glucose levels in moxonidine-treated SHROB were reduced relative to untreated controls from 60 min onwards. Insulin secretion was facilitated at 30 min (83% greater) and 60 min (67% greater) postchallenge compared with control SHROB. In skeletal muscle, moxonidine treatment increased the expression of the insulin receptor beta subunit by 19% in SHROB but was without effect in SHR. The level of insulin receptor substrate-1 (IRS-1) protein was decreased by 60% in control SHROB compared with lean SHR. Moxonidine treatment enhanced the expression and insulin-stimulated phosphorylation of IRS-1 protein in skeletal muscle in SHROB by 74 and 27%, respectively, and in SHR by 40 and 56%, respectively. Moxonidine increased the levels of expression of IRS-1 protein in liver in SHR by 275% and in SHROB by 260%. These findings indicate that chronic inhibition of sympathetic activity with moxonidine therapy can lower free fatty acids and significantly improve insulin secretion, glucose disposal, and expression of key insulin signaling intermediates in an animal model of obese hypertension.
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PMID:Mechanisms of antihyperglycemic effects of moxonidine in the obese spontaneously hypertensive Koletsky rat (SHROB). 986 64

Insulin resistance and hypertension commonly occur together. Pharmacological inhibition of the renin-angiotensin system has been found to reduce not only hypertension, but also insulin resistance. This raises the possibility that the renin-angiotensin system may interact with insulin signalling. We have investigated the relationship between insulin and angiotensin II (AII) intracellular signalling in vivo using an intact rat heart model, and in vitro using rat aorta smooth muscle cells (RASMC). Results generated in the in vivo studies indicate that, like insulin, AII stimulates tyrosine phosphorylation of the insulin receptor substrates IRS-1 and IRS-2. This leads to binding of IRS-1 and IRS-2 to PI3-kinase. However, in contrast to the effect of insulin. IRS-1- and IRS-2-associated PI3-kinase activity is inhibited by AII in a dose-dependent manner. Moreover, AII inhibits insulin-stimulated IRS-1/IRS-2-associated PI3-kinase activity. The in vivo effects of AII are mediated via the AT1 receptor. The results of the in vitro studies indicate that AII inhibits insulin-stimulated, IRS-1-associated PI3-kinase activity by interfering with the docking of IRS-1 with the p85 regulatory subunit of PI3-kinase. It appears that AII achieves this effect by stimulating serine phosphorylation of the insulin receptor beta-subunit IRS-1, and the p85 regulatory subunit of PI3-kinase. These actions result in the inhibition of normal interactions between the insulin signalling pathway components. Thus, we believe that AII negatively modulates insulin signalling by stimulating multiple serine phosphorylation events in the early components of the insulin signalling cascade. Overactivity of the renin-angiotensin system is likely to impair insulin signalling and contribute to insulin resistance observed in essential hypertension.
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PMID:Crosstalk between insulin and angiotensin II signalling systems. 1032 50

Hypertension and insulin resistance are often part of a complex set of abnormalities including obesity, hyperlipidemia, and glucose intolerance, described as syndrome X. Besides a common genetic basis, insulin resistance and hypertension might be linked by excessive activity of the sympathetic nervous system. We studied the effects of chronic inhibition of sympathetic activity with the antihypertensive agent moxonidine on glucose metabolism in the genetically obese SHR Koletsky rat (SHROB), a unique animal model which closely resembles human syndrome X, expressing genetic obesity, hypertension, and hyperlipidemia. Moxonidine, a selective I1-imidazoline receptor agonist, was administered to SHROB and SHR for 90 days in food at 8 mg/kg/day. Moxonidine not only lowered blood pressure, but also reduced fasting insulin levels by 49% in SHROB, and reduced plasma free fatty acids by 30%. In lean SHR, moxonidine treatment decreased circulating free fatty acids by 33% compared to controls. During oral glucose tolerance tests, blood glucose levels in moxonidine-treated SHROB were reduced from 60 min onwards, and there was a sharply higher insulin secretion post-challenge compared to control SHROB. Western blot analysis of insulin signaling proteins showed that IRS-1 was decreased 42% in control SHROB compared with SHR. Moxonidine treatment enhanced the expression of IRS-1 protein in skeletal muscle by 74% in SHROB and 40% in SHR. Moxonidine increased expression of IRS-1 protein in liver by 245% in SHROB and 268% in SHR. Long-term inhibition of sympathetic activity with moxonidine therapy lowered free fatty acids and significantly improved insulin secretion, glucose disposal, and expression of key insulin signaling intermediates. Thus, moxonidine should be considered for the treatment of multiple metabolic and cardiovascular abnormalities associated with syndrome X.
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PMID:Anti-hyperglycemic activity of moxonidine: metabolic and molecular effects in obese spontaneously hypertensive rats. 1032 53

Angiotensin-converting enzyme (ACE) inhibitors are antihypertensive agents, that inhibit the conversion of angiotensin I to angiotensin II, resulting in smooth-muscle relaxation and a reduction of vascular resistance. Recently, it has been suggested that ACE inhibitors improve insulin resistance in diabetic patients. To investigate the effect of an ACE inhibitor on insulin sensitivity, insulin signaling, and circulation, imidapril was administered orally or intraduodenally to Zucker fatty rats. Oral administration of imidapril improved insulin sensitivity based on the results of an oral glucose tolerance test (OGTT) and a decrease in urinary glucose secretion. Phosphatidylinositol 3-kinase (PI 3-kinase) activity associated with hepatic insulin receptor substrate-1 (IRS-1) in the insulin-stimulated condition was significantly enhanced 110% without a significant alteration in tyrosine phosphorylation of IRS-1 in the imidapril-treated group. In muscle, IRS-1 tyrosine phosphorylation and PI 3-kinase activity associated with IRS-1 in the insulin-stimulated condition were enhanced 70% and 20%, respectively, in the imidapril-treated group. In contrast, an alteration of the IRS-2 pathway was observed only in liver; a significant insulin-induced increase in the IRS-2-associated PI 3-kinase over the basal level was observed in the imidapril-treated group but not in the control. In addition, treatment with imidapril was shown to significantly reduce blood pressure and increase blood flow in the liver and muscle. These results suggest that the ACE inhibitor imidapril may improve insulin sensitivity not only by acting directly on the insulin signaling pathway but also by increasing blood flow in tissues via normalization of vascular resistance, a major cause of hypertension.
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PMID:Imidapril, an angiotensin-converting enzyme inhibitor, improves insulin sensitivity by enhancing signal transduction via insulin receptor substrate proteins and improving vascular resistance in the Zucker fatty rat. 1053 86

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