Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

ANG II (angiotensin II) facilitates catecholamine release from the adrenal medulla and neuronal NE (noradrenaline) release. Since animal experiments point to specific sympatho-inhibitory properties of the AT1 (ANG II type 1)-receptor blocker EPRO (eprosartan), the primary aim of this study was to clarify if EPRO inhibits sympathetic reactivity in humans as determined by the effect of EPRO on insulin-induced catecholamine release. Sixteen healthy male volunteers were randomized in a double-blind cross-over study to receive a single dose of EPRO (600 mg) compared with placebo, followed by insulin-induced hypoglycaemia [0.15 IU (international unit)/kg of body weight; intravenous bolus] on two study days 1 week apart. From baseline to the end of hypoglycaemia (170 min), the sympatho-adrenal reactivity was mapped by invasive continuous blood pressure monitoring and repeated measurements of FBF (forearm blood flow), arterial and venous concentrations of glucose, catecholamines [EPI (adrenaline) and NE (noradrenaline)], renin, ANG II and aldosterone. EPRO induced an 8-10-fold increase in plasma renin and ANG II concentrations compared with placebo. Plasma glucose decreased equally during placebo and EPRO from baseline 5.9 mmol/l to 1.9 mmol/l and 2.1 mmol/l respectively, inducing a 17-fold increase in arterial EPI concentration at peak. The AUC (area under the curve) during hypoglycaemia for arterial EPI concentrations was 314+/-48 nmol.min.l-1 in placebo compared with 254+/-26 nmol.min.l-1 following EPRO treatment (P=0.14). EPRO attenuated the corresponding AUC for the EPI-induced pulse pressure response (4670+/-219 mmHg.min in EPRO compared with 5004+/-266 mmHg.min in placebo; P=0.02). Moreover, EPRO caused a less pronounced increase in FBF compared with placebo (402+/-30 compared with 479+/-46 ml.100 g-1 of body weight; P=0.04). Musculocutaneous NE release was not affected by EPRO and the AUC for NE release was 51.69+/-15.5 pmol.min-1.100 g-1 of body weight in placebo compared with 39.35+/-18.2 pmol.min-1.100 g-1 of body weight after EPRO treatment (P=0.57). In conclusion, EPRO did not significantly inhibit sympathetic reactivity compared with placebo; however, it blunted the haemodynamic responses elicited by the sympatho-adrenal stimulation which only tended to be attenuated by this drug.
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PMID:Effect of eprosartan on catecholamines and peripheral haemodynamics in subjects with insulin-induced hypoglycaemia. 1538 7

Evidence has accumulated that some of the angiotensin II AT1 receptor antagonists have insulin-sensitizing property. We thus examined the effect of telmisartan on insulin action using 3T3-L1 adipocytes. With standard differentiation inducers, a higher dose of telmisartan effectively facilitated differentiation of 3T3-L1 preadipocytes. Treatment of both differentiating adipocytes and fully differentiated adipocytes with telmisartan caused a dose-dependent increase in mRNA levels for PPARgamma target genes such as aP2 and adiponectin. By contrast, telmisartan attenuated 11beta-hydroxysteroid dehydrogenase type 1 mRNA level in differentiated adipocytes. Of note, we demonstrated for the first time that telmisartan augmented GLUT4 protein expression and 2-deoxy glucose uptake both in basal and insulin-stimulated state of adipocytes, which may contribute, at least partly, to its insulin-sensitizing ability.
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PMID:An angiotensin II AT1 receptor antagonist, telmisartan augments glucose uptake and GLUT4 protein expression in 3T3-L1 adipocytes. 1549 86

Elevated glucose concentration is implicated to play major role in development of diabetic associated vascular complications. It was previously reported that angiotensin II (Ang II) induced contractile response is enhanced in thoracic aorta of diabetic rats. In the present study, the effect of high glucose (HG, 25 mM) exposure for 2h on Ang II cumulative concentration response curves recorded isometrically was studied in thoracic aortic rings isolated from male Sprague-Dawley rats pretreated with streptozotocin (STZ, 65 mg kg(-1) i.p.) or vehicle at 8 weeks prior to the study. Ang II induced contraction via AT1 receptor was significantly enhanced (by 60 +/- 2 %) in HG exposed thoracic aortic rings isolated from vehicle treated but not STZ treated rats. However, there was no change in the pD2 of Ang II while potassium chloride (KCl) induced contraction was unaltered. Ang II induced contractile response was blocked by valsartan (100 microM, selective AT1 receptor antagonist) but not PD 123,319 (100 microM, selective and potent AT2 receptor antagonist). Exposure of aortic rings from control rats to 25 mM mannitol or sucrose for 2 h did not have any effect on the Ang II induced contraction. Tempol (100 microM, a cell permeable superoxide dismutase mimetic) partially reduced the augmented Ang II response in HG exposed aortic rings, while it did not affect the Ang II responses in normal glucose (NG 5.5 mM) exposed aortic rings isolated from control rats. [3H] Ang II binding at AT1 receptors was unaltered in vascular smooth muscle membranes prepared from thoracic aorta exposed to HG for 2 h compared to NG exposed aortic rings. From our results, we conclude that high glucose concentration augments Ang II mediated contraction via AT1 receptors and reactive oxygen species partly contribute to this augmented contraction.
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PMID:High glucose concentration augments angiotensin II mediated contraction via AT1 receptors in rat thoracic aorta. 1550 93

For each known diabetic at least one new patient is diagnosed when the 75-g OGTT is used for screening. For early diagnosis in high risk groups, the oral glucose tolerance test is indispensable since ca. 30% of the asymptomatic diabetes cases are identified on the basis of a 2-hour postchallenge glucose value of > 11.1 mmol/l. In controlled studies on persons with IGT, every second diabetes case could be prevented through lifestyle modifications beginning in childhood. Three-year studies showed that the incidence of diabetes could be reduced by about one-third with the medications acarbose, metformin and orlistat. The observation that statins, ACE inhibitors and AT1 blockers also contributed to a reduction of new diabetes cases was made in studies on the prevention of coronary heart diseases.
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PMID:[Screening, prevention and early therapy of type 2 diabetics]. 1554 May 35

The inhibition of the renin-angiotensin system (RAS) with either angiotensin converting enzyme inhibitors (ACEIs) or AT1 angiotensin receptor blockers (ARBs) consistently and significantly reduces the incidence of type 2 diabetes in patients with hypertension or congestive heart failure. The mechanisms underlying this protective effect appear to be complex and may involve an improvement of both insulin sensitivity and insulin secretion. These two effects may result, at least in part, from the well known effects of these pharmacological agents on the vascular system on the one hand, on the ionic balance on the other hand. Indeed, the vasodilation induced by ACEIs or ARBs could improve the blood circulation in skeletal muscles, thus favouring peripheral insulin action, but also in the pancreas, thus promoting insulin secretion. Preserving cellular potassium and magnesium pools by blocking the aldosterone effects could also improve both cellular insulin action and insulin secretion. However, besides these classical effects, new mechanisms have been recently suggested. A direct effect of the inhibition of angiotensin and/or of the enhancement of bradykinin on various steps of the insulin cascade signalling has been described as well an increase in GLUT4 glucose transporters after RAS inhibition. Furthermore, it has been demonstrated that angiotensin II inhibits adipogenic differentiation of human adipocytes via A1 receptors and, therefore, it has been hypothesised that RAS blockade may prevent diabetes by promoting the recruitment and differentiation of adipocytes. Finally, some lipophilic ARBs appear to induce PPAR-gamma activity in the adipose tissue. Hence, the protection against type 2 diabetes observed after RAS inhibition may be partially linked to a thiazolidinedione-like effect. In conclusion, numerous physiological and biochemical mechanisms could explain the protective effect of RAS inhibition against the development of type 2 diabetes in individuals with arterial hypertension or congestive heart failure. What might be the main mechanism in the overall protection effect of ACEIs or ARBs remains an open question.
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PMID:Renin-angiotensin system inhibition prevents type 2 diabetes mellitus. Part 2. Overview of physiological and biochemical mechanisms. 1567 19

Hyperglycemia was reported to enhance angiotensin (Ang) II generation in rat cardiomyocytes, and Ang II inhibition reduces cardiovascular morbidity and mortality in diabetic patients. In diabetic patients, the enhanced activation of intracellular pathways related with myocyte hypertrophy and gene expression might enhance the progression of cardiac damage. Therefore, we investigated the effects of glucose on Ang II-mediated activation of Janus-activated kinase (JAK)-2, a tyrosine kinase related with myocyte hypertrophy and cytokine and fibrogenetic growth factor overexpression, in ventricular myocytes isolated from nonfailing human hearts (n = 5) and failing human hearts (n = 8). In nonfailing myocytes, JAK2 phosphorylation was enhanced by Ang II only in the presence of high glucose (25 mmol/l) via Ang II type I (AT1) receptors (+79% vs. normal glucose, P < 0.05). JAK2 activation was prevented by inhibitors of reactive oxygen species (ROS) generation (diphenyleneiodonium [DPI], tiron, and apocynin). In myocytes isolated from failing hearts, JAK2 phosphorylation was enhanced by high glucose alone (+107%, P < 0.05). High glucose-induced JAK2 activation was blunted by both ACE inhibition (100 nmol/l ramipril) and AT1 antagonism (1 mumol/l valsartan), thus revealing that the effects are mediated by autocrine Ang II production. Inhibition of ROS generation also prevented high glucose-induced JAK2 phosphorylation. In conclusion, in human nonfailing myocytes, high glucose allows Ang II to activate JAK2 signaling, whereas in failing myocytes, hyperglycemia alone is able to induce Ang II generation, which in turn activates JAK2 via enhanced oxidative stress.
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PMID:Hyperglycemia activates JAK2 signaling pathway in human failing myocytes via angiotensin II-mediated oxidative stress. 1567 97

Recent studies have shown that F2-isoprostane levels-a marker for lipid peroxidation-are increased in human renovascular hypertension but not in essential hypertension. Angiotensin II specifically stimulates F2-isoprostane production through activation of the AT1 receptor. The objective was to determine whether there is a relationship between the level of oxidative stress evaluated by measuring urinary F2-isoprostanes levels and polymorphisms of genes involved in the renine angiotensin aldosterone system (RAAS) regulation. The population studied included 100 subjects, 65 of whom were healthy normotensives; the other 35 were suffering from untreated, essential hypertension. The polymorphisms studied concern the genes encoding angiotensin I-converting enzyme (ACE/in16del/ins), angiotensin II receptor type I (AGTR1/A+39C[A+1166C] and AGTR1/A-153G), angiotensinogen (AGT/M235T), and aldosterone synthase (CYP11B2/T344C). Oxidative stress was evaluated by measuring urinary F2-isoprostanes levels. The characteristics of the population were as follows: men/women = 46/56; age = 50 +/- 10 years; BMI = 24 +/- 3 kg/m2; SBP = 131.7 +/- 17.2 mm Hg; DBP = 84.6 +/- 10.4 mm Hg. In univariate analysis, urinary F2-isoprostane levels were significantly lower in the presence of the G allele of AGTR1/A-153G (56 +/- 17 vs 76 +/- 39 pmol/mmol creatinine; P < 0.001, and P < 0.01 after Bonferroni correction for 10 tests). In multivariate analysis, taking into account BP, age, gender, BMI, plasma glucose, and total cholesterol, the G allele of AGTR1/A-153G is linked independently to urinary F2-isoprostanes level (P < 0.01). Our data suggest that F2-isoprostane level depends at least in part on the A-153G polymorphism of the angiotensin II AT1 receptor gene. The clinical and prognostic relevance of this polymorphism requires further investigation.
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PMID:F2-Isoprostane level is associated with the angiotensin II type 1 receptor -153A/G gene polymorphism. 1568 14

The present study was performed to evaluate the potential role and functional interaction of angiotensin II AT1 and AT2 receptors (AT1R and AT2R) in the regulation of blood pressure and glucose homeostasis in fructose-induced insulin-resistant, hypertensive rats. Male Sprague-Dawley rats on fructose-enriched or regular diets for 4 weeks were subjected to 2-step euglycemic euinsulinemic (EEI) and euglycemic hyperinsulinemic (EHI) clamp studies with [3-3H]glucose infusion. After a 40-minute basal period, selective AT1R and AT2R antagonists, losartan (LOS, 10 mg/kg IV bolus) and PD123319 (PD, 50 microg/kg/min), alone or in combination were separately given to control and fructose-fed groups in the 2 clamp periods. The results showed that during the EEI period, LOS significantly reduced the elevated blood pressure in fructose-fed rats, whereas PD further increased fructose-induced high blood pressure. Coadministration of LOS and PD did not alter the elevated blood pressure in fructose-fed rats. Administration of LOS and/or PD failed to change the blood pressure in control rats. During the EHI period, blockade of both AT1R and AT2R eliminated the insulin-induced blood pressure elevation in control and fructose-fed rats. Hepatic glucose production (HGP) did not alter among groups in the basal and EEI periods. Insulin infusion (EHI period) markedly suppressed HGP in control rats, but this suppressive effect was significantly attenuated in fructose-fed rats. LOS administration further reduced the insulin-induced suppression of HGP in fructose-fed rats. The whole-body glucose uptakes (rates of glucose disappearance, Rd) during the basal and EEI periods were similar among groups. During the EHI period, Rd was markedly increased in all groups and the magnitude of increase was significantly greater in control rats than in fructose-fed rats except those with LOS treatment. LOS treatment also redirected Rd in favor of glycolysis in fructose rats, but not in control rats, during the EEI and EHI periods. The effects of LOS on glycolysis during the 2 clamp periods and on HGP during the EHI period were reversed when PD was concomitantly administered, but PD alone did not alter glucose metabolism throughout the experiment in fructose-fed rats. Administration of LOS and/or PD did not change the glucose metabolism in control rats. Our data suggest that AT2R can counterbalance the AT1R-mediated effects on blood pressure and glucose metabolism in fructose-induced insulin-resistant, hypertensive rats. Furthermore, AT1R- and AT2R-mediated effects on blood pressure are disassociated with their actions on glucose metabolism in this hypertensive model.
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PMID:Functional interaction of AT1 and AT2 receptors in fructose-induced insulin resistance and hypertension in rats. 1569 Mar 8

The renin-angiotensin system plays a critical role in the pathogenesis of obesity, obesity-associated hypertension, and insulin resistance. However, the biological actions of angiotensin II (AII) on insulin sensitivity remain controversial. Because angiotensinogen and AII receptors are expressed on adipose tissue, we investigated the effect of AII on the insulin sensitivity of isolated rat adipocytes. The results of a receptor binding assay showed the maximal AII binding capacity of adipocytes to be 8.3 +/- 0.9 fmol/7 x 10(6) cells and the dissociation constant to be 2.72 +/- 0.11 nM. Substantial expression of both type 1 and 2 AII (AT1 and AT2) receptors was detected by RT-PCR. AII had no effect on basal glucose uptake, but significantly potentiated insulin-stimulated glucose uptake; this effect was abolished by the AT1 antagonist, losartan. In addition, AII did not alter the insulin binding capacity of adipocytes, but increased insulin-stimulated tyrosine phosphorylation of the insulin receptor beta-subunit, Akt phosphorylation, and translocation of glucose transporter 4 to the plasma membrane. AII potentiated insulin-stimulated glucose uptake through the AT1 receptor and by alteration of the intracellular signaling of insulin. Intraperitoneal injection of Sprague Dawley rats with AII increased insulin sensitivity in vivo. In conclusion, we have shown that AII enhances insulin sensitivity both in vitro and in vivo, suggesting that dysregulation of the insulin-sensitizing effect of AII may be involved in the development of insulin resistance.
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PMID:Angiotensin II enhances insulin sensitivity in vitro and in vivo. 1570 82

There is experimental evidence of an interaction between the angiotensin system and lipid metabolism. The aim of this study was to evaluate whether a block of the angiotensin system achieved both by ACE inhibition and angiotensin II-AT1 receptor blockade could affect the plasma lipid profile and, if so, what relationship exists between these possible changes and glucose metabolism and blood pressure. In 50 patients with type 2 diabetes and hypertension, treated with diabetes drugs and enalapril, we evaluated the glycemic and lipid profile together with the HOMA insulin-resistance index, blood pressure and microalbuminuria at baseline and 3 months after the addition of valsartan. At the second evaluation, blood pressure was reduced as expected, whereas the glycemic profile, the HOMA index, and the body mass index were unchanged. Total cholesterol, LDL-c, and apoprotein B were reduced during combination therapy (P = 0.003, P = 0.001, and P = 0.004, respectively), plasma HDL-c was slightly though significantly increased (P = 0.024), whereas apoprotein A and triglyceride levels did not change. After adjustment for the insulin resistance index and for blood pressure, the reduction of LDL-c and apoprotein B and the increase in HDL-c remained significant. The variation in lipid profile was not related to the changes in blood pressure. Moreover, the addition of valsartan to enalapril was associated with a reduction in microalbuminuria, which remained significant after adjustment for LDL-c or blood pressure changes. Thus, the greater degree of renin-angiotensin system blockade or specific pharmacodynamic effects of valsartan could account for the changes in plasma lipid profile observed in this study.
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PMID:Changes in plasma lipids during renin-angiotensin system blockade by combination therapy (enalapril plus valsartan) in patients with diabetes and hypertension. 1577 26


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