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)

Having previously demonstrated that glucose transporter-4 (GLUT4) expression was reduced in aortas and carotid arteries of deoxycorticosterone acetate (DOCA) salt-hypertensive rats, we hypothesized that troglitazone (TG), through activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma), would stabilize GLUT4 expression and possibly preserve the differentiated phenotype in vascular smooth muscle cells. In DOCA salt-hypertensive rats treated with TG (100 mg/day), there was a significant (P < 0.001) decrease in systolic blood pressure (BP; 149.9 +/- 4.4 mmHg) compared with the untreated DOCA salt-hypertensive rats (202.2 +/- 10.34 mmHg). Separate trials with rosiglitazone (RS; 3 mg/day) demonstrated a significant (P < 0.001) decrease in BP (DOCA salt, 164.2 +/- 9.8 vs. DOCA-RS, 124.9 +/- 3.7 mmHg) comparable to that with TG. Expression of GLUT4, h-caldesmon, and smooth muscle myosin heavy chain SM2 was significantly decreased in aortas of DOCA salt-hypertensive rats and was reversed by TG to levels similar to those in aortas of sham-treated rats. TG (50 microM) induced GLUT4 and h-caldesmon expression in 24-h culture of explanted carotid arteries of DOCA salt-hypertensive rats, and the endogenous PPAR-gamma ligand 15-deoxy-Delta(12-14)-prostaglandin J(2) (PGJ(2); 20 microM) and TG (50 microM) similarly increased GLUT4, h-caldesmon, and SM2 protein expression in explanted aortas. The expression of activated, phosphorylated Akt was increased by PGJ(2) and TG with no significant effect on total Akt levels. Inhibition of phosphorylated Akt expression using the phosphatidylinositol 3-kinase inhibitor LY-294002 (16 microM) abrogated the increased expression of h-caldesmon and SM2. These data demonstrate that PPAR-gamma agonists maintain or induce expression of markers of the contractile phenotype independently of their effects on hypertension, and that this effect may be mediated through activation of phosphatidylinositol 3-kinase/Akt.
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PMID:Effects of PPAR-gamma ligands on vascular smooth muscle marker expression in hypertensive and normal arteries. 1534 87

The phosphatidylinositol 3-kinase (PI3-K) pathway, which activates serine/threonine protein kinase Akt, enhances endothelial nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) production. We investigated the involvement of the PI3-K/Akt pathway in the relaxation responses to acetylcholine (ACh) and clonidine in a new type 2 diabetic model (streptozotocin plus nicotinamide-induced diabetic mice). Plasma glucose and insulin levels were significantly elevated in our model, and intravenous glucose tolerance tests revealed clear abnormalities in glucose tolerance and insulin responsiveness. Although in our model the ACh-induced relaxation and NOx- (NO2-+NO3-)/cGMP production were unchanged, the clonidine-induced and insulin-induced relaxations and NOx-/cGMP production were all greatly attenuated. In control mice, the clonidine-induced and insulin-induced relaxations were each abolished by LY294002 and by Wortmannin (inhibitors of PI3-K), and also by Akt-inhibitor treatment. The ACh-induced relaxation was unaffected by such treatments in either group of mice. The expression level of total Akt protein was significantly decreased in the diabetic mice aorta, but those for the p85 and p110gamma subunits of PI3-K were not. The clonidine-induced Ser-473 phosphorylation of Akt through PI3-K was significantly decreased in our model; however, that induced by ACh was not. These results suggest that relaxation responses and NO production mediated via the PI3-K/Akt pathway are decreased in this type 2 diabetic model. This may be a major cause of endothelial dysfunction (and the resulting hypertension) in type 2 diabetes.
Hypertension 2004 Dec
PMID:Impairment of PI3-K/Akt pathway underlies attenuated endothelial function in aorta of type 2 diabetic mouse model. 1550 17

Whereas glucocorticoids are important blood pressure regulators via an action on peripheral circulation, their roles in central cardiovascular regulation are less known. This study evaluated the short-term cardiovascular effect of glucocorticoid in the nucleus tractus solitarii (NTS) and delineated the underlying molecular mechanisms. In Sprague-Dawley rats maintained under propofol anesthesia, microinjection bilaterally into the NTS of a synthetic glucocorticoid, dexamethasone (Dex; 12.5, 25, 50, or 100 pmol), elicited hypertensive and tachycardiac responses. The initial cardiovascular responses, which lasted 15 to 30 min, were blunted by coadministration of a selective GABA(A) or GABA(B) receptor antagonist, bicuculline (15 pmol) or 2-hydroxy saclofen (150 pmol). The delayed responses, which endured at least 90 min and entailed maintained hypertension and tachycardia, were reversed by selective glucocorticoid type II receptor (GR) antagonist mifepristone (100 or 200 pmol), phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one] (20 nmol), or nitric-oxide synthase inhibitor N(G)-monomethyl-l-arginine acetate (5 nmol), but not by the RNA synthesis inhibitor actinomycin D (20 nmol). Moreover, Dex induced an association of GR with the regulatory subunit of PI3K, p85alpha, in a ligand-dependent manner and promoted serine/threonine kinase Akt phosphorylation that was blocked by coadministration of mifepristone or LY294002. These cardiovascular and molecular responses occurred when translocation of activated GR into the nucleus was minimal. Our results indicate that Dex acts on the NTS to elicit hypertension and tachycardia via both a GR-independent interaction with GABA(A) and GABA(B) receptors and a GR-dependent but nontranscriptional mechanism that involves activation of PI3K/Akt pathway.
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PMID:Receptor-independent activation of GABAergic neurotransmission and receptor-dependent nontranscriptional activation of phosphatidylinositol 3-kinase/protein kinase Akt pathway in short-term cardiovascular actions of dexamethasone at the nucleus tractus solitarii of the rat. 1552 51

Inorganic and organic compounds of vanadium have been shown to exhibit a large range of insulinomimetic effects in the cardiovascular system, including stimulation of glucose transporter 4 (GLUT-4) translocation and glucose transport in adult cardiomyocytes. Furthermore, administration of vanadium compounds improves cardiac performance and smooth muscle contractility, and modulates blood pressure in various models of hypertension and insulin resistance. Vanadium compounds are potent inhibitors of protein tyrosine phosphatases. As a result, they promote an increase in protein tyrosine phosphorylation of several key components of the insulin signaling pathway, leading to the upregulation of phosphatidylinositol 3-kinase and protein kinase B, two enzymes involved in mediating GLUT-4 trans location and glucose transport. In addition, vanadium has also been shown to activate p38 mitogen-activated protein kinase and increase Ca2+ levels in several cell types. The ability of vanadium compounds to activate these signaling events may be responsible for their ability to modulate cardiovascular functions.
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PMID:Vanadium and the cardiovascular functions. 1557 43

Essential hypertension is frequently associated with insulin resistance of skeletal muscle glucose transport, with a potential role of angiotensin II in the pathogenesis of both conditions. The male heterozygous TG(mREN2)27 rat harbors the mouse transgene for renin, exhibits local elevations in angiotensin II, and is an excellent model of both hypertension and insulin resistance. The present study was designed to investigate the potential cellular mechanisms for insulin resistance in this hypertensive animal model, including an assessment of elements of the insulin-signaling pathway. Compared with nontransgenic, normotensive Sprague-Dawley control rats, male heterozygous TG(mREN2)27 rats displayed elevated (P < 0.05) fasting plasma insulin (74%), an exaggerated insulin response (108%) during an oral glucose tolerance test, and reduced whole body insulin sensitivity. TG(mREN2)27 rats also exhibited decreased insulin-mediated glucose transport and glycogen synthase activation in both the type IIb epitrochlearis (30 and 46%) and type I soleus (22 and 64%) muscles. Importantly, there were significant reductions (approximately 30-50%) in insulin stimulation of tyrosine phosphorylation of the insulin receptor beta-subunit and insulin receptor substrate-1 (IRS-1), IRS-1 associated with the p85 subunit of phosphatidylinositol 3-kinase, Akt Ser473 phosphorylation, and Ser9 phosphorylation of glycogen synthase kinase-3beta in epitrochlearis and soleus muscles of TG(mREN2)27 rats. Soleus muscle triglyceride concentration was 25% greater in the transgenic group compared with nontransgenic animals. Collectively, these data provide the first evidence that the insulin resistance of the hypertensive male heterozygous TG(mREN2)27 rat can be attributed to specific defects in the insulin-signaling pathway in skeletal muscle.
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PMID:Defective insulin signaling in skeletal muscle of the hypertensive TG(mREN2)27 rat. 1565 91

Male heterozygous TG(mREN2)27 rats (TGR) overexpress a murine renin transgene, display marked hypertension, and have insulin resistance of skeletal muscle glucose transport and insulin signaling. We have shown previously that voluntary exercise training by TGR improves insulin-mediated skeletal muscle glucose transport (Kinnick TR, Youngblood EB, O'Keefe MP, Saengsirisuwan V, Teachey MK, and Henriksen EJ. J Appl Physiol 93: 805-812, 2002). The present study evaluated whether this training-induced enhancement of muscle glucose transport is associated with upregulation of critical insulin signaling elements, including insulin receptor substrate-1 (IRS-1), phosphatidylinositol 3-kinase, Akt, and glycogen synthase kinase-3. TGR remained sedentary or ran spontaneously in activity wheels for 6 wk, averaging 7.1 +/- 0.8 km/day by the end of week 3 and 4.3 +/- 0.5 km/day over the final week of training. Exercise training reduced total abdominal fat by 20% (P < 0.05) in TGR runners (2.64 +/- 0.01% of body weight) compared with sedentary TGR controls (3.28 +/- 0.01%). Insulin-stimulated (2 mU/ml) glucose transport activity in soleus muscle was 36% greater in TGR runners compared with sedentary TGR controls. However, the protein expression and functionality of tyrosine phosphorylation of insulin receptor and IRS-1, IRS-1 associated with the p85 regulatory subunit of phosphatidylinositol 3-kinase, and Ser473 phosphorylation of Akt were not altered by exercise training. Only insulin-stimulated glycogen synthase kinase-3beta Ser9 phosphorylation was increased (22%) by exercise training. These results indicate that voluntary exercise training in TGR can enhance insulin-mediated glucose transport in skeletal muscle, as well as reduce total abdominal fat mass. However, this adaptive response in muscle occurs independently of modifications in the proximal elements of the insulin signaling cascade.
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PMID:Voluntary exercise training enhances glucose transport but not insulin signaling capacity in muscle of hypertensive TG(mREN2)27 rats. 1571 10

Insulin resistance is a major player in the pathogenesis of the metabolic syndrome and type 2 diabetes, and yet, the mechanisms responsible for it remain poorly understood. Magnetic resonance spectroscopy studies in humans suggest that a defect in insulin-stimulated glucose transport in skeletal muscle is the primary metabolic abnormality in insulin-resistant type 2 diabetics. Fatty acids appear to cause this defect in glucose transport by inhibiting insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-1 associated phosphatidylinositol 3-kinase activity. A number of different metabolic abnormalities may increase intramyocellular/intrahepatic fatty acid metabolites; these include increased fat delivery to muscle/liver as a consequence of either excess energy intake or defects in adipocyte fat metabolism and acquired or inherited defects in mitochondrial fatty acid oxidation. Understanding the molecular/biochemical defects responsible for insulin resistance is beginning to unveil novel therapeutic targets for treatment of the metabolic syndrome and type 2 diabetes.
Hypertension 2005 May
PMID:Mechanisms of insulin resistance in humans and possible links with inflammation. 1582 95

Insulin resistance clusters with hyperlipidemia, impaired glucose tolerance, and hypertension as metabolic syndrome X. We tested a low molecular weight insulin receptor activator, demethylasterriquinone B-1 (DMAQ-B1), and a novel indole peroxisome proliferator-activated receptor gamma agonist, 2-(2-(4-phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid (PPEIA), in spontaneously hypertensive obese rats (SHROB), a genetic model of syndrome X. Agents were given orally for 19 days. SHROB showed fasting normoglycemia but impaired glucose tolerance after an oral load, as shown by increased glucose area under the curve (AUC) [20,700 mg x min/ml versus 8100 in lean spontaneously hypertensive rats (SHR)]. Insulin resistance was indicated by 20-fold excess fasting insulin and increased insulin AUC (6300 ng x min/ml versus 990 in SHR). DMAQ-B1 did not affect glucose tolerance (glucose AUC = 21,300) but reduced fasting insulin 2-fold and insulin AUC (insulin AUC = 4300). PPEIA normalized glucose tolerance (glucose AUC = 9100) and reduced insulin AUC (to 3180) without affecting fasting insulin. PPEIA also increased food intake, fat mass, and body weight gain (81 +/- 12 versus 45 +/- 8 g in untreated controls), whereas DMAQ-B1 had no effect on body weight but reduced subscapular fat mass. PPEIA but not DMAQ-B1 reduced blood pressure. In skeletal muscle, insulin-stimulated phosphorylation of the insulin receptor and insulin receptor substrate protein 1-associated phosphatidylinositol 3-kinase activity were decreased by 40 to 55% in SHROB relative to lean SHR. PPEIA, but not DMAQ-B1, enhanced both insulin actions. SHROB also showed severe hypertriglyceridemia (355 +/- 42 mg/dl versus 65 +/- 3 in SHR) attenuated by both agents (DMAQ-B1, 228 +/- 18; PPEIA, 79 +/- 3). Both these novel antidiabetic agents attenuate insulin resistance and hypertriglyceridemia associated with metabolic syndrome but via distinct mechanisms.
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PMID:Therapeutic actions of an insulin receptor activator and a novel peroxisome proliferator-activated receptor gamma agonist in the spontaneously hypertensive obese rat model of metabolic syndrome X. 1583 94

Insulin resistance is frequently associated with hypertension, but the mechanism underlying this association remains speculative. Although insulin is known to modify renal tubular functions, little is known about roles of insulin receptor substrates (IRS) in the renal insulin actions. For clarifying these issues, the effects of insulin on the rate of bicarbonate absorption (JHCO3-) were compared in isolated renal proximal tubules from wild-type, IRS1-deficient (IRS1-/-), and IRS2-deficient (IRS2-/-) mice. In wild-type mice, physiologic concentrations of insulin significantly increased JHCO3-. This stimulation was completely inhibited by wortmannin and LY-294002, indicating that the phosphatidylinositol 3-kinase pathway mediates the insulin action. The stimulatory effect of insulin on JHCO3- was completely preserved in IRS1-/- mice but was significantly attenuated in IRS2-/- mice. Similarly, insulin-induced Akt phosphorylation was preserved in IRS1-/- mice but was markedly attenuated in IRS2-/- mice. Furthermore, insulin-induced tyrosine phosphorylation of IRS2 was more prominent than that of IRS1. These results indicate that IRS2 plays a major role in the stimulation of renal proximal absorption by insulin. Because defects at the level of IRS1 may underlie at least some forms of insulin resistance, sodium retention, facilitated by hyperinsulinemia through the IRS1-independent pathway, could be an important factor in pathogenesis of hypertension in insulin resistance.
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PMID:Roles of insulin receptor substrates in insulin-induced stimulation of renal proximal bicarbonate absorption. 1597 95

1. The growth enzyme phosphatidylinositol 3-kinase (PI3K) was recently implicated in the mediation of arterial spontaneous tone, an event observed in arteries from hypertensive, but not normotensive, subjects that contributes to changes in total peripheral resistance in the hypertensive state. We have shown this occurrence in experimentally induced models of hypertension. However, because the majority of hypertension is genetically based, it is important to demonstrate a similar change in genetically hypertensive animals. 2. Aorta from spontaneously hypertensive rats (SHR; systolic blood pressure = 183 +/- 4 mmHg) and Wistar Kyoto (WKY) rats (115 +/- 2 mmHg) were isolated for the measurement of isometric contractile force. Aorta from SHR displayed small increases (approximately 5% maximum phenylephrine (PE)-induced contraction) in spontaneous tone, whereas aorta from WKY rats displayed none. The non-selective PI3K inhibitor LY294002 (20 micromol/L) and the selective inhibitor of the p110delta catalytic subunit of PI3K IC87114 (20 micromol/L) caused a fall of basal tone in SHR aorta (20 +/- 7 and 24 +/- 6% of the initial PE contraction, respectively), but did not alter tone in arteries from WKY rats. LY294002, but not IC87114, normalized the increased potency of noradrenaline (NA) observed in aorta from SHR (-log EC50 values for NA in the presence of vehicle in WKY rats and SHR 7.5 +/- 0.1 and 7.8 +/- 0.1, respectively (P < 0.05); -log EC(50) values for NA in the presence of LY294002 in WKY rats and SHR 7.0 +/- 0.1 and 7.0 +/- 0.1, respectively). 3. Biochemical expression of the p110 catalytic and p85 regulator subunits of PI3K in western analyses revealed no difference in expression of the regulatory p85alpha or p110alpha protein subunits between WKY rats and SHR; p110gamma was not detected. In contrast, p110delta expression was increased greater than 30% in aorta from SHR compared with WKY rats (827.6 +/- 88.5 vs 576.8 +/- 53.4 arbitrary densitometry units, respectively). Immunohistochemical analyses revealed expression of the p110delta isoform in the smooth muscle of arteries. 4. These data underscore the relevance of an enzyme historically classified as one committed to growth/anti-apoptosis in modifying contractility and supports involvement of PI3K in genetically based hypertension.
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PMID:Upregulated function of phosphatidylinositol-3-kinase in genetically hypertensive rats: a moderator of arterial hypercontractility. 1617 47

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