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Acute Nitric Oxide Synthase Inhibition Accelerates Transendothelial Insulin Efflux In Vivo.
Williams IM, McClatchey PM, Bracy DP, Valenzuela FA, Wasserman DH
(2018) Diabetes 67: 1962-1975
MeSH Terms: Animals, Biological Transport, Blood Pressure, Blotting, Western, Glucose, Insulin, Male, Mice, Inbred C57BL, NG-Nitroarginine Methyl Ester, Nitric Oxide, Nitric Oxide Synthase, Transendothelial and Transepithelial Migration
Show Abstract · Added March 26, 2019
Before insulin can stimulate glucose uptake in muscle, it must be delivered to skeletal muscle (SkM) through the microvasculature. Insulin delivery is determined by SkM perfusion and the rate of movement of insulin across the capillary endothelium. The endothelium therefore plays a central role in regulating insulin access to SkM. Nitric oxide (NO) is a key regulator of endothelial function and stimulates arterial vasodilation, which increases SkM perfusion and the capillary surface area available for insulin exchange. The effects of NO on transendothelial insulin efflux (TIE), however, are unknown. We hypothesized that acute reduction of endothelial NO would reduce TIE. However, intravital imaging of TIE in mice revealed that reduction of NO by l--nitro-l-arginine methyl ester (l-NAME) enhanced the rate of TIE by ∼30% and increased total extravascular insulin delivery. This accelerated TIE was associated with more rapid insulin-stimulated glucose lowering. Sodium nitroprusside, an NO donor, had no effect on TIE in mice. The effects of l-NAME on TIE were not due to changes in blood pressure alone, as a direct-acting vasoconstrictor (phenylephrine) did not affect TIE. These results demonstrate that acute NO synthase inhibition increases the permeability of capillaries to insulin, leading to an increase in delivery of insulin to SkM.
© 2018 by the American Diabetes Association.
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MeSH Terms
CD70 Exacerbates Blood Pressure Elevation and Renal Damage in Response to Repeated Hypertensive Stimuli.
Itani HA, Xiao L, Saleh MA, Wu J, Pilkinton MA, Dale BL, Barbaro NR, Foss JD, Kirabo A, Montaniel KR, Norlander AE, Chen W, Sato R, Navar LG, Mallal SA, Madhur MS, Bernstein KE, Harrison DG
(2016) Circ Res 118: 1233-43
MeSH Terms: Animals, Blood Pressure, CD27 Ligand, Hypertension, Inflammation Mediators, Kidney Diseases, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, NG-Nitroarginine Methyl Ester, Sodium Chloride, Dietary, T-Lymphocytes
Show Abstract · Added April 25, 2016
RATIONALE - Accumulating evidence supports a role of adaptive immunity and particularly T cells in the pathogenesis of hypertension. Formation of memory T cells, which requires the costimulatory molecule CD70 on antigen-presenting cells, is a cardinal feature of adaptive immunity.
OBJECTIVE - To test the hypothesis that CD70 and immunologic memory contribute to the blood pressure elevation and renal dysfunction mediated by repeated hypertensive challenges.
METHODS AND RESULTS - We imposed repeated hypertensive challenges using either N(ω)-nitro-L-arginine methyl ester hydrochloride (L-NAME)/high salt or repeated angiotensin II stimulation in mice. During these challenges effector memory T cells (T(EM)) accumulated in the kidney and bone marrow. In the L-NAME/high-salt model, memory T cells of the kidney were predominant sources of interferon-γ and interleukin-17A, known to contribute to hypertension. L-NAME/high salt increased macrophage and dendritic cell surface expression of CD70 by 3- to 5-fold. Mice lacking CD70 did not accumulate T(EM) cells and did not develop hypertension to either high salt or the second angiotensin II challenge and were protected against renal damage. Bone marrow-residing T(EM) cells proliferated and redistributed to the kidney in response to repeated salt feeding. Adoptively transferred T(EM) cells from hypertensive mice homed to the bone marrow and spleen and expanded on salt feeding of the recipient mice.
CONCLUSIONS - Our findings illustrate a previously undefined role of CD70 and long-lived T(EM) cells in the development of blood pressure elevation and end-organ damage that occur on delayed exposure to mild hypertensive stimuli. Interventions to prevent repeated hypertensive surges could attenuate formation of hypertension-specific T(EM) cells.
© 2016 American Heart Association, Inc.
1 Communities
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13 MeSH Terms
Aminoglycoside-mediated relaxation of the ductus arteriosus in sepsis-associated PDA.
Vucovich MM, Cotton RB, Shelton EL, Goettel JA, Ehinger NJ, Poole SD, Brown N, Wynn JL, Paria BC, Slaughter JC, Clark RH, Rojas MA, Reese J
(2014) Am J Physiol Heart Circ Physiol 307: H732-40
MeSH Terms: Animals, Chemokine CXCL12, Ductus Arteriosus, Ductus Arteriosus, Patent, Gentamicins, Humans, In Vitro Techniques, Indomethacin, Infant, Newborn, Interferon-gamma, Interleukins, Lipopolysaccharides, Mice, Mice, Inbred C57BL, NG-Nitroarginine Methyl Ester, Sepsis, Tumor Necrosis Factor-alpha, Vasodilation
Show Abstract · Added April 9, 2015
Sepsis is strongly associated with patency of the ductus arteriosus (PDA) in critically ill newborns. Inflammation and the aminoglycoside antibiotics used to treat neonatal sepsis cause smooth muscle relaxation, but their contribution to PDA is unknown. We examined whether: 1) lipopolysaccharide (LPS) or inflammatory cytokines cause relaxation of the ex vivo mouse DA; 2) the aminoglycosides gentamicin, tobramycin, or amikacin causes DA relaxation; and 3) newborn infants treated with aminoglycosides have an increased risk of symptomatic PDA (sPDA). Changes in fetal mouse DA tone were measured by pressure myography in response to LPS, TNF-α, IFN-γ, macrophage-inflammatory protein 2, IL-15, IL-13, CXC chemokine ligand 12, or three aminoglycosides. A clinical database of inborn patients of all gestations was analyzed for association between sPDA and aminoglycoside treatment. Contrary to expectation, neither LPS nor any of the inflammatory mediators caused DA relaxation. However, each of the aminoglycosides caused concentration-dependent vasodilation in term and preterm mouse DAs. Pretreatment with indomethacin and N-(G)-nitro-L-arginine methyl ester did not prevent gentamicin-induced DA relaxation. Gentamicin-exposed DAs developed less oxygen-induced constriction than unexposed DAs. Among 488,349 infants who met the study criteria, 40,472 (8.3%) had sPDA. Confounder-adjusted odds of sPDA were higher in gentamicin-exposed infants, <25 wk and >32 wk. Together, these findings suggest that factors other than inflammation contribute to PDA. Aminoglycoside-induced vasorelaxation and inhibition of oxygen-induced DA constriction support the paradox that antibiotic treatment of sepsis may contribute to DA relaxation. This association was also found in newborn infants, suggesting that antibiotic selection may be an important consideration in efforts to reduce sepsis-associated PDA.
Copyright © 2014 the American Physiological Society.
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18 MeSH Terms
Nitric oxide reduces Cl⁻ absorption in the mouse cortical collecting duct through an ENaC-dependent mechanism.
Pech V, Thumova M, Dikalov SI, Hummler E, Rossier BC, Harrison DG, Wall SM
(2013) Am J Physiol Renal Physiol 304: F1390-7
MeSH Terms: Absorption, Aldosterone, Amiloride, Angiotensin II, Animals, Anion Transport Proteins, Chloride-Bicarbonate Antiporters, Chlorides, Epithelial Sodium Channels, Female, In Vitro Techniques, Kidney Tubules, Collecting, Male, Mice, Mice, Knockout, NG-Nitroarginine Methyl Ester, Nitric Oxide, Nitric Oxide Donors, Nitric Oxide Synthase, Sodium, Sulfate Transporters
Show Abstract · Added March 31, 2015
Since nitric oxide (NO) participates in the renal regulation of blood pressure, in part, by modulating transport of Na⁺ and Cl⁻ in the kidney, we asked whether NO regulates net Cl⁻ flux (JCl) in the cortical collecting duct (CCD) and determined the transporter(s) that mediate NO-sensitive Cl⁻ absorption. Cl⁻ absorption was measured in CCDs perfused in vitro that were taken from aldosterone-treated mice. Administration of an NO donor (10 μM MAHMA NONOate) reduced JCl and transepithelial voltage (VT) both in the presence or absence of angiotensin II. However, reducing endogenous NO production by inhibiting NO synthase (100 μM N(G)-nitro-L-arginine methyl ester) increased JCl only in the presence of angiotensin II, suggesting that angiotensin II stimulates NO synthase activity. To determine the transport process that mediates NO-sensitive changes in JCl, we examined the effect of NO on JCl following either genetic ablation or chemical inhibition of transporters in the CCD. Since the application of hydrochlorothiazide (100 μM) or bafilomycin (5 nM) to the perfusate or ablation of the gene encoding pendrin did not alter NO-sensitive JCl, NO modulates JCl independent of the Na⁺-dependent Cl⁻/HCO₃⁻ exchanger (NDCBE, Slc4a8), the A cell apical plasma membrane H⁺-ATPase and pendrin. In contrast, both total and NO-sensitive JCl and VT were abolished with application of an epithelial Na(+) channel (ENaC) inhibitor (3 μM benzamil) to the perfusate. We conclude that NO reduces Cl⁻ absorption in the CCD through a mechanism that is ENaC-dependent.
1 Communities
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21 MeSH Terms
Upregulation of Nox1 in vascular smooth muscle leads to impaired endothelium-dependent relaxation via eNOS uncoupling.
Dikalova AE, Góngora MC, Harrison DG, Lambeth JD, Dikalov S, Griendling KK
(2010) Am J Physiol Heart Circ Physiol 299: H673-9
MeSH Terms: Analysis of Variance, Angiotensin II, Animals, Blood Pressure, Blotting, Western, Endothelium, Vascular, Hydrogen Peroxide, Hypertension, Mice, Mice, Transgenic, Muscle, Smooth, Vascular, NADH, NADPH Oxidoreductases, NADPH Oxidase 1, NG-Nitroarginine Methyl Ester, Nitric Oxide, Nitric Oxide Synthase Type III, Polymerase Chain Reaction, Up-Regulation, Vasodilation
Show Abstract · Added December 10, 2013
Recent work has made it clear that oxidant systems interact. To investigate potential cross talk between NADPH oxidase (Nox) 1 upregulation in vascular smooth muscle and endothelial function, transgenic mice overexpressing Nox1 in smooth muscle cells (Tg(SMCnox1)) were subjected to angiotensin II (ANG II)-induced hypertension. As expected, NADPH-dependent superoxide generation was increased in aortas from Nox1-overexpressing mice. Infusion of ANG II (0.7 mg x kg(-1) x day(-1)) for 2 wk potentiated NADPH-dependent superoxide generation and hydrogen peroxide production compared with similarly treated negative littermate controls. Endothelium-dependent relaxation was impaired in transgenic mice, and bioavailable nitric oxide was markedly decreased. To test the hypothesis that eNOS uncoupling might contribute to endothelial dysfunction, the diet was supplemented with tetrahydrobiopterin (BH(4)). BH(4) decreased aortic superoxide production, partially restored bioavailable nitric oxide in aortas of ANG II-treated Tg(SMCnox1) mice, and significantly improved endothelium-dependent relaxation in these mice. Western blot analysis revealed less dimeric eNOS in Tg(SMCnox1) mice compared with the wild-type mice; however, total eNOS was equivalent. Pretreatment of mouse aortas with the eNOS inhibitor N(G)-nitro-L-arginine methyl ester decreased ANG II-induced superoxide production in Tg(SMCnox1) mice compared with wild-type mice, indicating that uncoupled eNOS is also a significant source of increased superoxide in transgenic mice. Thus overexpression of Nox1 in vascular smooth muscle leading to enhanced production of reactive oxygen species in response to ANG II causes eNOS uncoupling and a decrease in nitric oxide bioavailability, resulting in impaired vasorelaxation.
1 Communities
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19 MeSH Terms
GTP cyclohydrolase I phosphorylation and interaction with GTP cyclohydrolase feedback regulatory protein provide novel regulation of endothelial tetrahydrobiopterin and nitric oxide.
Li L, Rezvan A, Salerno JC, Husain A, Kwon K, Jo H, Harrison DG, Chen W
(2010) Circ Res 106: 328-36
MeSH Terms: Animals, Binding Sites, Biopterin, Blotting, Western, Carotid Arteries, Casein Kinase II, Cell Line, Cells, Cultured, Endothelial Cells, Enzyme Inhibitors, GTP Cyclohydrolase, Humans, Intracellular Signaling Peptides and Proteins, Mice, Mice, Inbred C57BL, Mutation, NG-Nitroarginine Methyl Ester, Nitric Oxide, Nitric Oxide Synthase Type III, Phosphorylation, RNA Interference, Stress, Mechanical
Show Abstract · Added December 10, 2013
RATIONALE - GTP cyclohydrolase I (GTPCH-1) is the rate-limiting enzyme involved in de novo biosynthesis of tetrahydrobiopterin (BH(4)), an essential cofactor for NO synthases and aromatic amino acid hydroxylases. GTPCH-1 undergoes negative feedback regulation by its end-product BH(4) via interaction with the GTP cyclohydrolase feedback regulatory protein (GFRP). Such a negative feedback mechanism should maintain cellular BH(4) levels within a very narrow range; however, we recently identified a phosphorylation site (S81) on human GTPCH-1 that markedly increases BH(4) production in response to laminar shear.
OBJECTIVE - We sought to define how S81 phosphorylation alters GTPCH-1 enzyme activity and how this is modulated by GFRP.
METHODS AND RESULTS - Using prokaryotically expressed proteins, we found that the GTPCH-1 phospho-mimetic mutant (S81D) has increased enzyme activity, reduced binding to GFRP and resistance to inhibition by GFRP compared to wild-type GTPCH-1. Using small interfering RNA or overexpressing plasmids, GFRP was shown to modulate phosphorylation of GTPCH-1, BH(4) levels, and NO production in human endothelial cells. Laminar, but not oscillatory shear stress, caused dissociation of GTPCH-1 and GFRP, promoting GTPCH-1 phosphorylation. We also found that both GTPCH-1 phosphorylation and GFRP downregulation prevents endothelial NO synthase uncoupling in response to oscillatory shear. Finally oscillatory shear was associated with impaired GTPCH-1 phosphorylation and reduced BH(4) levels in vivo.
CONCLUSIONS - These studies provide a new mechanism for regulation of endothelial GTPCH-1 by its phosphorylation and interplay with GFRP. This mechanism allows for escape from GFRP negative feedback and permits large amounts of BH(4) to be produced in response to laminar shear stress.
1 Communities
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22 MeSH Terms
Heat shock protein 90-eNOS interactions mature with postnatal age in the pulmonary circulation of the piglet.
Aschner JL, Zeng H, Kaplowitz MR, Zhang Y, Slaughter JC, Fike CD
(2009) Am J Physiol Lung Cell Mol Physiol 296: L555-64
MeSH Terms: Acetylcholine, Age Factors, Animals, Animals, Newborn, HSP90 Heat-Shock Proteins, In Vitro Techniques, NG-Nitroarginine Methyl Ester, Nitric Oxide Synthase Type III, Proto-Oncogene Proteins c-akt, Pulmonary Artery, S-Nitroso-N-Acetylpenicillamine, Swine, Vascular Resistance
Show Abstract · Added May 20, 2014
Binding of endothelial nitric oxide synthase (eNOS) to the chaperone protein, Hsp90, promotes coupled eNOS synthetic activity. Using resistance level pulmonary arteries (PRA) from 2-day-, 5- to 7-day-, and 12-day-old piglets, we tested the hypothesis that Hsp90-eNOS interactions are developmentally regulated in the early neonatal period. PRA were isolated for coimmunoprecipitation and immunoblot analyses or cannulated for continuous diameter measurements using the pressurized myography technique. NOS inhibition caused less constriction in PRA from 2-day- compared with 5- to 7-day- and 12-day-old piglets. No age-related differences were found in dilation responses to an NO donor or in protein expression of Hsp90, phospho-eNOS (Ser(1177)), Akt, phospho-Akt, or caveolin-1. Compared with the older animals, PRA from 2-day-old piglets had higher total eNOS expression but displayed less binding of eNOS to Hsp90 and Akt. Hsp90 antagonism with radicicol induced greatest constriction in PRA from 12-day-old piglets. ACh stimulation caused dilation in PRA from 5- to 7-day- and 12-day-old but not 2-day-old animals, despite rapid and equivalent ACh-mediated eNOS phosphorylation (Ser(1177)) in all three age groups. Hsp90 inhibition abolished ACh-mediated dilation in PRA from the older piglets. ACh failed to stimulate Hsp90-eNOS binding in 2-day-old but induced a significant increase in Hsp90-eNOS coimmunoprecipitation in PRA from the older age groups, which was blocked by Hsp90 antagonism. We conclude that physical interactions between Hsp90 and eNOS mature over the first weeks of life, likely contributing to the postnatal fall in pulmonary vascular resistance and changes in agonist-induced pulmonary vascular responses characteristic of the early neonatal period.
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13 MeSH Terms
Regulation of the fetal mouse ductus arteriosus is dependent on interaction of nitric oxide and COX enzymes in the ductal wall.
Reese J, O'Mara PW, Poole SD, Brown N, Tolentino C, Eckman DM, Aschner JL
(2009) Prostaglandins Other Lipid Mediat 88: 89-96
MeSH Terms: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid, Animals, Cyclooxygenase Inhibitors, Drug Interactions, Ductus Arteriosus, Female, Fetus, In Vitro Techniques, Indomethacin, Mice, Myography, NG-Nitroarginine Methyl Ester, Nitric Oxide, Nitric Oxide Donors, Pregnancy, Prostaglandin-Endoperoxide Synthases, Time Factors, Vasoconstriction, Vasoconstrictor Agents, Vasodilation
Show Abstract · Added April 9, 2015
Nitric oxide (NO) and cyclooxygenase (COX)-derived prostaglandins are critical regulators of the fetal ductus arteriosus. To examine the interaction of these pathways within the ductus wall, the ductus arteriosus of term and preterm fetal mice was evaluated by pressurized myography. The isolated preterm ductus was more sensitive to NOS inhibition than at term. Sequential NOS and COX inhibition caused 36% constriction of the preterm ductus regardless of drug order. In contrast, constriction of the term ductus was dependent on the sequence of inhibition; NOS inhibition prior to COX inhibition produced greater constriction than when inhibitors were given in reverse order (36+/-6% versus 23+/-5%). Selective COX-1 or COX-2 inhibition prior to N(G)-nitro-l-arginine methyl ester (l-NAME) induced the expected degree of constriction. However, NOS inhibition followed by selective COX-2 inhibition caused unexpected ductal dilation. These findings are consistent with NO-induced activation of COX in the ductus arteriosus wall and the production of a COX-2-derived constrictor prostanoid that contributes to the balance of vasoactive forces that maintain fetal ductus arteriosus tone.
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20 MeSH Terms
Dimethyl amiloride improves glucose homeostasis in mouse models of type 2 diabetes.
Gunawardana SC, Head WS, Piston DW
(2008) Am J Physiol Endocrinol Metab 294: E1097-108
MeSH Terms: Amiloride, Amino Acids, Cyclic, Animals, Arginine, Blood Glucose, Diabetes Mellitus, Type 2, Disease Models, Animal, Drug Synergism, Homeostasis, Hydrogen-Ion Concentration, Insulin, Insulin Secretion, Insulin-Secreting Cells, Keto Acids, Ketoglutarate Dehydrogenase Complex, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, NG-Nitroarginine Methyl Ester, Nitric Oxide Synthase Type I, Sodium-Calcium Exchanger
Show Abstract · Added November 1, 2012
Dimethyl amiloride (DMA) enhances insulin secretion in the pancreatic beta-cell. DMA also enhances time-dependent potentiation (TDP) and enables TDP to occur in situations where it is normally absent. As we have demonstrated before, these effects are mediated in part through inhibition of neuronal nitric oxide synthase (nNOS), resulting in increased availability of arginine. Thus both DMA and arginine have the potential to correct the secretory defect in diabetes by enabling or enhancing TDP. In the current study we have demonstrated the ability of these agents to improve blood glucose homeostasis in three mouse models of type 2 diabetes. The pattern of TDP under different conditions indicates that inhibition of NOS is not the only mechanism through which DMA exerts its positive effects. Thus we also have explored another possible mechanism through which DMA enables/enhances TDP, via the activation of mitochondrial alpha-ketoglutarate dehydrogenase.
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23 MeSH Terms
Hepatic portal venous delivery of a nitric oxide synthase inhibitor enhances net hepatic glucose uptake.
Moore MC, Dicostanzo CA, Smith MS, Farmer B, Rodewald TD, Neal DW, Williams PE, Cherrington AD
(2008) Am J Physiol Endocrinol Metab 294: E768-77
MeSH Terms: Animals, Blood Glucose, Carbon, Catheterization, Dogs, Dose-Response Relationship, Drug, Enzyme Inhibitors, Fatty Acids, Nonesterified, Female, Glycerol, Hyperglycemia, Hyperinsulinism, Lactic Acid, Liver, Male, Molsidomine, NG-Nitroarginine Methyl Ester, Nitric Oxide, Nitric Oxide Synthase, Portal Vein, Postprandial Period
Show Abstract · Added December 10, 2013
Hepatic portal venous infusion of nitric oxide synthase (NOS) inhibitors causes muscle insulin resistance, but the effects on hepatic glucose disposition are unknown. Conscious dogs underwent a hyperinsulinemic (4-fold basal) hyperglycemic (hepatic glucose load 2-fold basal) clamp, with assessment of liver metabolism by arteriovenous difference methods. After 90 min (P1), dogs were divided into two groups: control (receiving intraportal saline infusion; n = 8) and LN [receiving N(G)-nitro-L-arginine methyl ester (L-NAME), a nonspecific NOS inhibitor; n = 11] intraportally at 0.3 mg x kg(-1) x min(-1) for 90 min (P2). During the final 60 min of study (P3), L-NAME was discontinued, and five LN dogs received the NO donor SIN-1 intraportally at 6 mug x kg(-1) x min(-1) while six received saline (LN/SIN-1 and LN/SAL, respectively). Net hepatic fractional glucose extraction (NHFE) in control dogs was 0.034 +/- 0.016, 0.039 +/- 0.015, and 0.056 +/- 0.019 during P1, P2, and P3, respectively. NHFE in LN was 0.045 +/- 0.009 and 0.111 +/- 0.007 during P1 and P2, respectively (P < 0.05 vs. control during P2), and 0.087 +/- 0.009 and 0.122 +/- 0.016 (P < 0.05) during P3 in LN/SIN-1 and LN/SAL, respectively. During P2, arterial glucose was 204 +/- 5 vs. 138 +/- 11 mg/dl (P < 0.05) in LN vs. control to compensate for L-NAME's effect on blood flow. Therefore, another group (LNlow; n = 4) was studied in the same manner as LN/SAL, except that arterial glucose was clamped at the same concentrations as in control. NHFE in LNlow was 0.052 +/- 0.008, 0.093 +/- 0.023, and 0.122 +/- 0.021 during P1, P2, and P3, respectively (P < 0.05 vs. control during P2 and P3), with no significant difference in glucose infusion rates. Thus, NOS inhibition enhanced NHFE, an effect partially reversed by SIN-1.
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21 MeSH Terms