Inhibition of myocardial glucose uptake by cGMP

1998 ◽  
Vol 274 (5) ◽  
pp. H1443-H1449 ◽  
Author(s):  
Christophe Depre ◽  
Vinciane Gaussin ◽  
Sylvie Ponchaut ◽  
Yvan Fischer ◽  
Jean-Louis Vanoverschelde ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Acid Oxidation ◽  
No Production ◽  
Heart Metabolism ◽  
No Donor ◽  
Myocardial Glucose Uptake ◽  
Cyclic Monophosphate ◽  
Heart Work ◽  
Cgmp Analog

Guanosine 3′,5′-cyclic monophosphate (cGMP), a second messenger of nitric oxide (NO), regulates myocardial contractility. It is not known whether this effect is accompanied by a change in heart metabolism. We report here the effects of 8-bromoguanosine 3′,5′-cyclic monophosphate (8-BrcGMP), a cGMP analog, on regulatory steps of glucose metabolism in isolated working rat hearts perfused with glucose as the substrate. When glucose uptake was stimulated by increasing the workload, addition of the cGMP analog totally suppressed this stimulation and accelerated net glycogen breakdown. 8-BrcGMP did not affect pyruvate dehydrogenase activity but activated acetyl-CoA carboxylase, the enzyme that produces malonyl-CoA, an inhibitor of long-chain fatty acid oxidation. To test whether glucose metabolism could also be affected by altering the intracellular concentration of cGMP, we perfused hearts with N G-nitro-l-arginine methyl ester (l-NAME), an inhibitor of NO synthase, or with S-nitroso- N-acetylpenicillamine (SNAP), a NO donor. Perfusion withl-NAME decreased cGMP and increased glucose uptake by 30%, whereas perfusion with SNAP resulted in opposite effects. None of these conditions affected adenosine 3′,5′-cyclic monophosphate concentration. Limitation of glucose uptake by SNAP or 8-BrcGMP decreased heart work, and this was reversed by adding alternative oxidizable substrates (pyruvate, β-hydroxybutyrate) together with glucose. Therefore, increased NO production decreases myocardial glucose utilization and limits heart work. This effect is mediated by cGMP, which is thus endowed with both physiological and metabolic properties.

scholarly journals SGLT2 Inhibition Does Not Affect Myocardial Fatty Acid Oxidation or Uptake, But Reduces Myocardial Glucose Uptake and Blood Flow in Individuals With Type 2 Diabetes– a Randomized Double-Blind, Placebo-Controlled Crossover Trial

2020 ◽  
Author(s):  
Katrine M. Lauritsen ◽  
Bent R.R. Nielsen ◽  
Lars P. Tolbod ◽  
Mogens Johannsen ◽  
Jakob Hansen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Oxygen Consumption ◽  
Glucose Uptake ◽  
Acid Oxidation ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Myocardial Glucose Uptake ◽  
Pet Ct ◽  
Sglt2 Inhibition

Sodium-glucose cotransporter 2 (SGLT2) inhibition reduces cardiovascular morbidity and mortality in individuals with type 2 diabetes. Beneficial effects have been attributed to increased ketogenesis, reduced cardiac fatty acid oxidation and diminished cardiac oxygen consumption. We therefore studied whether SGLT2 inhibition altered cardiac oxidative substrate consumption, efficiency, and perfusion. <p>13 individuals with type 2 diabetes were studied after four weeks treatment with empagliflozin and placebo in a randomized, double-blind, placebo-controlled crossover study. Myocardial palmitate and glucose uptake were measured with <sup>11</sup>C-palmitate and <sup>18</sup>F-FDG PET/CT. Oxygen consumption and myocardial external efficiency (MEE) were measured with <sup>11</sup>C-acetate PET/CT. Resting and adenosine stress myocardial blood flow (MBF) and myocardial flow reserve (MFR) were measured using <sup>15</sup>O-H<sub>2</sub>O PET/CT. </p> <p>Empagliflozin did not affect myocardial FFA uptake but reduced myocardial glucose uptake by 57% (p<0.001). Empagliflozin did not change myocardial oxygen consumption or MEE. Empagliflozin reduced resting MBF by 13% (p<0.01), but did not significantly affect stress MBF or MFR.</p> <p>In conclusion, SGLT2 inhibition did not affect myocardial FFA uptake, but channeled myocardial substrate utilization from glucose towards other sources and reduced resting MBF. However, the observed metabolic and hemodynamic changes were modest and most likely contribute only partially to the cardioprotective effect of SGLT2 inhibition. </p>

scholarly journals Qiliqiangxin Enhances Cardiac Glucose Metabolism and Improves Diastolic Function in Spontaneously Hypertensive Rats

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Jingfeng Wang ◽  
Zhiming Li ◽  
Yanyan Wang ◽  
Jingjing Zhang ◽  
Weipeng Zhao ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Diastolic Function ◽  
Spontaneously Hypertensive Rat ◽  
Small Animal ◽  
Small Animal Pet ◽  
Spontaneously Hypertensive ◽  
Key Enzymes ◽  
Atp Production ◽  
Myocardial Glucose Uptake

Cardiac diastolic dysfunction has emerged as a growing type of heart failure. The present study aims to explore whether Qiliqiangxin (QL) can benefit cardiac diastolic function in spontaneously hypertensive rat (SHR) through enhancement of cardiac glucose metabolism. Fifteen 12-month-old male SHRs were randomly divided into QL-treated, olmesartan-treated, and saline-treated groups. Age-matched WKY rats served as normal controls. Echocardiography and histological analysis were performed. Myocardial glucose uptake was determined by 18F-FDG using small-animal PET imaging. Expressions of several crucial proteins and key enzymes related to glucose metabolism were also evaluated. As a result, QL improved cardiac diastolic function in SHRs, as evidenced by increased E′/A′and decreased E/E′ (P<0.01). Meanwhile, QL alleviated myocardial hypertrophy, collagen deposits, and apoptosis (P<0.01). An even higher myocardial glucose uptake was illustrated in QL-treated SHR group (P<0.01). Moreover, an increased CS activity and ATP production was observed in QL-treated SHRs (P<0.05). QL enhanced cardiac glucose utilization and oxidative phosphorylation in SHRs by upregulating AMPK/PGC-1α axis, promoting GLUT-4 expression, and regulating key enzymes related to glucose aerobic oxidation such as HK2, PDK4, and CS (P<0.01). Our data suggests that QL improves cardiac diastolic function in SHRs, which may be associated with enhancement of myocardial glucose metabolism.

Abstract 3305: FDG PET Imaging in the PRKAG2 Cardiac Syndrome Demonstrates Altered Myocardial Glucose Uptake

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Andrew C Ha ◽  
Jennifer Renaud ◽  
Stephanie Thorn ◽  
Rob deKemp ◽  
Keiichiro Yoshinaga ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Pet Imaging ◽  
Plasma Glucose ◽  
Fdg Pet ◽  
Adult Patients ◽  
Myocardial Glucose Uptake ◽  
Cardiac Syndrome ◽  
The Mean ◽  
Normal Controls

Background : The PRKAG2 gene encodes for the gamma-2 subunit of AMP-activated protein kinase (AMPK), a protein implicated in the regulation of myocardial glucose metabolism. In humans, mutations of the PRKAG2 gene result in a cardiomyopathy characterized by ventricular pre-excitation, atrioventricular conduction disease, and cardiac hypertrophy. It is recognized that altered cardiac glucose metabolism and abnormal glycogen stores are responsible for the clinical manifestations of this syndrome. Since myocardial glucose uptake can be measured with 2-[ 18 F]Fluoro-2-deoxyglucose dynamic positron emission tomography ([ 18 F]FDG PET), we examined whether adult patients with an identified Arg302Gln PRKAG2 mutation have altered myocardial glucose uptake using this imaging modality. Methods: [ 18 F]FDG PET was performed in 5 adult patients with the Arg302Gln PRKAG2 mutation (PRKAG2) and in 6 healthy volunteers (Control) with a hyperinsulinemic euglycemic clamp protocol. The fractional rate of radiotracer uptake (K) is derived from PATLAK analysis. The rate of myocardial glucose uptake (rMGU) of the left ventricle (LV) is calculated as (K / LC) x P glucose , where P glucose represents the mean plasma glucose level during imaging. LC (lump constant) corrects for the differences in the transport and phosphorylation of [ 18 F]FDG and glucose. Results are expressed as mean ± standard deviation and are analyzed with the student t-test. Results: The mean rMGU in the PRKAG2 group was significantly lower than the control group. There was no difference in the mean plasma glucose levels between the 2 groups. (Table ) Conclusion: Myocardial glucose uptake is reduced in adult patients with mutation of the PRKAG2 gene when compared to normal controls. Measurement of rMGU using [ 18 F]FDG PET imaging appears to be a useful tool to investigate the pathophysiology of the PRKAG2 cardiac syndrome and to potentially distinguish this metabolic cardiomyopathy from other etiolgies. Mean rate of myocardial glucose uptake between patients with the PRKAG2 mutation and normal controls

scholarly journals ADMA injures the glomerular filtration barrier: role of nitric oxide and superoxide

2009 ◽  
Vol 296 (6) ◽  
pp. F1386-F1395 ◽  
Author(s):  
Mukut Sharma ◽  
Zongmin Zhou ◽  
Hiroto Miura ◽  
Andreas Papapetropoulos ◽  
Ellen T. McCarthy ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Glomerular Filtration ◽  
Soluble Guanylyl Cyclase ◽  
Oxidase Inhibitor ◽  
No Production ◽  
Dependent Manner ◽  
Glomerular Filtration Barrier ◽  
No Donor ◽  
Filtration Barrier ◽  
Cgmp Analog

Chronic kidney disease (CKD) is associated with decreased renal nitric oxide (NO) production and increased plasma levels of methylarginines. The naturally occurring guanidino-methylated arginines N-monomethyl-l-arginine (l-NMMA) and asymmetric dimethyl-l-arginine (ADMA) inhibit NO synthase activity. We hypothesized that ADMA and l-NMMA compromise the integrity of the glomerular filtration barrier via NO depletion. We studied the effect of ADMA on albumin permeability (Palb) in isolated glomeruli and examined whether this effect involves NO- and superoxide (O2•−)-dependent mechanisms. ADMA at concentrations found in circulation of patients with CKD decreased cGMP and increased Palb in a dose-dependent manner. A similar increase in Palb was caused by l-NMMA but at a concentration two orders of magnitude higher than that of ADMA. NO donor DETA-NONOate or cGMP analog abrogated the effect of ADMA on Palb. The SOD mimetic tempol or the NAD(P)H oxidase inhibitor apocynin also prevented the ADMA-induced increase in Palb. The NO-independent soluble guanylyl cyclase (sGC) activator BAY 41–2272, at concentrations that increased glomerular cGMP production, attenuated the ADMA-induced increase in Palb. Furthermore, sGC incapacitation by the heme site-selective inhibitor ODQ increased Palb. We conclude that ADMA compromises the integrity of the filtration barrier by altering the bioavailability of NO and O2•− and that NO-independent activation of sGC preserves the integrity of this barrier under conditions of NO depletion. NO-independent activation of sGS may be a useful pharmacotherapeutic approach for preservation of glomerular function in CKD thereby reducing the risk for cardiovascular events.

Impaired pyruvate oxidation but normal glucose uptake in diabetic pig heart during dobutamine-induced work

1996 ◽  
Vol 271 (6) ◽  
pp. H2320-H2329 ◽  
Author(s):  
J. L. Hall ◽  
W. C. Stanley ◽  
G. D. Lopaschuk ◽  
J. A. Wisneski ◽  
R. D. Pizzurro ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Lactate Production ◽  
Diabetic Group ◽  
Control Group ◽  
Acid Oxidation ◽  
Myocardial Glucose Uptake ◽  
Pyruvate Oxidation ◽  
Malonyl Coa ◽  
Lactate Uptake ◽  
Cpt I

We tested the hypothesis that diabetes impairs myocardial glucose uptake and pyruvate oxidation under normal conditions and during a dobutamine-induced increase in work. We also tested the hypothesis that an increase in work would result in a decrease in the levels of malonyl CoA, a potent inhibitor of carnitine palmitoyltransferase I (CPT I). Streptozotocin-diabetic micropigs were compared with a nondiabetic control group (n = 8 per group). Triglyceride emulsion, glucose, and somatostatin were infused into the nondiabetic group to create an acute diabetic-like state. In accord with our hypothesis, malonyl CoA decreased significantly with dobutamine in both groups, providing a possible mechanism for increased fatty acid oxidation through relieved inhibition on CPT I. In the absence of dobutamine, glucose uptake and tracer-measured lactate uptake were decreased by 57 and 80%, respectively, in the diabetic group. Dobutamine infusion resulted in similar increases in cardiac contractility, oxygen consumption, and glucose uptake in both groups despite reductions of 50-65% in GLUT-4 and GLUT-1 protein in the diabetic group. Diabetic animals possessed a defect in myocardial pyruvate oxidation, as reflected in increased lactate production, and depressed lactate uptake and pyruvate dehydrogenase activity under control and dobutamine conditions. In conclusion, the major derangement in carbohydrate metabolism in diabetic myocardium was not in glycolysis but, rather, in pyruvate oxidation.

scholarly journals Insulin signaling requires glucose to promote lipid anabolism in adipocytes

2020 ◽  
Vol 295 (38) ◽  
pp. 13250-13266
Author(s):  
James R. Krycer ◽  
Lake-Ee Quek ◽  
Deanne Francis ◽  
Armella Zadoorian ◽  
Fiona C. Weiss ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Insulin Signaling ◽  
Carbon Sources ◽  
Lipid Synthesis ◽  
Acid Oxidation ◽  
Carbon Substrate ◽  
Metabolic Tracing

Adipose tissue is essential for metabolic homeostasis, balancing lipid storage and mobilization based on nutritional status. This is coordinated by insulin, which triggers kinase signaling cascades to modulate numerous metabolic proteins, leading to increased glucose uptake and anabolic processes like lipogenesis. Given recent evidence that glucose is dispensable for adipocyte respiration, we sought to test whether glucose is necessary for insulin-stimulated anabolism. Examining lipogenesis in cultured adipocytes, glucose was essential for insulin to stimulate the synthesis of fatty acids and glyceride–glycerol. Importantly, glucose was dispensable for lipogenesis in the absence of insulin, suggesting that distinct carbon sources are used with or without insulin. Metabolic tracing studies revealed that glucose was required for insulin to stimulate pathways providing carbon substrate, NADPH, and glycerol 3-phosphate for lipid synthesis and storage. Glucose also displaced leucine as a lipogenic substrate and was necessary to suppress fatty acid oxidation. Together, glucose provided substrates and metabolic control for insulin to promote lipogenesis in adipocytes. This contrasted with the suppression of lipolysis by insulin signaling, which occurred independently of glucose. Given previous observations that signal transduction acts primarily before glucose uptake in adipocytes, these data are consistent with a model whereby insulin initially utilizes protein phosphorylation to stimulate lipid anabolism, which is sustained by subsequent glucose metabolism. Consequently, lipid abundance was sensitive to glucose availability, both during adipogenesis and in Drosophila flies in vivo. Together, these data highlight the importance of glucose metabolism to support insulin action, providing a complementary regulatory mechanism to signal transduction to stimulate adipose anabolism.

scholarly journals Novel Effects of the Gastrointestinal Hormone Secretin on Cardiac Metabolism and Renal Function

2021 ◽  
Author(s):  
Sanna Laurila ◽  
Eleni Rebelos ◽  
Minna Lahesmaa ◽  
Lihua Sun ◽  
Katharina Schnabl ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Renal Clearance ◽  
Gastrointestinal Hormones ◽  
Cardiac Metabolism ◽  
Drug Candidate ◽  
Gastrointestinal Hormone ◽  
Future Studies ◽  
Myocardial Glucose Uptake ◽  
Heart Work ◽  
Positron Emission

The cardiac benefits of gastrointestinal hormones have been of interest in recent years. The aim of this study was to explore the myocardial and renal effects of the gastrointestinal hormone secretin in the GUTBAT trial (NCT03290846). A placebo-controlled crossover study was conducted on 15 healthy males in fasting conditions, where subjects were blinded to the intervention. Myocardial glucose uptake was measured with [18F]2-fluoro-2-deoxy-D-glucose ([18F]FDG) positron emission tomography. Kidney function was measured with [18F]FDG renal clearance and estimated glomerular filtration rate (eGFR). Secretin increased myocardial glucose uptake compared to placebo (secretin vs. placebo, mean + standard deviation, 15.5 + 7.4 vs. 9.7 + 4.9 μmol/100g/min, 95% confidence interval (CI) [2.2, 9.4], p=0.004). Secretin also increased [18F]FDG renal clearance (44.5 + 5.4 vs. 39.5 + 8.5 ml/min, 95%CI[1.9, 8.1], p=0.004) and eGFR was significantly increased from baseline after secretin, compared to placebo (17.8 + 9.8 vs. 6.0 + 5.2 Δml/min/1.73m2, 95%CI[6.0, 17.6], p=0.001). Our results implicate that secretin increases heart work and renal filtration, making it an interesting drug candidate for future studies in heart and kidney failure.

Constitutive and permissive roles of nitric oxide activity in embryonic ciliary cells

2003 ◽  
Vol 285 (2) ◽  
pp. R348-R355 ◽  
Author(s):  
Shandra A. Doran ◽  
Cam Ha Tran ◽  
Cagla Eskicioglu ◽  
Tev Stachniak ◽  
Kee-Chan Ahn ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Soluble Guanylate Cyclase ◽  
Beat Frequency ◽  
Ciliary Beat Frequency ◽  
No Production ◽  
Moderate Increase ◽  
No Donor ◽  
Cgmp Analog ◽  
Ly 83583 ◽  
Oxide Synthase

Embryos of Helisoma trivolvis exhibit cilia-driven rotation within the egg capsule during development. In this study we examined whether nitric oxide (NO) is a physiological regulator of ciliary beating in cultured ciliary cells. The NO donor S-nitroso- N-acetylpenicillamine (SNAP; 1–1,000 μM) produced a dose-dependent increase in ciliary beat frequency (CBF). In contrast, the nitric oxide synthase (NOS) inhibitor 7-nitroindazole (10 and 100 μM) inhibited the basal CBF and blocked the stimulatory effects of serotonin (100 μM). NO production in response to serotonin was investigated with 4,5-diaminofluorescein diacetate imaging. Although SNAP (100 μM) produced a rise in NO levels in all cells, only 22% of cells responded to serotonin with a moderate increase. The cGMP analog 8-bromo-cGMP (8-Br-cGMP; 0.2 and 2 mM) increased CBF, and the soluble guanylate cyclase inhibitor LY-83583 (10 μM) blocked the cilioexcitatory effects of SNAP and serotonin. These data suggest that NO has a constitutive cilioexcitatory effect in Helisoma embryos and that the stimulatory effects of serotonin and NO work through a cGMP pathway. It appears that in Helisoma cilia, NO activity is necessary, but not sufficient, to fully mediate the cilioexcitatory action of serotonin.

scholarly journals SGLT2 Inhibition Does Not Affect Myocardial Fatty Acid Oxidation or Uptake, But Reduces Myocardial Glucose Uptake and Blood Flow in Individuals With Type 2 Diabetes– a Randomized Double-Blind, Placebo-Controlled Crossover Trial

2020 ◽  
Author(s):  
Katrine M. Lauritsen ◽  
Bent R.R. Nielsen ◽  
Lars P. Tolbod ◽  
Mogens Johannsen ◽  
Jakob Hansen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Oxygen Consumption ◽  
Glucose Uptake ◽  
Acid Oxidation ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Myocardial Glucose Uptake ◽  
Pet Ct ◽  
Sglt2 Inhibition

Sodium-glucose cotransporter 2 (SGLT2) inhibition reduces cardiovascular morbidity and mortality in individuals with type 2 diabetes. Beneficial effects have been attributed to increased ketogenesis, reduced cardiac fatty acid oxidation and diminished cardiac oxygen consumption. We therefore studied whether SGLT2 inhibition altered cardiac oxidative substrate consumption, efficiency, and perfusion. <p>13 individuals with type 2 diabetes were studied after four weeks treatment with empagliflozin and placebo in a randomized, double-blind, placebo-controlled crossover study. Myocardial palmitate and glucose uptake were measured with <sup>11</sup>C-palmitate and <sup>18</sup>F-FDG PET/CT. Oxygen consumption and myocardial external efficiency (MEE) were measured with <sup>11</sup>C-acetate PET/CT. Resting and adenosine stress myocardial blood flow (MBF) and myocardial flow reserve (MFR) were measured using <sup>15</sup>O-H<sub>2</sub>O PET/CT. </p> <p>Empagliflozin did not affect myocardial FFA uptake but reduced myocardial glucose uptake by 57% (p<0.001). Empagliflozin did not change myocardial oxygen consumption or MEE. Empagliflozin reduced resting MBF by 13% (p<0.01), but did not significantly affect stress MBF or MFR.</p> <p>In conclusion, SGLT2 inhibition did not affect myocardial FFA uptake, but channeled myocardial substrate utilization from glucose towards other sources and reduced resting MBF. However, the observed metabolic and hemodynamic changes were modest and most likely contribute only partially to the cardioprotective effect of SGLT2 inhibition. </p>

scholarly journals Ischemic-LTP in Striatal Spiny Neurons of both Direct and Indirect Pathway Requires the Activation of D1-Like Receptors and NO/Soluble Guanylate Cyclase/cGMP Transmission

2012 ◽  
Vol 33 (2) ◽  
pp. 278-286 ◽  
Author(s):  
Sara Arcangeli ◽  
Alessandro Tozzi ◽  
Michela Tantucci ◽  
Cristiano Spaccatini ◽  
Antonio de Iure ◽  
...  
Keyword(s):  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Sch 23390 ◽  
Glucose Deprivation ◽  
Long Term Potentiation ◽  
No Production ◽  
Indirect Pathway ◽  
No Donor ◽  
Spiny Neurons ◽  
Cgmp Analog

Striatal medium-sized spiny neurons (MSNs) are highly vulnerable to ischemia. A brief ischemic insult, produced by oxygen and glucose deprivation (OGD), can induce ischemic long-term potentiation (i-LTP) of corticostriatal excitatory postsynaptic response. Since nitric oxide (NO) is involved in the pathophysiology of brain ischemia and the dopamine D1/D5-receptors (D1-like-R) are expressed in striatal NOS-positive interneurons, we hypothesized a relation between NOS-positive interneurons and striatal i-LTP, involving D1R activation and NO production. We investigated the mechanisms involved in i-LTP induced by OGD in corticostriatal slices and found that the D1-like-R antagonist SCH-23390 prevented i-LTP in all recorded MSNs. Immunofluorescence analysis confirmed the induction of i-LTP in both substance P-positive, (putative D1R-expressing) and adenosine A2A-receptor-positive (putative D2R-expressing) MSNs. Furthermore, i-LTP was dependent on a NOS/cGMP pathway since pharmacological blockade of NOS, guanylate-cyclase, or PKG prevented i-LTP. However, these compounds failed to prevent i-LTP in the presence of a NO donor or cGMP analog, respectively. Interestingly, the D1-like-R antagonism failed to prevent i-LTP when intracellular cGMP was pharmacologically increased. We propose that NO, produced by striatal NOS-positive interneurons via the stimulation of D1-like-R located on these cells, is critical for i-LTP induction in the entire population of MSNs involving a cGMP-dependent pathway.

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