A Soluble Guanylate Cyclase-Dependent Mechanism Is Involved in the Regulation of Net Hepatic Glucose Uptake by Nitric Oxide in Vivo

To determine the role of nitric oxide in regulating net hepatic glucose uptake (NHGU) in vivo, studies were performed on three groups of 42-h-fasted conscious dogs using a nitric oxide donor [3-morpholinosydnonimine (SIN-1)]. The experimental period was divided into period 1 (0–90 min) and period 2 (P2; 90–240 min). At 0 min, somatostatin was infused peripherally, and insulin (4-fold basal) and glucagon (basal) were given intraportally. Glucose was delivered intraportally (22.2 μmol·kg−1·min−1) and peripherally (as needed) to increase the hepatic glucose load twofold basal. At 90 min, an infusion of SIN-1 (4 μg·kg−1·min−1) was started in a peripheral vein (PeSin-1, n = 10) or the portal vein (PoSin-1, n = 12) while the control group received saline (SAL, n = 8). Both peripheral and portal infusion of SIN-1, unlike saline, significantly reduced systolic and diastolic blood pressure. Heart rate rose in PeSin-1 and PoSin-1 (96 ± 5 to 120 ± 10 and 88 ± 6 to 107 ± 5 beats/min, respectively, P < 0.05) but did not change in response to saline. NHGU during P2 was 31.0 ± 2.4 and 29.9 ± 2.0 μmol·kg−1·min−1 in SAL and PeSin-1, respectively but was 23.7 ± 1.7 in PoSin-1 ( P < 0.05). Net hepatic carbon retention during P2 was significantly lower in PoSin-1 than SAL or PeSin-1 (21.4 ± 1.2 vs. 27.1 ± 1.5 and 26.1 ± 1.0 μmol·kg−1·min−1). Nonhepatic glucose uptake did not change in response to saline or SIN-1 infusion. In conclusion, portal but not peripheral infusion of the nitric oxide donor SIN-1 inhibited NHGU.

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Abstract 1415: Activation of Soluble Guanylate Cyclase Regulates Phosphodiesterase 5A Localization and Restores Anti-adrenergic Action of Sildenafil despite Nitric Oxide Synthase Inhibition

Circulation ◽

10.1161/circ.116.suppl_16.ii_291 ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Takahiro Nagayama ◽

Manling Zhang ◽

Eiki Takimoto ◽

David A Kass

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Guanylate Cyclase ◽

Cyclic Gmp ◽

Soluble Guanylate Cyclase ◽

Synergistic Effects ◽

Adrenergic Stimulation ◽

Adrenergic Activity ◽

Oxide Synthase

Background: We have shown that inhibition of cyclic GMP-phosphodiesterase 5A (PDE5A) by sildenafil (SIL) blunts cardiomyocyte β-adrenergic stimulation, but this effect depends on the activity of endothelial nitric oxide synthase (eNOS) to generate a specific pool of cyclic GMP. PDE5A normally localizes at Z-bands in myocytes, but localization is more diffuse in cells with eNOS chronically inhibited. Here, we tested whether the influence of eNOS on PDE5A localization and anti-adrenergic action depends upon cyclic GMP. Methods and Results: Mouse in vivo hemodynamics were assessed by pressure-volume analysis. Isoproterenol (ISO: 20 ng/kg/min, iv ) stimulated contractility was inhibited by SIL (100 μg/kg/min, iv ), however this did not occur in mice given N w -nitro-L-arginine methyl ester (L-NAME: 1 mg/mL in drinking water for 1 week) to inhibit NOS. Myocytes transfected with an adenoviral vector encoding a fusion protein (PDE5A-DSred) in vivo were subsequently isolated and examined for PDE5A/α-actinin localization. Normal cells showed strong co-localization, whereas L-NAME-treated cells had diffuse PDE5A distribution. If L-NAME was stopped for 1-wk washout, SIL regained anti-adrenergic activity, and PDE5A z-band localization was restored. If L-NAME was continued but combined with Bay 41– 8543 (BAY: 30 mg/kg/day, po ), a soluble guanylate cyclase (sGC) activator, both PDE5A localization and SIL anti-adrenergic action were also restored. Chronic L-NAME suppressed phosphorylation of vasodilator-stimulated protein (VASP), a marker of protein kinase G (PKG) activity, in hearts acutely exposed to ISO+SIL. After L-NAME washout or L-NAME+BAY, VASP phosphorylation with ISO+SIL was restored. Conclusion: NOS-dependent modulation of both PDE5A sarcomere localization and anti-adrenergic activity depends upon sGC-derived cyclic GMP, and is linked to PKG activation. This suggests sGC activators may have synergistic effects with PDE5A inhibitors.

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Factors Which Regulate Net Hepatic Glucose Uptake In Vivo

Journal of Parenteral and Enteral Nutrition ◽

10.1177/014860719101500371s ◽

1991 ◽

Vol 15 (3) ◽

pp. 71S-73S ◽

Cited By ~ 10

Author(s):

Alan D. Cherrington ◽

Michael J. Pagliassotti ◽

Sharon R. Myers ◽

Bess Adkins-Marshall ◽

Owen P. Mcguinness

Keyword(s):

Glucose Uptake ◽

Hepatic Glucose ◽

Hepatic Glucose Uptake

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Soluble guanylate cyclase stimulation mitigates skeletal and cardiac muscle dysfunction in a mdx model of Duchenne muscular dystrophy

10.1101/2021.02.14.431156 ◽

2021 ◽

Author(s):

Ling Zhang ◽

Yuanyuan Xu ◽

Keyvan Yousefi ◽

Camila I. Irion ◽

Roger A. Alvarez ◽

...

Keyword(s):

Nitric Oxide ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Guanylate Cyclase ◽

Soluble Guanylate Cyclase ◽

Signal Propagation ◽

Guanosine Monophosphate ◽

Muscle Pathology ◽

Mdx Mice

AbstractThe impairment of neuronal nitric oxide synthase (nNOS) signaling contributes to disease pathology in the muscle wasting disorder Duchenne muscular dystrophy (DMD). nNOS signal propagation occurs through nitric oxide sensitive soluble guanylate cyclase (sGC), a critical source of cyclic guanosine monophosphate (cGMP) in muscle. Although both nNOS and sGC activity are impaired in DMD patients, little is known about sGC as a therapeutic target. In this study, we tested the hypothesis that stimulating sGC activity with the allosteric agonist BAY41-8543 mitigates striated muscle pathology in the mdx4cv mouse model of DMD. In contrast to DMD patients, mdx mice exhibited greater basal sGC activity than wild type controls with preservation of cGMP levels due partly to upregulation of sGC in some muscles. Stimulating sGC activity in mdx mice with BAY41-8543 substantially reduced skeletal muscle damage, macrophage densities and inflammation and significantly increased resistance to contraction-induced fatigue. BAY41-8543 also enhanced in vivo diaphragm function while reducing breathing irregularities suggesting improved respiratory function. BAY41-8543 attenuated cardiac hypertrophic remodeling, fibrosis and diastolic dysfunction including left atrium enlargement in aged mdx mice. Overall, sGC stimulation significantly mitigated skeletal and cardio-respiratory dysfunction in mdx4cv mice. Importantly, this study provides compelling pre-clinical evidence supporting sGC as a novel target in DMD and the repurposing of FDA-approved sGC stimulators, such as riociguat and veraciguat, as a novel therapeutic approach for DMD.

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Intraportal glucose delivery enhances the effects of hepatic glucose load on net hepatic glucose uptake in vivo.

Journal of Clinical Investigation ◽

10.1172/jci115273 ◽

1991 ◽

Vol 88 (1) ◽

pp. 158-167 ◽

Cited By ~ 77

Author(s):

S R Myers ◽

D W Biggers ◽

D W Neal ◽

A D Cherrington

Keyword(s):

Glucose Uptake ◽

Glucose Load ◽

Hepatic Glucose ◽

Hepatic Glucose Uptake

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A physiological increase in the hepatic glycogen level does not affect the response of net hepatic glucose uptake to insulin

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00043.2009 ◽

2009 ◽

Vol 297 (2) ◽

pp. E358-E366 ◽

Cited By ~ 16

Author(s):

Jason J. Winnick ◽

Zhibo An ◽

Mary Courtney Moore ◽

Christopher J. Ramnanan ◽

Ben Farmer ◽

...

Keyword(s):

Glucose Uptake ◽

Glycogen Synthesis ◽

Control Period ◽

In Vivo Studies ◽

Hepatic Glycogen ◽

Glycogen Level ◽

Hepatic Glucose ◽

Glycogen Deposition ◽

Hepatic Glucose Uptake

To determine the effect of an acute increase in hepatic glycogen on net hepatic glucose uptake (NHGU) and disposition in response to insulin in vivo, studies were performed on two groups of dogs fasted 18 h. During the first 4 h of the study, somatostatin was infused peripherally, while insulin and glucagon were replaced intraportally in basal amounts. Hyperglycemia was brought about by glucose infusion, and either saline ( n = 7) or fructose ( n = 7; to stimulate NHGU and glycogen deposition) was infused intraportally. A 2-h control period then followed, during which the portal fructose and saline infusions were stopped, allowing NHGU and glycogen deposition in the fructose-infused animals to return to rates similar to those of the animals that received the saline infusion. This was followed by a 2-h experimental period, during which hyperglycemia was continued but insulin infusion was increased fourfold in both groups. During the initial 4-h glycogen loading period, NHGU averaged 1.18 ± 0.27 and 5.55 ± 0.53 mg·kg−1·min−1 and glycogen synthesis averaged 0.72 ± 0.24 and 3.98 ± 0.57 mg·kg−1·min−1 in the saline and fructose groups, respectively ( P < 0.05). During the 2-h hyperinsulinemic period, NHGU rose from 1.5 ± 0.4 and 0.9 ± 0.2 to 3.1 ± 0.6 and 2.5 ± 0.5 mg·kg−1·min−1 in the saline and fructose groups, respectively, a change of 1.6 mg·kg−1·min−1 in both groups despite a significantly greater liver glycogen level in the fructose-infused group. Likewise, the metabolic fate of the extracted glucose (glycogen, lactate, or carbon dioxide) was not different between groups. These data indicate that an acute physiological increase in the hepatic glycogen content does not alter liver glucose uptake and storage under hyperglycemic/hyperinsulinemic conditions in the dog.

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Hemodynamic Effects of a Soluble Guanylate Cyclase Stimulator, Riociguat, and an Activator, Cinaciguat, During NO-Modulation in Healthy Pigs

Journal of Cardiovascular Pharmacology and Therapeutics ◽

10.1177/1074248420940897 ◽

2020 ◽

Vol 26 (1) ◽

pp. 75-87

Author(s):

Torvind Næsheim ◽

Ole-Jakob How ◽

Truls Myrmel

Keyword(s):

Nitric Oxide ◽

Guanylate Cyclase ◽

Pulmonary Circulation ◽

High Throughput Screening ◽

Soluble Guanylate Cyclase ◽

Vascular Control ◽

Vascular Effects ◽

Vast Number ◽

Systolic And Diastolic Function

Cardiovascular diseases are often characterized by dysfunctional endothelium. To compensate for the related lack of nitric oxide (NO), a class of soluble guanylate cyclase (sGC) stimulators and activators have been developed with the purpose of acting downstream of NO in the NO-sGC-cGMP cascade. These drugs have been discovered using photoaffinity labeling of sGC and high-throughput screening of a vast number of chemical compounds. Therefore, an understanding of the integrated physiological effects of these drugs in vivo is necessary on the path to clinical application. We have characterized the integrated hemodynamic impact of the sGC stimulator riociguat and the activator cinaciguat in different NO-states in healthy juvenile pigs (n = 30). We assessed the vascular effects in both systemic and pulmonary circulation, the contractile effects in the right and left ventricles, and the effects on diastolic cardiac functions. Nitric oxide-tone in these pigs were set by using the NO-blocker l-NAME and by infusion of nitroglycerine. The studies show a more pronounced vasodilatory effect in the systemic than pulmonary circulation for both drugs. Riociguat acts integrated with NO in an additive manner, while cinaciguat, in principle, completely blocks the endogenous NO effect on vascular control. Neither compound demonstrated pronounced cardiac effects but had unloading effect on both systolic and diastolic function. Thus, riociguat can potentially act in various disease states as a mean to increase NO-tone if systemic vasodilation can be balanced. Cinaciguat is a complicated drug to apply clinically due to its almost complete lack of integration in the NO-tone and balance.

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