scholarly journals Relative sensitivity of soluble guanylate cyclase and mitochondrial respiration to endogenous nitric oxide at physiological oxygen concentration

2007 ◽  
Vol 405 (2) ◽  
pp. 223-231 ◽  
Author(s):  
Félix Rodríguez-Juárez ◽  
Enara Aguirre ◽  
Susana Cadenas
Keyword(s):  
Nitric Oxide ◽  
Oxygen Consumption ◽  
Oxygen Concentration ◽  
Guanylate Cyclase ◽  
Mitochondrial Respiration ◽  
Soluble Guanylate Cyclase ◽  
Atmospheric Oxygen ◽  
Cellular Respiration ◽  
Cell Physiology ◽  
Experimental Conditions

Nitric oxide (NO) is a widespread biological messenger that has many physiological and pathophysiological roles. Most of the physiological actions of NO are mediated through the activation of sGC (soluble guanylate cyclase) and the subsequent production of cGMP. NO also binds to the binuclear centre of COX (cytochrome c oxidase) and inhibits mitochondrial respiration in competition with oxygen and in a reversible manner. Although sGC is more sensitive to endogenous NO than COX at atmospheric oxygen tension, the more relevant question is which enzyme is more sensitive at physiological oxygen concentration. Using a system in which NO is generated inside the cells in a finely controlled manner, we determined cGMP accumulation by immunoassay and mitochondrial oxygen consumption by high-resolution respirometry at 30 μM oxygen. In the present paper, we report that the NO EC50 of sGC was approx. 2.9 nM, whereas that required to achieve IC50 of respiration was 141 nM (the basal oxygen consumption in the absence of NO was 14±0.8 pmol of O2/s per 106 cells). In accordance with this, the NO–cGMP signalling transduction pathway was activated at lower NO concentrations than the AMPKs (AMP-activated protein kinase) pathway. We conclude that sGC is approx. 50-fold more sensitive than cellular respiration to endogenous NO under our experimental conditions. The implications of these results for cell physiology are discussed.

scholarly journals Localization of Soluble Guanylate Cyclase Activity in the Guinea Pig Cochlea Suggests Involvement in Regulation of Blood Flow and Supporting Cell Physiology

1997 ◽  
Vol 45 (10) ◽  
pp. 1401-1408 ◽  
Author(s):  
James D. Fessenden ◽  
Jochen Schacht
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Guinea Pig ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Lateral Wall ◽  
Supporting Cell ◽  
Nerve Fibers ◽  
Cell Physiology ◽  
Cgmp Pathway

Although the nitric oxide/cGMP pathway has many important roles in biology, studies of this system in the mammalian cochlea have focused on the first enzyme in the pathway, nitric oxide synthase (NOS). However, characterization of the NO receptor, soluble guanylate cyclase (sGC), is crucial to determine the cells targeted by NO and to develop rational hypotheses of the function of this pathway in auditory processing. In this study we characterized guinea pig cochlear sGC by determining its enzymatic activity and cellular localization. In cytosolic fractions of auditory nerve, lateral wall tissues, and co-chlear neuroepithelium, addition of NO donors resulted in three- to 15-fold increases in cGMP formation. NO-stimulated sGC activity was not detected in particulate fractions. We also localized cochlear sGC activity through immunocytochemical detection of NO-stimulated cGMP. sGC activity was detected in Hensen's and Deiters' cells of the organ of Corti, as well as in vascular pericytes surrounding small capillaries in the lateral wall tissues and sensory neuroepithelium. sGC activity was not observed in sensory cells. Using NADPH-diaphorase histochemistry, NOS was localized to pillar cells and nerve fibers underlying hair cells. These results indicate that the NO/cGMP pathway may influence diverse elements of the auditory system, including cochlear blood flow and supporting cell physiology.

Reversible inhibition of cellular respiration by nitric oxide in vascular inflammation

2001 ◽  
Vol 281 (6) ◽  
pp. H2256-H2260 ◽  
Author(s):  
Vilmante Borutaite ◽  
Anita Matthias ◽  
Hatty Harris ◽  
Salvador Moncada ◽  
Guy C. Brown
Keyword(s):  
Nitric Oxide ◽  
Oxygen Consumption ◽  
Soluble Guanylate Cyclase ◽  
Vascular Inflammation ◽  
Interferon Γ ◽  
Cellular Respiration ◽  
Tissue Respiration ◽  
Reversible Inhibition ◽  
Lower Oxygen ◽  
Cellular Oxygen

Incubation of rat aortas with endotoxin and interferon-γ for 24 h resulted in an aortic oxygen consumption that was substantially inhibited and strongly oxygen dependent (37% inhibition at 160 μM O2 and 62% inhibition at 80 μM O2 relative to untreated aortas). This respiratory inhibition was reversed by a nitric oxide (NO) scavenger (oxyhemoglobin) or by an inhibitor of inducible NO synthase [ N-(3-(aminomethyl)benzyl)acetamide · 2HCl, 1400W], but not by an inhibitor of soluble guanylate cyclase (1 H-[1,2,4]oxadiazolo[4,3-a]-quinoxalin-1-one). Addition of 1 μM NO to untreated aortas caused rapid and reversible inhibition of oxygen consumption that was greater at lower oxygen concentrations. Incubation of endothelial cells isolated from rat aortas with endotoxin and interferon-γ for 24 h resulted in a steady-state NO concentration of ∼0.5 μM and 90% inhibition of cellular oxygen consumption that was immediately reversed by an NO scavenger (oxyhemoglobin). These results suggest that during inflammation and sepsis, tissue respiration may be substantially reduced due to inhibition by NO of cytochrome oxidase.

Nitric oxide-independent stimulation of soluble guanylate cyclase reduces organ damage in experimental low-renin and high-renin models

2010 ◽  
Vol 28 (8) ◽  
pp. 1666-1675 ◽  
Author(s):  
Yuliya Sharkovska ◽  
Philipp Kalk ◽  
Bettina Lawrenz ◽  
Michael Godes ◽  
Linda Sarah Hoffmann ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Organ Damage ◽  
Stimulation Of

YC-1, a nitric oxide-independent activator of soluble guanylate cyclase, inhibits platelet-rich thrombosis in mice

1997 ◽  
Vol 320 (2-3) ◽  
pp. 161-166 ◽  
Author(s):  
Che-Ming Teng ◽  
Chin-Chung Wu ◽  
Feng-Nien Ko ◽  
Fang-Yu Lee ◽  
Sheng-Chu Kuo
Keyword(s):  
Nitric Oxide ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase

O14. Functional knockout of the soluble guanylate cyclase alpha 1 subunit leads to gender-specific hypertension while retaining sensitivity to nitric oxide

Nitric Oxide ◽  
2006 ◽  
Vol 14 (4) ◽  
pp. 4-5
Author(s):  
Patrick Yves Sips ◽  
Emmanuel Buys ◽  
Elke Rogge ◽  
Sofie Nimmegeers ◽  
Mieke Dewerchin ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Gender Specific

scholarly journals Differential synergy with nitric oxide across a panel of soluble guanylate cyclase stimulators

2015 ◽  
Vol 29 (S1) ◽  
Author(s):  
Kimberly Long ◽  
Kim Tang ◽  
Renee Sarno ◽  
Rob Solinga ◽  
Jaime Masferrer
Keyword(s):  
Nitric Oxide ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase

scholarly journals Butyl Isocyanide as a Probe of the Activation Mechanism of Soluble Guanylate Cyclase

2007 ◽  
Vol 282 (49) ◽  
pp. 35741-35748 ◽  
Author(s):  
Emily R. Derbyshire ◽  
Michael A. Marletta
Keyword(s):  
Nitric Oxide ◽  
Binding Site ◽  
Guanylate Cyclase ◽  
Electronic Absorption ◽  
Soluble Guanylate Cyclase ◽  
Activation Mechanism ◽  
Activation Process ◽  
Absorbance Maximum ◽  
No Activation ◽  
Allosteric Activator

Nitric oxide (NO) is a physiologically relevant activator of the hemoprotein soluble guanylate cyclase (sGC). In the presence of NO, sGC is activated several hundredfold above the basal level by a mechanism that remains to be elucidated. The heme ligand n-butyl isocyanide (BIC) was used to probe the mechanism of NO activation of sGC. Electronic absorption spectroscopy was used to show that BIC binds to the sGC heme, forming a 6-coordinate complex with an absorbance maximum at 429 nm. BIC activates sGC 2-5-fold, and synergizes with the allosteric activator YC-1, to activate the enzyme 15-25-fold. YC-1 activates the sGC-BIC complex, and leads to an increase in both the Vmax and Km. BIC was also used to probe the mechanism of NO activation. The activity of the sGC-BIC complex increases 15-fold in the presence of NO, without displacing BIC at the heme, which is consistent with previous reports that proposed the involvement of a non-heme NO binding site in the activation process.

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