Skeletal muscle force and actomyosin ATPase activity reduced by nitric oxide donor

1997 ◽  
Vol 83 (4) ◽  
pp. 1326-1332 ◽  
Author(s):  
William J. Perkins ◽  
Young-Soo Han ◽  
Gary C. Sieck
Keyword(s):  
Nitric Oxide ◽  
Mechanical Properties ◽  
Atpase Activity ◽  
Muscle Force ◽  
Isometric Force ◽  
Nitric Oxide Donor ◽  
No Donor ◽  
Single Fibers ◽  
Actomyosin Atpase ◽  
Cross Bridge

Perkins, William J., Young-Soo Han, and Gary C. Sieck.Skeletal muscle force and actomyosin ATPase activity reduced by nitric oxide donor. J. Appl. Physiol.83(4): 1326–1332, 1997.—Nitric oxide (NO) may exert direct effects on actin-myosin cross-bridge cycling by modulating critical thiols on the myosin head. In the present study, the effects of the NO donor sodium nitroprusside (SNP; 100 μM to 10 mM) on mechanical properties and actomyosin adenosinetriphosphatase (ATPase) activity of single permeabilized muscle fibers from the rabbit psoas muscle were determined. The effects of N-ethylmaleimide (NEM; 5–250 μM), a thiol-specific alkylating reagent, on mechanical properties of single fibers were also evaluated. Both NEM (≥25 μM) and SNP (≥1 mM) significantly inhibited isometric force and actomyosin ATPase activity. The unloaded shortening velocity of SNP-treated single fibers was decreased, but to a lesser extent, suggesting that SNP effects on isometric force and actomyosin ATPase were largely due to decreased cross-bridge recruitment. The calcium sensitivity of SNP-treated single fibers was also decreased. The effects of SNP, but not NEM, on force and actomyosin ATPase activity were reversed by treatment with 10 mMdl-dithiothreitol, a thiol-reducing agent. We conclude that the NO donor SNP inhibits contractile function caused by reversible oxidation of contractile protein thiols.

Inhibition of tetrahydrobiopterin biosynthesis impairs endothelium-dependent relaxations in canine basilar artery

1997 ◽  
Vol 273 (2) ◽  
pp. H718-H724 ◽  
Author(s):  
H. Kinoshita ◽  
S. Milstien ◽  
C. Wambi ◽  
Z. S. Katusic
Keyword(s):  
Nitric Oxide ◽  
Superoxide Dismutase ◽  
Nitric Oxide Synthase ◽  
Endothelial Function ◽  
Isometric Force ◽  
Cerebral Arteries ◽  
Calcium Ionophore ◽  
Nitric Oxide Donor ◽  
Ionophore A23187 ◽  
Oxide Synthase

Tetrahydrobiopterin is an essential cofactor in biosynthesis of nitric oxide. The present study was designed to determine the effect of decreased intracellular tetrahydrobiopterin levels on endothelial function of isolated cerebral arteries. Blood vessels were incubated for 6 h in minimum essential medium (MEM) in the presence or absence of a GTP cyclohydrolase I inhibitor, 2,4-diamino-6-hydroxypyrimidine (DAHP, 10(-2) M). Rings with and without endothelium were suspended for isometric force recording in the presence of a cyclooxygenase inhibitor, indomethacin (10(-5) M). In arteries with endothelium, DAHP significantly reduced intracellular levels of tetrahydrobiopterin. DAHP in combination with a precursor of the salvage pathway of tetrahydrobiopterin biosynthesis, sepiapterin (10(-4) M), not only restored but increased levels of tetrahydrobiopterin above control values. In DAHP-treated arteries, endothelium-dependent relaxations to bradykinin (10(-10)-10(-6) M) or calcium ionophore A23187 (10(-9)-10(-6) M) were significantly reduced, whereas endothelium-independent relaxations to a nitric oxide donor, 3-morpholinosydnonimine (10(-9)-10(-4) M), were not affected. When DAHP-treated arteries with endothelium were incubated with sepiapterin (10(-4) M) or superoxide dismutase (150 U/ml), relaxations to bradykinin and A23187 were restored to control levels. In contrast, superoxide dismutase did not affect endothelium-dependent relaxations in arteries incubated in MEM. A nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (10(-4) M), abolished relaxations to bradykinin or A23187 in control arteries and in DAHP-treated arteries. These studies demonstrate that in cerebral arteries, decreased intracellular levels of tetrahydrobiopterin can reduce endothelium-dependent relaxations. Production of superoxide anions during activation of dysfunctional endothelial nitric oxide synthase appears to be responsible for the impairment of endothelial function.

scholarly journals Effect of an ADP analog on isometric force and ATPase activity of active muscle fibers

2003 ◽  
Vol 284 (4) ◽  
pp. C816-C825 ◽  
Author(s):  
Christina Karatzaferi ◽  
Kathryn H. Myburgh ◽  
Marc K. Chinn ◽  
Kathleen Franks-Skiba ◽  
Roger Cooke
Keyword(s):  
Creatine Kinase ◽  
Simple Model ◽  
Atpase Activity ◽  
Isometric Force ◽  
Psoas Muscle ◽  
Isometric Tension ◽  
Active Muscle ◽  
Absolute Value ◽  
Cross Bridge ◽  
Skinned Muscle

The role played by ADP in modulating cross-bridge function has been difficult to study, because it is hard to buffer ADP concentration in skinned muscle preparations. To solve this, we used an analog of ADP, spin-labeled ADP (SL-ADP). SL-ADP binds tightly to myosin but is a very poor substrate for creatine kinase or pyruvate kinase. Thus ATP can be regenerated, allowing well-defined concentrations of both ATP and SL-ADP. We measured isometric ATPase rate and isometric tension as a function of both [SL-ADP], 0.1–2 mM, and [ATP], 0.05–0.5 mM, in skinned rabbit psoas muscle, simulating fresh or fatigued states. Saturating levels of SL-ADP increased isometric tension (by P′), the absolute value of P′ being nearly constant, ∼0.04 N/mm2, in variable ATP levels, pH 7. Tension decreased (50–60%) at pH 6, but upon addition of SL-ADP, P′ was still ∼0.04 N/mm2. The ATPase was inhibited competitively by SL-ADP with an inhibition constant, K i, of ∼240 and 280 μM at pH 7 and 6, respectively. Isometric force and ATPase activity could both be fit by a simple model of cross-bridge kinetics.

scholarly journals Dopamine in the ink defence system of Sepia officinalis: biosynthesis, vesicular compartmentation in mature ink gland cells, nitric oxide (NO)/cGMP-induced depletion and fate in secreted ink1

2004 ◽  
Vol 378 (3) ◽  
pp. 785-791 ◽  
Author(s):  
Gabriella FIORE ◽  
Annarita POLI ◽  
Anna Di COSMO ◽  
Marco d'ISCHIA ◽  
Anna PALUMBO
Keyword(s):  
Nitric Oxide ◽  
Tyrosine Hydroxylase ◽  
Physical Adsorption ◽  
Signalling Pathway ◽  
Nitric Oxide Donor ◽  
Sepia Officinalis ◽  
Release Process ◽  
No Donor ◽  
Cgmp Signalling ◽  
Incubation Experiments

The biosynthesis, localization and fate of catecholamines in the ink gland of the cuttlefish Sepia officinalis were investigated by combined biochemical and immunohistocytochemical methodologies. HPLC analysis of crude ink gland extracts indicated the presence of dopa (2.18±0.82 nmol/mg of protein) and DA (dopamine, 0.06±0.02 nmol/mg of protein), but no detectable noradrenaline or adrenaline. DA was shown to derive from l-tyrosine, according to experiments performed by incubating intact ink glands with [l-14C]tyrosine. The biosynthetic process involves a tyrosine hydroxylase and a dopa decarboxylase pathway and is independent of tyrosinase. The tyrosine hydroxylase activity was detected under conditions of tyrosinase suppression in the cytosolic fraction, but not in the melanosomal fraction, of ink gland extracts, and the presence of the enzyme was confirmed by Western-blot analysis. Dopa and DA were found to be released from the ink glands by processes controlled through the NMDA-nitric oxide-cGMP (where NMDA stands for N-methyl-d-aspartate) signalling pathway, as apparent from incubation experiments performed with [l-14C]tyrosine in the presence of NMDA, diethylamine NONOate (diethylamine diazeniumdiolate), a nitric oxide donor, 8-bromo-cGMP or a guanylyl cyclase inhibitor. Immunohistochemical results coupled with electron microscopy indicated that DA was concentrated in vesicles specifically localized in the mature melanin-producing cells of the ink gland proximal to the lumen and separated from the melanin-containing melanosomes. NMDA receptor stimulation or exposure to an NO donor caused a marked loss of DA immunoreactivity in mature cells, consistent with a release process. In the lumen of the ink gland, where mature exhausted cells pour their contents, DA immunoreactivity was found to be associated with the melanin granules, due apparently to physical adsorption. Overall, these results point to DA as a marker of cell maturation in Sepia ink gland subject to release by the NO/cGMP signalling pathway, and disclose apparently overlooked DA–melanin interactions in secreted ink of possible relevance to the defence mechanism.

scholarly journals Synthesis and characterization of a fluorinated S-nitrosothiol as the nitric oxide donor for fluoropolymer-based biomedical device applications

2018 ◽  
Vol 6 (38) ◽  
pp. 6142-6152 ◽  
Author(s):  
Yang Zhou ◽  
Qi Zhang ◽  
Jianfeng Wu ◽  
Chuanwu Xi ◽  
Mark E. Meyerhoff
Keyword(s):  
Nitric Oxide ◽  
Polyvinylidene Fluoride ◽  
Nitric Oxide Donor ◽  
Synthesis And Characterization ◽  
No Donor ◽  
Fluorinated Polymer ◽  
Biomedical Device ◽  
Device Applications

The first nitric oxide (NO) releasing fluorinated polymer was developed via incorporating a new fluorinated NO donor into polyvinylidene fluoride tubing.

Nitric oxide donor stimulated increase of cyclic GMP in the goldfish retina

2001 ◽  
Vol 18 (6) ◽  
pp. 849-856 ◽  
Author(s):  
WILLIAM H. BALDRIDGE ◽  
ANDY J. FISCHER
Keyword(s):  
Nitric Oxide ◽  
Optic Nerve ◽  
Ganglion Cells ◽  
Soluble Guanylyl Cyclase ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Nitric Oxide Donor ◽  
No Donor ◽  
Intracellular Signalling Pathway ◽  
Teleost Retina

Nitric oxide (NO) activates soluble guanylyl cyclase (sGC) and the resulting increase in cyclic guanosine monophosphate (cGMP) is an important intracellular signalling pathway in the vertebrate retina. Immunocytochemical detection of cGMP following exposure to NO donors has proven an effective method of identifying cells that express sGC. While such an approach has proven useful for the study of several vertebrate retinas, it has not been applied to the well-characterized teleost retina. Therefore, in the present study, we have applied this approach to the retina of the goldfish (Carassius auratus). In the presence of the phosphodiesterase (PDE) inhibitor 3-isobutyl-1-methylxanthine (IBMX), incubation of goldfish eyecups in Ringer's solution containing (±)-S-nitroso-N-acetylpenicillamine (SNAP) increased cGMP-like immunoreactivity (cG-ir) in bipolar, horizontal, amacrine, and ganglion cells and in ganglion cell axons and optic nerve. Weak labeling was observed in horizontal cells but no change in cG-ir was noted within photoreceptors. The NO donor-stimulated increases of cG-ir in horizontal, bipolar, amacrine, and ganglion cells are consistent with known physiological effects of NO on these neurons. The physiological significance of NO action at the level of optic nerve is not known. The lack of an effect of SNAP on cG-ir in photoreceptors was unexpected, as there are known physiological actions of NO, mediated by cGMP, on these neurons. Although this may be due to insufficient sensitivity of immunolabeling, this result may indicate a difference between isoforms of sGC or cGMP PDE in these neurons, compared to neurons where exogenous NO increased cG-ir.

scholarly journals Local infusion of the nitric oxide donor sin-1 after angioplasty: Effects on intimal hyperplasia in porcine coronary arteries

2003 ◽  
Vol 44 (4) ◽  
pp. 395-402
Author(s):  
J. Harnek ◽  
E. Zoucas ◽  
R. Sjuve ◽  
A. Arner ◽  
E. Ekblad ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Coronary Arteries ◽  
Intimal Hyperplasia ◽  
Percutaneous Transluminal Coronary Angioplasty ◽  
Local Delivery ◽  
Nitric Oxide Donor ◽  
Histological Evaluation ◽  
No Donor ◽  
Luminal Diameter ◽  
Transluminal Coronary Angioplasty

Purpose: To investigate the development of intimal hyperplasia in response to percutaneous transluminal coronary angioplasty (PTCA) followed by local delivery of the nitric oxide (NO) donor 3-morpholino-sydnonimine (SIN-1). Material and Methods: Overdilation PTCA was performed in coronary arteries in 20 healthy pigs. One of the dilated segments was additionally treated with local delivery of SIN-1 for 10 min. Segments distal to the treated part of the arteries served as controls. Arteries were radiographically depicted and analyzed after 1 and 8 weeks for actin, myosin and intermediate filaments (IF), nitric oxide synthetase (NOS) and histological evaluation. Results: Segments treated with PTCA+SIN-1 showed a significantly ( p = 0.03) larger luminal diameter compared with PTCA only treated segments. The luminal loss after SIN-1 was not significant compared with the diameter prior to treatment. Endothelial NOS content was significantly lower in the PTCA+SIN-1 group compared with the PTCA group after 1 ( p = 0.03) and 8 weeks ( p = 0.013). IF/actin ratio after 1 week was significantly increased in PTCA-treated segments compared with untreated controls ( p = 0.004), and compared with PTCA+SIN-1-treated segments ( p = 0.004). Conclusion: PTCA-induced intimal hyperplasia was potently inhibited by local delivery of the NO donor SIN-1. Momentary events at the time of injury play a significant role in the development of intimal hyperplasia and long-lasting down-regulation of the endothelial NOS expression after SIN-1 exposure is suggested. The IF/actin ratio can be useful as an early marker of intimal hyperplasia.

The nitric oxide donor molsidomine rescues cardiac function in rats with chronic kidney disease and cardiac dysfunction

2010 ◽  
Vol 299 (6) ◽  
pp. H2037-H2045 ◽  
Author(s):  
Lennart G. Bongartz ◽  
Branko Braam ◽  
Marianne C. Verhaar ◽  
Maarten Jan M. Cramer ◽  
Roel Goldschmeding ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Low Dose ◽  
Left Ventricular Systolic Dysfunction ◽  
Systolic Dysfunction ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
No Synthase ◽  
Nitric Oxide Donor ◽  
No Production ◽  
No Donor

We recently developed a rat model of cardiorenal failure that is characterized by severe left ventricular systolic dysfunction (LVSD) and low nitric oxide (NO) production that persisted after temporary low-dose NO synthase inhibition. We hypothesized that LVSD was due to continued low NO availability and might be reversed by supplementing NO. Rats underwent a subtotal nephrectomy and were treated with low-dose NO synthase inhibition with Nω-nitro-l-arginine up to week 8. After 3 wk of washout, rats were treated orally with either the long-acting, tolerance-free NO donor molsidomine (Mols) or vehicle (Veh). Cardiac and renal function were measured on weeks 11, 13, and 15. On week 16, LV hemodynamics and pressure-volume relationships were measured invasively, and rats were killed to quantify histological damage. On week 15, blood pressure was mildly reduced and creatinine clearance was increased by Mols (both P < 0.05). Mols treatment improved ejection fraction (53 ± 3% vs. 37 ± 2% in Veh-treated rats, P < 0.001) and stroke volume (324 ± 33 vs. 255 ± 15 μl in Veh-treated rats, P < 0.05). Rats with Mols treatment had lower end-diastolic pressures (8.5 ± 1.1 mmHg) than Veh-treated rats (16.3 ± 3.5 mmHg, P < 0.05) and reduced time constants of relaxation (21.9 ± 1.8 vs. 30.9 ± 3.3 ms, respectively, P < 0.05). The LV end-systolic pressure-volume relationship was shifted to the left in Mols compared with Veh treatment. In summary, in a model of cardiorenal failure with low NO availability, supplementing NO significantly improves cardiac systolic and diastolic function without a major effect on afterload.

Abstract 13295: Novel Experimental Therapeutics for COVID-19 Derived From a Nitric Oxide Donor

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
John F Schmedtje ◽  
Zahra Assar
Keyword(s):  
Nitric Oxide ◽  
Protein Interactions ◽  
In Silico ◽  
Vascular Endothelial Cells ◽  
Specific Binding ◽  
Nitric Oxide Donor ◽  
Isosorbide Mononitrate ◽  
Vascular Endothelial ◽  
No Donor ◽  
Glide Docking

Urea transport protein B, the product of the gene SLC14A1 , facilitates transport of urea, water and urea analogues across cell membranes. SLC14A1 mRNA is overexpressed in human vascular endothelial cells in culture under hypoxic (1% oxygen) conditions compared with normoxia. This leads to transport of urea out of the endothelial cell and likely contributes to the reduction in eNOS (endothelial nitric oxide synthase) pathway activity in hypoxia. NO has antiviral activity. Novel compounds were developed by binding a urea-like moiety to the backbone of the generic agent isosorbide mononitrate, a well-known NO donor, to combat vascular endothelial dysfunction in COVID-19, a disease characterized by systemic hypoxia and inflammation due to SARS-CoV-2 infection. A study of drug-protein interactions was undertaken using in silico modelling. Novel compounds were studied against 9 key SARS-CoV-2 targets using Maestro, Schrödinger Suite software (Glide docking). Docking scores and intermolecular interactions within the target’s key binding amino acid residues were studied to compare investigational compounds and known antivirals. Several novel agents tested had a better Glide Score (a prediction of ligand affinity) against the papain-like protease (PL pro ) of SARS-CoV-2 compared with known antiviral drugs. PL pro is considered to be a primary target for therapeutic inhibition of the SARS viruses. The candidate compounds CR-305, CR-607, CR-510 and CR-605 were all superior to Remdesivir, GS-441524, Lopinavir, Boceprevir, and Ribavirin. Given the known direct antiviral action of NO and evidence of specific binding of these compounds to the PL pro of SARS-CoV-2 based on the in silico results, we conclude there is a high likelihood these novel compounds will prove to be of therapeutic value against COVID-19. CR-305 appears to have a higher affinity to SARS-CoV-2 than other antivirals as it sits firmly in the PL pro catalytic pocket and makes the most of key interactions with the catalytic pocket residues: Gly163, Asp164, Gln271 and Tyr264. These data call for a new focus on these novel antiviral agents as they appear to bind with an increased avidity to PL pro (compared with other known antivirals) while targeting delivery of NO to the SARS-CoV-2 virus in COVID-19.

scholarly journals Sildenafil-nitric oxide donor combination promotes ventricular tachyarrhythmias in the swine right ventricle

2002 ◽  
Vol 282 (5) ◽  
pp. H1787-H1792 ◽  
Author(s):  
Moshe Swissa ◽  
Toshihiko Ohara ◽  
Moon-Hyoung Lee ◽  
Sanjay Kaul ◽  
Prediman K. Shah ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Donor ◽  
Tyrode Solution ◽  
No Donor ◽  
Maximum Slope ◽  
No Donors ◽  
Restitution Curve ◽  
Rapid Pacing ◽  
Drug Free ◽  
Endocardial Activation

We tested the hypothesis that sildenafil, singly or in combination with nitric oxide (NO) donors, promotes ventricular tachycardia (VT) and ventricular fibrillation (VF). Vulnerability to VT/VF was tested by rapid pacing in eight isolated normal swine right ventricles (RV). The endocardial activation was optically mapped, and the dynamic action potential duration (APD) restitution curves were constructed with metal microelectrodes. At baseline, no VT/VF could be induced. Sildenafil (0.2 μg/ml) or NO donor singly or in combination did not alter VT/VF vulnerability. However, when 2 μg/ml sildenafil was combined with NO donors, the incidence of VT and VF rose significantly ( P < 0.01). VT with a single periodic wavefront was induced in five of eight RVs, and VF with multiple wavefronts was induced in all eight RVs. The sildenafil-NO donor pro-VT/VF combination significantly increased the maximum slope of the APD restitution curve and the amplitude of the APD alternans. The pro-VT/VF effects of sildenafil were reversible after drug-free Tyrode solution perfusion. We conclude that a sildenafil (2 μg/ml) and NO donor combination increases VT/VF vulnerability in the normal RV by a mechanism compatible with the restitution hypothesis.

scholarly journals Nitric oxide impairs Ca2+ activation and slows cross-bridge cycling kinetics in skeletal muscle

2001 ◽  
Vol 91 (5) ◽  
pp. 2233-2239 ◽  
Author(s):  
Leo M. A. Heunks ◽  
Mark J. Cody ◽  
Paige C. Geiger ◽  
P. N. Richard Dekhuijzen ◽  
Gary C. Sieck
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Rate Constant ◽  
Fiber Length ◽  
Psoas Muscle ◽  
Bound State ◽  
No Donor ◽  
Cross Bridge ◽  
Cross Bridges ◽  
Spermine Nonoate

The effects of the nitric oxide (NO) donor spermine NONOate (Sp-NO, 1.0 mM) on cross-bridge recruitment and cross-bridge cycling kinetics were studied in permeabilized rabbit psoas muscle fibers. Fibers were activated at various Ca2+ concentrations (pCa, negative logarithm of Ca2+ concentration), and the pCa at which force was maximal (pCa 4.0) and ∼50% of maximal (pCa50 5.6) were determined. Fiber stiffness was determined using 1-kHz sinusoidal length perturbations, and the fraction of cross bridges in the force-generating state was estimated by the ratio of stiffness during maximal (pCa 4.0) and submaximal (pCa 5.6) Ca2+ activation to stiffness during rigor (at pCa 4.0). Cross-bridge cycling kinetics were evaluated by measuring the rate constant for force redevelopment after quick release (by 15% of optimal fiber length, L o) and restretch of the fiber to L o. Exposing fibers to Sp-NO for 10 min reduced force and the fraction of cross bridges in the force-generating state at maximal and submaximal (pCa50) Ca2+activation. However, the effects of Sp-NO were more pronounced during submaximal Ca2+ activation. Sp-NO also reduced the rate constant for force redevelopment but only during submaximal Ca2+ activation. We conclude that Sp-NO reduces Ca2+ sensitivity by decreasing the number of cross bridges in the strongly bound state and also impairs cross-bridge cycling kinetics during submaximal activation.

Sign in / Sign up

Export Citation Format

Share Document