scholarly journals Exercise training induces eNOS coupling and restores relaxation in coronary arteries of heart failure rats

2018 ◽  
Vol 314 (4) ◽  
pp. H878-H887 ◽  
Author(s):  
Gisele K. Couto ◽  
Suliana M. Paula ◽  
Igor L. Gomes-Santos ◽  
Carlos Eduardo Negrão ◽  
Luciana V. Rossoni
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Heart Failure ◽  
Exercise Training ◽  
Coronary Arteries ◽  
Guanylyl Cyclase ◽  
Soluble Guanylyl Cyclase ◽  
No Production ◽  
Gtp Cyclohydrolase ◽  
No Bioavailability

Exercise training (ET) has emerged as a nonpharmacological therapy for cardiovascular diseases because of its helpful milieu for improving vascular function. The aim of the present study was to assess whether ET reverses the alterations in vascular reactivity observed in heart failure (HF)-related coronary arteries and to elucidate the molecular mechanisms involved in these adjustments. Male Wistar rats were subjected to either coronary artery ligation or sham operation. Four weeks after the surgery, rats were divided into two groups: untrained HF (UHF) and exercise-trained HF (THF). ET was conducted on a treadmill for 8 wk. An untrained SO group was included in the study as a normal control. ET restored the impaired acetylcholine (ACh)- and sodium nitroprusside-induced relaxation in coronary arteries to levels of the control. Oxidative stress and reduced nitric oxide (NO) production were observed in UHF, whereas ET restored both parameters to the levels of the control. Expression levels of endothelial NO synthase (eNOS) and soluble guanylyl cyclase subunits were increased in coronary arteries of UHF rats but reduced in THF rats. Tetrahydrobiopterin restored ACh-induced NO production in the UHF group, indicating that eNOS was uncoupled. ET increased the eNOS dimer-to-monomer ratio and expression of GTP cyclohydrolase 1, thus increasing NO bioavailability. Taken together, these findings demonstrate that ET reverses the dysfunction of the NO/soluble guanylyl cyclase pathway present in coronary arteries of HF rats. These effects of ET are associated with increased GTP cyclohydrolase 1 expression, restoration of NO bioavailability, and reduced oxidative stress through eNOS coupling. NEW & NOTEWORTHY The present study provides a molecular basis for the exercise-induced improvement in coronary arteries function in heart failure. Increasing the expression of GTP cyclohydrolase 1, the rate-limiting enzyme in the de novo biosynthesis of tetrahydrobiopterin, exercise training couples endothelial nitric oxide synthase, reduces oxidative stress, and increases nitric oxide bioavailability and sensitivity in coronary arteries of heart failure rats.

Maturational changes in the regulation of pulmonary vascular tone by nitric oxide in neonatal rats

2007 ◽  
Vol 293 (5) ◽  
pp. L1261-L1270 ◽  
Author(s):  
Louis G. Chicoine ◽  
Michael L. Paffett ◽  
Mark R. Girton ◽  
Matthew J. Metropoulus ◽  
Mandar S. Joshi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Guanylyl Cyclase ◽  
Vascular Tone ◽  
Age Groups ◽  
Soluble Guanylyl Cyclase ◽  
No Production ◽  
Sprague Dawley ◽  
No Donor ◽  
Early Postnatal Development ◽  
Old Rats

Nitric oxide (NO) is an important regulator of vasomotor tone in the pulmonary circulation. We tested the hypothesis that the role NO plays in regulating vascular tone changes during early postnatal development. Isolated, perfused lungs from 7- and 14-day-old Sprague-Dawley rats were studied. Baseline total pulmonary vascular resistance (PVR) was not different between age groups. The addition of KCl to the perfusate caused a concentration-dependent increase in PVR that did not differ between age groups. However, the nitric oxide synthase (NOS) inhibitor Nω-nitro-l-arginine augmented the K+-induced increase in PVR in both groups, and the effect was greater in lungs from 14-day-old rats vs. 7-day-old rats. Lung levels of total endothelial, inducible, and neuronal NOS proteins were not different between groups; however, the production rate of exhaled NO was greater in lungs from 14-day-old rats compared with those of 7-day-old rats. Vasodilation to 0.1 μM of the NO donor spermine NONOate was greater in 14-day lungs than in 7-day lungs, and lung levels of both soluble guanylyl cyclase and cGMP were greater at 14 days than at 7 days. Vasodilation to 100 μM of the cGMP analog 8-(4-chlorophenylthio)guanosine-3′,5′-cyclic monophosphate was greater in 7-day lungs than in 14-day lungs. Our results demonstrate that the pulmonary vascular bed depends more on NO production to modulate vascular tone at 14 days than at 7 days of age. The observed differences in NO sensitivity may be due to maturational increases in soluble guanylyl cyclase protein levels.

TNF-alpha and IFN-gamma induce expression of nitric oxide synthase in cultured rat medullary interstitial cells

1995 ◽  
Vol 269 (2) ◽  
pp. F212-F217 ◽  
Author(s):  
K. S. Lau ◽  
O. Nakashima ◽  
G. R. Aalund ◽  
L. Hogarth ◽  
K. Ujiie ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Nitric Oxide Synthase ◽  
Vascular Smooth Muscle ◽  
Guanylyl Cyclase ◽  
Soluble Guanylyl Cyclase ◽  
Tnf Alpha ◽  
No Production ◽  
Ifn Gamma ◽  
Oxide Synthase

Cytokines increase the expression of the inducible (type II) nitric oxide synthase (NOS) in macrophages, liver, and renal epithelial cells. Previously, we found that cultured rat medullary interstitial cells (RMIC) contain high levels of soluble guanylyl cyclase. To determine whether these cells can also produce NO, we studied the effects of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) on NO production, NOS II mRNA, and NOS II protein expression. Both TNF-alpha and IFN-gamma, in the presence of a low concentration of the other cytokine, caused dose-dependent increases in NO production. Exposure to TNF-alpha and IFN-gamma stimulated the production of NOS II mRNA, as determined by Northern blotting. Restriction mapping of reverse transcription-polymerase chain reaction products indicated that normal cells contained macrophage NOS II, whereas cytokine-stimulated cells contained primarily vascular smooth muscle NOS II and some macrophage NOS II. The appearance of NOS II protein was demonstrated by Western blotting. RMIC cell guanosine 3',5'-cyclic monophosphate accumulation increased 129-fold in response to the cytokines. NOS inhibitors decreased nitrite production. We conclude that 1) TNF-alpha and IFN-gamma induce the expression of vascular smooth muscle NOS II and production of NO in RMIC, and 2) NO acts as an autocrine activator of the soluble guanylyl cyclase in RMIC.

Endothelium-derived NO, but not cyclic GMP, is required for hypoxic augmentation in isolated porcine coronary arteries

2011 ◽  
Vol 301 (6) ◽  
pp. H2313-H2321 ◽  
Author(s):  
Calvin K. Y. Chan ◽  
Judith Mak ◽  
Yuansheung Gao ◽  
Ricky Y. K. Man ◽  
Paul M. Vanhoutte
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase ◽  
Coronary Arteries ◽  
Cyclic Gmp ◽  
Guanylyl Cyclase ◽  
Calcium Influx ◽  
Soluble Guanylyl Cyclase ◽  
Isometric Tension ◽  
Nitric Oxide Donor ◽  
Atpase Inhibitor

The present study investigated the mechanism underlying the transient potentiation of vasoconstriction by hypoxia in isolated porcine coronary arteries. Isometric tension was measured in rings with or without endothelium. Hypoxia (Po2 <30 mmHg) caused a transient further increase in tension (hypoxic augmentation) in contracted (with U46619) preparations. The hypoxic response was endothelium dependent and abolished by inhibitors of nitric oxide synthase [ Nω-nitro-l-arginine methyl ester (l-NAME)] or soluble guanylyl cyclase (ODQ and NS2028). The addition of DETA NONOate (nitric oxide donor) in the presence of l-NAME restored the hypoxic augmentation, suggesting the involvement of the nitric oxide pathway. However, the same was not observed after incubation with 8-bromo-cyclic GMP, atrial natriuretic peptide, or isoproterenol. Assay of the cyclic GMP content showed no change upon exposure to hypoxia in preparations with and without endothelium. Incubation with protein kinase G and protein kinase A inhibitors did not inhibit the hypoxic augmentation. Thus the hypoxic augmentation is dependent on nitric oxide and soluble guanylyl cyclase but independent of cyclic GMP. The hypoxic augmentation persisted in calcium-free buffer and in the presence of nifedipine, ruling out a role for extracellular calcium influx. Hypoxia did not alter the intracellular calcium concentration, as measured by confocal fluorescence microscopy. This observation and the findings that hypoxic augmentation is enhanced by thapsigargin (sarco/endoplasmic reticulum calcium ATPase inhibitor) and inhibited by HA1077 or Y27632 (Rho kinase inhibitors) demonstrate the involvement of calcium sensitization in the phenomenon.

Abstract 16763: Mechanical Circulatory Support Promotes Myocardial Nitric Oxide Signaling in Heart Failure Patients

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
David J Polhemus ◽  
Ya-Xiong Tao ◽  
Steven C Koenig ◽  
Sumanth D Prabhu ◽  
David Lefer
Keyword(s):  
Nitric Oxide ◽  
Heart Failure ◽  
Soluble Guanylyl Cyclase ◽  
Left Ventricular ◽  
Circulatory Support ◽  
Nitric Oxide Signaling ◽  
Protein Levels ◽  
Patients With Heart Failure ◽  
No Bioavailability ◽  
Preclinical Animal Models

Introduction: The integrity of the cardiovascular system is dependent on the continuous generation of nitric oxide (NO). Reduction in NO bioavailability is central to the development of cardiovascular disorders and patients with heart failure (HF) exhibit blunted endothelium-dependent flow-mediated dilation in indicating diminished NO release. We have previously reported that patients with heart failure have marked reductions in circulating NO metabolites and that NO-based therapies significantly reverse left ventricular (LV) dysfunction in preclinical animal models of HF. Methods: Plasma and left ventricular (LV) tissue were collected in HF patients (n=10) at the time of left ventricular assist device (LVAD) implantation. Plasma and LV tissue were again collected in the same 10 patients at the time of cardiac transplantation. Plasma and cardiac nitrite concentrations were determined by ion chromatography methods and nitrosylated protein (RXNO) levels were measured by chemiluminescence detection. Cyclic guanosine 5’-monophosphate (cGMP) was analyzed using radioimmunoassay technique. Results: Results: Following LVAD implantation, RXNO (NO-bound protein) levels were significantly elevated in both circulation and in the LV (10.2 nM vs. 33.3 nM, p < 0.05). Downstream NO signaling activates soluble guanylyl cyclase to form cGMP. Interestingly, LV cGMP levels were significantly augmented post-LVAD implantation (p<0.01). In contrast, plasma and cardiac nitrite (NO2) levels remained unchanged. Conclusions: These data strongly suggest that cardiovascular remodeling accompanying LVAD implantation promotes endothelial nitric oxide synthase (eNOS) function and increases NO bioavailability and signaling.

Abstract 227: Activity of Soluble Guanylyl Cyclase, the Nitric Oxide Receptor, is Modulated by Cysteines Redox

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Samba Couloubaly ◽  
Nazish Sayed ◽  
Jamila Hedhli ◽  
Padmamalini Baskaran ◽  
Annie Beuve
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Smooth Muscle ◽  
Guanylyl Cyclase ◽  
Vascular Reactivity ◽  
Mutational Analysis ◽  
Soluble Guanylyl Cyclase ◽  
Cellular Level ◽  
In The Wild ◽  
Redox Sensing

The enzyme soluble guanylyl cyclase (sGC) increases cellular level of the second messenger cGMP upon stimulation by nitric oxide (NO), whose role is exemplified in the cardiovascular system where it governs smooth muscle cell proliferation, vascular relaxation and platelet aggregation. Various pathologies like diabetes, hypertension and hypercholesterolemia are associated with enhanced oxidative stress with increased formation of reactive oxygen (ROS) and nitrogen species (RNS). We recently showed that cysteines beta1C243 and beta1C122 are S-nitrosylated in sGC leading to its desensitization. We have now identified by Mass Spectrometry, two additional cysteines (beta1C571 and alpha1C516) as potentially modified. Our hypothesis is that loss in vascular reactivity in oxidative pathologies is mediated, in part, by desensitization of sGC via thiols oxidation. We studied the effect of oxidative stress on sGC in primary vascular smooth muscle cells (VSMC) by directly exposing them to hydrogen peroxide (H2O2) in the absence or presence of a catalase inhibitor Amino-Triazole (AT). H2O2 induced inhibition of NO-stimulated sGC activity in VSMC and in COS 7 cells transiently transfected with sGC. Desensitization of sGC was further increased in VSMC treated with both H2O2 and AT. Next, we conducted mutational analysis of the 4 cysteines to assess their involvement in redox sensing. Replacement of C571 and C122 eliminated the oxidative-dependent desensitization observed in the wild-type. In addition, peroxynitrite, a strong oxidant, inhibited the NO-stimulated sGC activity in a purified system without oxidation of the heme. In conclusion, our results suggest that sGC activity is directly modulated by the redox state of the cells. Moreover, the identified 4 cysteines can be modified by both ROS and RNS suggesting a complex modulation. Ultimately, our goal is to determine whether loss of vascular reactivity in oxidative pathophysiologies is in part mediated by desensitization of sGC and what are the involved cysteines. This work was supported by NIH GM067640, HL089771.

scholarly journals Modulation of Vasodilator Response via the Nitric Oxide Pathway after Acute Methyl Mercury Chloride Exposure in Rats

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
S. Omanwar ◽  
B. Saidullah ◽  
K. Ravi ◽  
M. Fahim
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Methyl Mercury ◽  
Vascular Reactivity ◽  
Mercury Chloride ◽  
No Production ◽  
Vasodilator Response ◽  
No Bioavailability ◽  
Chloride Treatment ◽  
Oxide Synthase

Mercury exposure induces endothelial dysfunction leading to loss of endothelium-dependent vasorelaxation due to decreased nitric oxide (NO) bioavailability via increased oxidative stress. Our aim was to investigate whether acute treatment with methyl mercury chloride changes the endothelium-dependent vasodilator response and to explore the possible mechanisms behind the observed effects. Wistar rats were treated with methyl mercury chloride (5 mg/kg,po.). The methyl mercury chloride treatment resulted in an increased aortic vasorelaxant response to acetylcholine (ACh). In methyl-mercury-chloride-exposed rats, the % change in vasorelaxant response of ACh in presence of Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME;10-4 M) was significantly increased, and in presence of glybenclamide (10-5 M), the response was similar to that of untreated rats, indicating the involvement of NO and not of endothelium-derived hyperpolarizing factor (EDHF). In addition, superoxide dismutase (SOD) + catalase treatment increased the NO modulation of vasodilator response in methyl-mercury-chloride-exposed rats. Our results demonstrate an increase in the vascular reactivity to ACh in aorta of rats acutely exposed to methyl mercury chloride. Methyl mercury chloride induces nitric oxide synthase (NOS) and increases the NO production along with inducing oxidative stress without affecting the EDHF pathway.

Further attenuation of endothelium-dependent relaxation imparted by natriuretic peptide receptor antagonism

1999 ◽  
Vol 277 (4) ◽  
pp. H1618-H1621 ◽  
Author(s):  
Paul W. Wennberg ◽  
Virginia M. Miller ◽  
Ton Rabelink ◽  
John C. Burnett
Keyword(s):  
Endothelial Cells ◽  
Natriuretic Peptide ◽  
Coronary Arteries ◽  
Guanylyl Cyclase ◽  
Soluble Guanylyl Cyclase ◽  
No Production ◽  
Natriuretic Peptide Receptor ◽  
Peptide Receptor ◽  
Peptide System ◽  
Endothelium Dependent Relaxation

Nitric oxide (NO) is an important endothelium-derived relaxing factor that functions via activation of soluble guanylyl cyclase and cGMP generation in vascular smooth muscle. Recently, studies have described the synthesis and secretion of C-type natriuretic peptide (CNP) from endothelial cells. This peptide also mediates relaxation via cGMP but through activation of particulate guanylyl cyclase. We tested the hypothesis that endothelium-dependent relaxations to acetylcholine or bradykinin in isolated canine coronary arteries involve both releases of NO and CNP. Rings of canine coronary arteries were incubated with either inhibitors of NO production ( N G-monomethyl-l-arginine,l-NMMA) or the natriuretic peptide receptor antagonist HS-142-1. CNP caused concentration-dependent relaxations of rings with and without endothelium. These relaxations were attenuated by HS-142-1. Relaxations to acetylcholine and bradykinin were attenuated byl-NMMA alone but not attenuated by HS-142-1 alone. Coinhibition withl-NMMA and HS-142-1 significantly inhibited acetylcholine- and bradykinin-induced relaxation to a magnitude greater than either inhibitor alone. In summary, a novel interaction between the NO and the natriuretic peptide system is demonstrated by increased attenuation of endothelium-dependent relaxations to acetylcholine and bradykinin when both NO synthase and natriuretic peptide receptors are inhibited. These investigations support the concept of release of multiple endothelium-derived factors in response to acetylcholine- and bradykinin-receptor stimulation in endothelial cells, which may include CNP, as well as NO.

scholarly journals Cyclic Guanosine Monophosphate Modulates Locomotor Acceleration Induced by Nitric Oxide but not Serotonin in Clione limacina Central Pattern Generator Swim Interneurons

2020 ◽  
Author(s):  
Thomas J Pirtle ◽  
Richard A Satterlie
Keyword(s):  
Nitric Oxide ◽  
Central Pattern Generator ◽  
Guanylyl Cyclase ◽  
Signal Transduction Pathway ◽  
Soluble Guanylyl Cyclase ◽  
Cyclic Guanosine Monophosphate ◽  
Pattern Generator ◽  
Guanosine Monophosphate ◽  
Cellular Changes ◽  
Clione Limacina

Abstract Typically, the marine mollusk, Clione limacina, exhibits a slow, hovering locomotor gait to maintain its position in the water column. However, the animal exhibits behaviorally relevant locomotor swim acceleration during escape response and feeding behavior. Both nitric oxide and serotonin mediate this behavioral swim acceleration. In this study, we examine the role that the second messenger, cGMP, plays in mediating nitric oxide and serotonin-induced swim acceleration. We observed that the application of an analog of cGMP or an activator of soluble guanylyl cyclase increased fictive locomotor speed recorded from Pd-7 interneurons of the animal’s locomotor central pattern generator. Moreover, inhibition of soluble guanylyl cyclase decreased fictive locomotor speed. These results suggest that basal levels of cGMP are important for slow swimming and that increased production of cGMP mediates swim acceleration in Clione. Because nitric oxide has its effect through cGMP signaling and because we show herein that cGMP produces cellular changes in Clione swim interneurons that are consistent with cellular changes produced by serotonin application, we hypothesize that both nitric oxide and serotonin function via a common signal transduction pathway that involves cGMP. Our results show that cGMP mediates nitric oxide-induced but not serotonin-induced swim acceleration in Clione.

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