Role of nitric oxide and cGMP in human septic serum-induced depression of cardiac myocyte contractility

1999 ◽  
Vol 276 (1) ◽  
pp. R265-R276 ◽  
Author(s):  
Anand Kumar ◽  
Rupinder Brar ◽  
Peter Wang ◽  
Linda Dee ◽  
Greg Skorupa ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Septic Shock ◽  
Cardiac Myocytes ◽  
Guanylate Cyclase ◽  
Cardiac Myocyte ◽  
Intracellular Cgmp ◽  
Human Septic Shock ◽  
Tnf Α ◽  
Myocyte Contractility

Previous studies have demonstrated the existence of a circulating myocardial depressant substance during human septic shock. We have recently identified this substance as a synergistic combination of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). This study utilized an in vitro cardiac myocyte assay to evaluate the potential mechanistic role of nitric oxide (NO) and cGMP in depression of myocyte contractility induced by TNF-α, IL-1β, TNF-α + IL-1β (at low concentrations), and human septic shock serum (HSS). TNF-α, IL-1β, TNF-α + IL-1β, and each of 5 sera from patients with acute septic shock caused depression of both maximum extent and peak velocity of cardiac myocyte shortening and an increase in intracellular cGMP concentration during 30 min of exposure (minimum P < 0.01). NO synthetase (NOS) and guanylate cyclase inhibitors such as N-methyl-l-arginine (l-NMA) and methylene blue prevented these effects; an excess ofl-arginine withl-NMA restored them (minimum P < 0.01). In contrast,d-arginine failed to reestablish cytokine-induced myocyte depression and cGMP accumulation prevented byl-NMA. Exposure of myocytes to TNF-α, IL-1β, or TNF-α + IL-1β produced a concentration-dependent increase in intracellular cGMP that paralleled the depression of cardiac myocyte contractility (minimum P < 0.001). In addition, TNF-α, IL-1β, TNF-α + IL-1β, or HSS application to cardiac myocytes resulted in increased NO gas generation, which was inhibited byl-NMA (minimum P < 0.01). Furthermore, unstimulated cardiac myocytes were shown to harbor constitutive but not inducible NOS activity. These data suggest that the sequential generation of NO by a constitutive NOS and cGMP by guanylate cyclase represents an important mechanism of cardiac myocyte depression by TNF-α, IL-1β, TNF-α + IL-1β, and the myocardial depressant substance(s) of septic shock.

Nitric oxide-dependent and -independent mechanisms are involved in TNF-α-induced depression of cardiac myocyte contractility

2007 ◽  
Vol 292 (5) ◽  
pp. R1900-R1906 ◽  
Author(s):  
Anand Kumar ◽  
Bhanu Paladugu ◽  
Joel Mensing ◽  
Aseem Kumar ◽  
Joseph E. Parrillo
Keyword(s):  
Nitric Oxide ◽  
Cardiac Myocytes ◽  
Cardiac Myocyte ◽  
Myocardial Dysfunction ◽  
Tracking System ◽  
Video Tracking ◽  
Neonatal Rat ◽  
Adrenergic Stimulation ◽  
Tnf Α ◽  
Myocyte Contractility

Previous studies have demonstrated the presence of myocardial depression in clinical and experimental septic shock. This response is mediated, in part, through circulating TNF-α-induced, nitric oxide-dependent, depression of basal myocyte contractility. Other mechanisms of early myocardial dysfunction involving decreased response to adrenergic stimulation may exist. This study evaluated the presence and nitric oxide dependence of impaired adrenergic response to TNF-α in in vitro cardiac myocytes. The contraction of electrically paced neonatal rat cardiac myocytes in tissue culture was quantified using a closed-loop video tracking system. TNF-α induced depression of baseline contractility over the first 20 min of cardiac myocyte exposure. This effect was blocked by N-methyl-arginine (NMA), a nitric oxide synthase inhibitor, in all studies. Contractile and cAMP response to increasing concentrations of isoproterenol was deficient in cardiac myocytes exposed to TNF-α regardless of the presence of NMA. In contrast, increasing concentrations of forskolin (a direct stimulant of adenylate cyclase) and dibutyryl cAMP (a metabolically active membrane-soluble analog of cAMP) completely reversed TNF-α-mediated depression, though only in the presence of NMA. Forskolin-stimulated cAMP generation remained intact regardless of NMA. Increasing concentrations of exogenous calcium chloride, unlike other inotropic agents, corrected TNF-α-mediated defects of contractility independent of the presence of NMA. These data suggest that TNF-α exposure is associated with a second nitric oxide-independent but calcium-dependent early depressant mechanism that is manifested by reduced contractile and cAMP response to β-adrenergic stimulation.

scholarly journals Intracellular Growth of Trypanosoma cruzi in Cardiac Myocytes Is Inhibited by Cytokine-Induced Nitric Oxide Release

2004 ◽  
Vol 72 (1) ◽  
pp. 359-363 ◽  
Author(s):  
Laura Edith Fichera ◽  
Maria Cecilia Albareda ◽  
Susana Adriana Laucella ◽  
Miriam Postan
Keyword(s):  
Nitric Oxide ◽  
Trypanosoma Cruzi ◽  
Cardiac Myocytes ◽  
Cardiac Myocyte ◽  
Parasite Growth ◽  
Inos Expression ◽  
No Production ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Ifn Γ

ABSTRACT The effect of interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α), and gamma interferon (IFN-γ) on Trypanosoma cruzi multiplication and nitric oxide (NO) production in cardiac myocytes was investigated. Cardiac myocyte cultures were obtained from neonatal Wistar rat hearts, infected with T. cruzi, and treated with IL-1β, TNF-α, IFN-γ, or N-monomethyl-l-arginine (l-NAME) for 72 h. Parasite growth was calculated from the number of infected cells in Giemsa-stained smears. Nitric oxide production was determined with the Griess reagent. Inducible nitric oxide synthase (iNOS) expression by cardiac myocytes was detected by Western blot. The results showed that the percentages of cardiac myocytes containing T. cruzi amastigotes in cytokine-treated cultures were significantly lower than in nontreated cultures. The addition of l-NAME reversed the inhibitory effect on parasite growth of IL-1β and TNF-α but not of IFN-γ. Nitrite levels released by T. cruzi-infected and noninfected cardiac myocyte cultures after 72 h of stimulation with IL-1β were significantly higher than those produced upon treatment with TNF-α, IFN-γ, or medium alone, regardless of the infection status. Nitrite levels in TNF-α-stimulated infected cultures were significantly higher than in untreated infected cultures and TNF-α-treated noninfected cultures. l-NAME inhibited IL-1β- but not TNF-α-induced NO production, indicating the presence of iNOS-dependent and iNOS-independent mechanisms for NO formation in this experimental system. iNOS expression was detected in infected and noninfected cardiac myocytes stimulated with IL-1 β and TNF-α but not with IFN-γ. These results suggest an important role for cardiac myocytes and locally secreted cytokines in the control of parasite multiplication in T. cruzi-induced myocarditis.

The Role of IL-1, IL-6, TNF-α and MIF in Relative Adrenal Insufficiency in Septic Shock: A Study in Piglet Model

2018 ◽  
Author(s):  
Bina Akura ◽  
Jose Batubara ◽  
Zakiudin Munasir ◽  
Gunati unknown ◽  
Joedo Prihartono ◽  
...  
Keyword(s):  
Septic Shock ◽  
Adrenal Insufficiency ◽  
Relative Adrenal Insufficiency ◽  
Tnf Α

Inhibition of the water channel aquaporin-1 prevents myocardial remodeling by blocking the transmembrane transport of hydrogen peroxide

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
V Montiel ◽  
R Bella ◽  
L Michel ◽  
E Robinson ◽  
J.C Jonas ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Cardiac Hypertrophy ◽  
Cardiac Myocytes ◽  
Cardiac Remodeling ◽  
Cardiac Myocyte ◽  
Water Channel ◽  
Transmembrane Transport ◽  
Funding Source ◽  
Water Pore

Abstract Background Pathological remodeling of the myocardium has long been known to involve oxidant signaling, but so far, strategies using systemic anti-oxidants have generally failed to prevent it. Aquaporins are a family of transmembrane water channels with thirteen isoforms currently known. Some isoforms have been implicated in oxidant signaling. AQP1 is the most abundant aquaporin in cardiovascular tissues but its specific role in cardiac remodeling remains unknown. Purpose We tested the role of AQP1 as a key regulator of oxidant-mediated cardiac remodeling amenable to targeted pharmacological therapy. Methods We used mice with genetic deletion of Aqp1 (and wild-type littermate), as well as primary isolates from the same mice and human iPSC/Engineered Heart Tissue to test the role of AQP1 in pro-hypertrophic signaling. Human cardiac myocyte-specific (PCM1+) expression of AQP's and genes involved in hypertrophic remodeling was studied by RNAseq and bioinformatic GO pathway analysis. Results RNA sequencing from human cardiac myocytes revealed that the archetypal AQP1 is a major isoform. AQP1 expression correlates with the severity of hypertrophic remodeling in patients with aortic stenosis. The AQP1 channel was detected at the plasma membrane of human and mouse cardiac myocytes from hypertrophic hearts, where it colocalizes with the NADPH oxidase-2 (NOX2) and caveolin-3. We show that hydrogen peroxide (H2O2), produced extracellularly, is necessary for the hypertrophic response of isolated cardiac myocytes and that AQP1 facilitates the transmembrane transport of H2O2 through its water pore, resulting in activation of oxidant-sensitive kinases in cardiac myocytes. Structural analysis of the amino acid residues lining the water pore of AQP1 supports its permeation by H2O2. Deletion of Aqp1 or selective blockade of AQP1 intra-subunit pore (with Bacopaside II) inhibits H2O2 transport in mouse and human cells and rescues the myocyte hypertrophy in human induced pluripotent stem cell-derived engineered heart muscle. This protective effect is due to loss of transmembrane transport of H2O2, but not water, through the intra-subunit pore of AQP1. Treatment of mice with clinically-approved Bacopaside extract (CDRI08) inhibitor of AQP1 attenuates cardiac hypertrophy and fibrosis. Conclusion We provide the first demonstration that AQP1 functions as an aqua-peroxiporin in primary rodent and human cardiac parenchymal cells. We show that cardiac hypertrophy is mediated by the transmembrane transport of H2O2 through the AQP1 water channel. Our studies open the way to complement the therapeutic armamentarium with specific blockers of AQP1 for the prevention of adverse remodeling in many cardiovascular diseases leading to heart failure. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): FRS-FNRS, Welbio

Nitric oxide inhibits neutrophil migration by a mechanism dependent on ICAM-1: Role of soluble guanylate cyclase

Nitric Oxide ◽  
2006 ◽  
Vol 15 (1) ◽  
pp. 77-86 ◽  
Author(s):  
Daniela Dal Secco ◽  
Ana P. Moreira ◽  
Andressa Freitas ◽  
João S. Silva ◽  
Marcos A. Rossi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Neutrophil Migration

Abstract 99: Hypotonic Swelling Promotes Nitric Oxide Release in Cardiac Ventricular Myocytes

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Luis Gonano ◽  
Malena Morell ◽  
Juan I Burgos ◽  
Martin Vila Petroff
Keyword(s):  
Nitric Oxide ◽  
Cardiac Myocytes ◽  
Cardiac Myocyte ◽  
Contractile Function ◽  
Cell Swelling ◽  
Contractile Dysfunction ◽  
Ischemia And Reperfusion ◽  
Hypotonic Solution ◽  
No Release ◽  
Hypotonic Swelling

Cardiac myocyte swelling occurs in multiple pathological situations and in particular contributes to the deleterious effects of ischemia and reperfusion by promoting contractile dysfunction. We investigated whether hypotonic swelling promotes nitric oxide (NO) release in cardiac myocytes and if so, whether it impacts on swelling induced contractile dysfunction. Perfusing rat cardiac myocytes, loaded with the NO sensor DAF-FM, with a hypotonic solution (HS; 217 mOsm), increased cell volume, reduced myocyte contraction and Ca2+ transient amplitude and significantly increased DAF-FM fluorescence. When cells were exposed to the HS supplemented with 2.5 mM of the NO synthase inhibitor L-NAME, cell swelling occurred in the absence of NO release. Swelling-induced NO release was also prevented by the NOS1 inhibitor, Nitroguanidine. In addition, Colchicine (an inhibitor of microtubule polymerization) prevented the increase in DAF-FM fluorescence induced by HS indicating that microtubule integrity is necessary for swelling-induced NO release. The swelling-induced negative inotropic effect was exacerbated in the presence of either L-NAME, Nitroguandine or the guanylate cyclase inhibitor, ODQ, suggesting that NOS1-derived NO provides contractile support via a GMP-dependent mechanism. Indeed, ODQ reduced Ca2+ wave velocity and the HS-induced increment in ryanodine receptor (RyR2) phosphorylation at site Ser2808 suggesting that in the context of hypotonic swelling, cGMP may contribute to preserve contractile function by enhancing SR Ca2+ release. Our findings suggest a novel mechanism for NO release in cardiac myocytes with putative pathophysiological relevance in the context of ischemia and reperfusion, where it may be cardioprotective by reducing the extent of contractile dysfunction associated with hypotonic swelling.

Nitric oxide enhancement of erythropoietin production in the isolated perfused rat kidney

1995 ◽  
Vol 269 (4) ◽  
pp. C917-C922 ◽  
Author(s):  
K. Yoshioka ◽  
J. W. Fisher
Keyword(s):  
Nitric Oxide ◽  
Rat Kidney ◽  
Mrna Levels ◽  
Isolated Perfused Rat Kidney ◽  
Intracellular Cgmp ◽  
Perfused Rat Kidney ◽  
Arterial Po2

We have previously reported that nitric oxide (NO) and guanosine 3',5'-cyclic monophosphate (cGMP) may be involved in the regulation of erythropoietin (Epo) production in response to hypoxia both in vivo and in vitro (20). In the present studies, we have used the isolated perfused rat kidney to assess the role of NO in oxygen sensing and Epo production. When arterial PO2 was reduced from 100 mmHg (normoxemic) to 30 mmHg (hypoxemic) in the perfusate of this system, perfusate levels of Epo were significantly increased. This hypoxia-induced increase in Epo production was significantly decreased by the addition of NG-nitro-L-arginine methyl ester (L-NAME; 1 mM) to the perfusates. Hypoxemic perfusion also produced a significant increase, and L-NAME significantly inhibited this increase, in intracellular cGMP levels in the kidney when compared with normoxemic perfused kidneys. Quantitative reverse transcription-polymerase chain reaction also revealed that hypoxemic perfusion produced significant increases in Epo mRNA levels in the kidney, which was blocked by L-NAME. Our findings further support an important role for the NO/cGMP system in hypoxic regulation of Epo production.

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