Molecular and pharmacological approaches to inhibiting nitric oxide after burn trauma

2003 ◽  
Vol 285 (4) ◽  
pp. H1616-H1625 ◽  
Author(s):  
Jean White ◽  
Deborah L. Carlson ◽  
Marita Thompson ◽  
David L. Maass ◽  
Billy Sanders ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cardiac Function ◽  
Total Body Surface Area ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Contractile Dysfunction ◽  
Wild Type ◽  
Burn Trauma ◽  
Cardiac Contractile ◽  
Cardiac Contractile Dysfunction

Whereas controversial, several studies have suggested that nitric oxide (NO) alters cardiac contractility via cGMP, peroxynitrite, or poly(ADP ribose) synthetase (PARS) activation. This study determined whether burn-related upregulation of myocardial inducible NO synthase (iNOS) and NO generation contributes to burn-mediated cardiac contractile dysfunction. Mice homozygous null for the iNOS gene (iNOS knockouts) were obtained from Jackson Laboratory. iNOS knockouts (KO) as well as wild-type mice were given a cutaneous burn over 40% of the total body surface area by the application of brass probes (1 × 2 × 0.3 cm) heated to 100°C to the animals' sides and back for 5 s (iNOS/KO burn and wild-type burn). Additional groups of iNOS KO and wild-type mice served as appropriate sham burn groups (iNOS/KO sham and wild-type sham). Cardiac function was assessed 24 h postburn by perfusing hearts ( n = 7–10 mice/group). Burn trauma in wild-type mice impaired cardiac function as indicated by the lower left ventricular pressure (LVP, 67 ± 2 mmHg) compared with that measured in wild-type shams (94 ± 2 mmHg, P < 0.001), a lower rate of LVP rise (+dP/d tmax, 1,620 ± 94 vs. 2,240 ± 58 mmHg/s, P < 0.001), and a lower rate of LVP fall (–dP/d tmax, 1,200 ± 84 vs. 1,800 ± 42 mmHg/s, P < 0.001). Ventricular function curves confirmed significant contractile dysfunction after burn trauma in wild-type mice. Burn trauma in iNOS KO mice produced fewer cardiac derangements compared with those observed in wild-type burns (LVP: 78 ± 5 mmHg; +dP/d t: 1,889 ± 160 mmHg/s; –dP/d t: 1,480 ± 154 mmHg/s). The use of a pharmacological approach to inhibit iNOS (aminoguanidine, given ip) in additional wild-type shams and burns confirmed the iNOS KO data. Whereas the absence of iNOS attenuated burn-mediated cardiac contractile dysfunction, these experiments did not determine the contribution of cardiac-derived NO versus NO generated by immune cells. However, our data indicate a role for NO in cardiac dysfunction after major trauma.

scholarly journals Feeding the fibrillating heart: Dichloroacetate improves cardiac contractile dysfunction following VF

2015 ◽  
Vol 309 (9) ◽  
pp. H1543-H1553 ◽  
Author(s):  
Mohammed Ali Azam ◽  
Cory S. Wagg ◽  
Stéphane Massé ◽  
Talha Farid ◽  
Patrick F. H. Lai ◽  
...  
Keyword(s):  
Glucose Oxidation ◽  
Contractile Function ◽  
Lactate Production ◽  
Left Ventricular ◽  
Global Ischemia ◽  
Contractile Dysfunction ◽  
Anaerobic Glycolysis ◽  
Cardiac Contractile Function ◽  
Cardiac Contractile ◽  
Cardiac Contractile Dysfunction

Ventricular fibrillation (VF) is an important cause of sudden cardiac arrest following myocardial infarction. Following resuscitation from VF, decreased cardiac contractile function is a common problem. During and following myocardial ischemia, decreased glucose oxidation, increased anaerobic glycolysis for cardiac energy production are harmful and energetically expensive. The objective of the present study is to determine the effects of dichloroacetate (DCA), a glucose oxidation stimulator, on cardiac contractile dysfunction following ischemia-induced VF. Male Sprague-Dawley rat hearts were Langendorff perfused in Tyrode's buffer. Once stabilized, hearts were subjected to 15 min of global ischemia and 5 min of aerobic reperfusion in the presence or absence of DCA. At the 6th min of reperfusion, VF was induced electrically, and terminated. Left ventricular (LV) pressure was measured using a balloon. Pretreatment with DCA significantly improved post-VF left ventricular developed pressure (LVDP) and dp/d tmax. In DCA-pretreated hearts, post-VF lactate production and pyruvate dehydrogenase (PDH) phosphorylation were significantly reduced, indicative of stimulated glucose oxidation, and inhibited anaerobic glycolysis by activation of PDH. Epicardial NADH fluorescence was increased during global ischemia above preischemic levels, but decreased below preischemia levels following VF, with no differences between nontreated controls and DCA-pretreated hearts, whereas DCA pretreatment increased NADH production in nonischemic hearts. With exogenous fatty acids (FA) added to the perfusion solution, DCA pretreatment also resulted in improvements in post-VF LVDP and dp/d tmax, indicating that the presence of exogenous FA did not affect the beneficial actions of DCA. In conclusion, enhancement of PDH activation by DCA mitigates cardiac contractile dysfunction following ischemia-induced VF.

scholarly journals Conditional increase in SERCA2a protein is able to reverse contractile dysfunction and abnormal calcium flux in established diabetic cardiomyopathy

2008 ◽  
Vol 295 (5) ◽  
pp. R1439-R1445 ◽  
Author(s):  
Jorge Suarez ◽  
Brian Scott ◽  
Wolfgang H. Dillmann
Keyword(s):  
Cardiac Function ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Contractility ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Calcium Flux ◽  
Calcium Handling ◽  
Contractile Dysfunction ◽  
Diabetic Mice ◽  
Perfused Heart

Diabetic cardiomyopathy is characterized by reduced cardiac contractility independent of vascular disease. A contributor to contractile dysfunction in the diabetic heart is impaired sarcoplasmic reticulum function with reduced sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2a) pump activity, leading to disturbed intracellular calcium handling. It is currently unclear whether increasing SERCA2a activity in hearts with existing diabetic cardiomyopathy could still improve calcium flux and contractile performance. To test this hypothesis, we generated a cardiac-specific tetracycline-inducible double transgenic mouse, which allows for doxycycline (DOX)-based inducible SERCA2a expression in which DOX exposure turns on SERCA2a expression. Isolated cardiomyocytes and Langendorff perfused hearts from streptozotocin-induced diabetic mice were studied. Our results show that total SERCA2a protein levels were decreased in the diabetic mice by 60% compared with control. SERCA2a increased above control values in the diabetic mice after DOX. Dysfunctional contractility in the diabetic cardiomyocyte was restored to normal by induction of SERCA2a expression. Calcium transients from diabetic cardiomyocytes showed a delayed rate of diastolic calcium decay of 66%, which was reverted toward normal after SERCA2a expression induced by DOX. Global cardiac function assessed in the diabetic perfused heart showed diminished left ventricular pressure, rate of contraction, and relaxation. These parameters were returned to control values by SERCA2a expression. In conclusion, we have used mice allowing for inducible expression of SERCA2a and could demonstrate that increased expression of SERCA2a leads to improved cardiac function in mice with an already established diabetic cardiomyopathy in absence of detrimental effects.

scholarly journals IκB overexpression in cardiomyocytes prevents NF-κB translocation and provides cardioprotection in trauma

2003 ◽  
Vol 284 (3) ◽  
pp. H804-H814 ◽  
Author(s):  
Deborah L. Carlson ◽  
D. Jean White ◽  
David L. Maass ◽  
Robin C. Nguyen ◽  
Brett Giroir ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cardiac Tissue ◽  
Nuclear Translocation ◽  
Total Body Surface Area ◽  
Nuclear Factor Κb ◽  
Cardiac Performance ◽  
Wild Type ◽  
Burn Trauma ◽  
Tnf Α ◽  
Cardiac Contractile Dysfunction

This study examined the effects of either IκBα overexpression (transgenic mice) or N-acetyl-leucinyl-leucinyl-norleucinal (ALLN) administration (proteosome inhibitor in wild-type mice) on cardiomyocyte secretion of tumor necrosis factor-α (TNF-α) and on cardiac performance after burn trauma. Transgenic mice were divided into four experimental groups. IκBα overexpressing mice were given a third-degree scald burn over 40% of the total body surface area or wild-type littermates were given either a scald or sham burn to provide appropriate controls. Pharmacological studies included ALLN (20 mg/kg) administration in either burned wild-type mice or wild-type shams. Burn trauma in wild-type mice promoted nuclear factor-κB (NF-κB) nuclear translocation, cardiomyocyte secretion of TNF-α, and impaired cardiac performance. IκBα overexpression or ALLN treatment of burn trauma prevented NF-κB activation in cardiac tissue, prevented cardiomyocyte secretion of TNF-α, and ablated burn-mediated cardiac contractile dysfunction. These data suggest that NF-κB activation and inflammatory cytokine secretion play a significant role in postburn myocardial abnormalities.

NITRIC OXIDE SYNTHASE IS NOT INVOLVED IN CARDIAC CONTRACTILE DYSFUNCTION IN A RAT MODEL OF ENDOTOXEMIA WITHOUT SHOCK

Shock ◽  
1997 ◽  
Vol 7 (2) ◽  
pp. 111-118 ◽  
Author(s):  
Xianzhong Meng ◽  
Lihua Ao ◽  
James M. Brown ◽  
Dave A. Fullerton ◽  
Anirban Banerjee ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Rat Model ◽  
Contractile Dysfunction ◽  
Cardiac Contractile ◽  
Cardiac Contractile Dysfunction ◽  
Oxide Synthase

Protein kinase C-ζ inhibition exerts cardioprotective effects in ischemia-reperfusion injury

2005 ◽  
Vol 289 (2) ◽  
pp. H898-H907 ◽  
Author(s):  
Aisha Phillipson ◽  
Ellen E. Peterman ◽  
Philip Taormina ◽  
Margaret Harvey ◽  
Richard J. Brue ◽  
...  
Keyword(s):  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Peptide Inhibitor ◽  
Contractile Dysfunction ◽  
Cardiac Contractile ◽  
No Release ◽  
Cardiac Contractile Dysfunction ◽  
Cardioprotective Effects ◽  
Pkc Ζ ◽  
Superoxide Release

Ischemia followed by reperfusion (I/R) in the presence of polymorphonuclear leukocytes (PMNs) results in marked cardiac contractile dysfunction. A cell-permeable PKC-ζ peptide inhibitor was used to test the hypothesis that PKC-ζ inhibition could attenuate PMN-induced cardiac contractile dysfunction by suppression of superoxide production from PMNs and increase nitric oxide (NO) release from vascular endothelium. The effects of the PKC-ζ peptide inhibitor were examined in isolated ischemic (20 min) and reperfused (45 min) rat hearts reperfused with PMNs. The PKC-ζ inhibitor (2.5 or 5 μM, n = 6) significantly attenuated PMN-induced cardiac dysfunction compared with I/R hearts ( n = 6) receiving PMNs alone in left ventricular developed pressure (LVDP) and the maximal rate of LVDP (+dP/d tmax) cardiac function indexes ( P < 0.01), and these cardioprotective effects were blocked by the NO synthase inhibitor, NG-nitro-l-arginine methyl ester (50 μM). Furthermore, the PKC-ζ inhibitor significantly increased endothelial NO release 47 ± 2% (2.5 μM, P < 0.05) and 54 ± 5% (5 μM, P < 0.01) over basal values from the rat aorta and significantly inhibited superoxide release from phorbol-12-myristate-13-acetate-stimulated rat PMNs by 33 ± 12% (2.5 μM) and 40 ± 8% (5 μM) ( P < 0.01). The PKC-ζ inhibitor significantly attenuated PMN infiltration into the myocardium by 46–48 ± 4% ( P < 0.01) at 2.5 and 5 μM, respectively. In conclusion, these results suggest that the PKC-ζ peptide inhibitor attenuates PMN-induced post-I/R cardiac contractile dysfunction by increasing endothelial NO release and by inhibiting superoxide release from PMNs thereby attenuating PMN infiltration into I/R myocardium.

Utrophin deficiency worsens cardiac contractile dysfunction present in dystrophin-deficient mdx mice

2005 ◽  
Vol 289 (6) ◽  
pp. H2373-H2378 ◽  
Author(s):  
Paul M. L. Janssen ◽  
Nitisha Hiranandani ◽  
Tessily A. Mays ◽  
Jill A. Rafael-Fortney
Keyword(s):  
Clinical Signs ◽  
Tissue Level ◽  
Mdx Mice ◽  
Contractile Dysfunction ◽  
Muscle Degeneration ◽  
Wild Type ◽  
Adrenergic Stimulation ◽  
Double Knockout ◽  
Cardiac Contractile ◽  
Cardiac Contractile Dysfunction

The loss of dystrophin in patients with Duchenne muscular dystrophy (DMD) causes devastating skeletal muscle degeneration and cardiomyopathy. Dystrophin-deficient ( mdx) mice have a much milder phenotype, whereas double knockout (DKO) mice lacking both dystrophin and its homolog, utrophin, exhibit the clinical signs observed in DMD patients. We have previously shown that DKO and mdx mice have similar severities of histological features of cardiomyopathy, but no contractile functional measurements of DKO heart have ever been carried out. To investigate whether DKO mice display cardiac dysfunction at the tissue level, contractile response of the myocardium was tested in small, unbranched, ultrathin, right ventricular muscles. Under near physiological conditions, peak isometric active developed tension (Fdev, in mN/mm2) at a stimulation frequency of 4 Hz was depressed in DKO mice (15.3 ± 3.7, n = 8) compared with mdx mice (24.2 ± 5.4, n = 7), which in turn were depressed compared with wild-type (WT) control mice (33.2 ± 4.5, n = 7). This reduced Fdev was also observed at frequencies within the murine physiological range; at 12 Hz, Fdev was (in mN/mm2) 11.4 ± 1.8 in DKO, 14.5 ± 4.2 in mdx, and 28.8 ± 5.4 in WT mice. The depression of Fdev was observed over the entire frequency range of 4–14 Hz and was significant between DKO versus mdx mice, as well as between DKO or mdx mice versus WT mice. Under β-adrenergic stimulation (1 μmol/l isoproterenol), Fdev in DKO preparations was only (in mN/mm2) 14.7 ± 5.1 compared with 30.9 ± 8.9 in mdx and 41.0 ± 4.9 in WT mice. These data show that cardiac contractile dysfunction of mdx mice is generally worsened in mice also lacking utrophin.

Gender-related differences in myocardial inflammatory and contractile responses to major burn trauma

2004 ◽  
Vol 286 (1) ◽  
pp. H202-H213 ◽  
Author(s):  
Jureta W. Horton ◽  
D. Jean White ◽  
David L. Maass
Keyword(s):  
Burn Injury ◽  
Inflammatory Responses ◽  
Total Body Surface Area ◽  
Left Ventricular Pressure ◽  
Experimental Models ◽  
Left Ventricular ◽  
Female Rats ◽  
Sprague Dawley ◽  
Burn Trauma ◽  
Major Burn

Gender-related differences in immune responses to hemorrhage and sepsis have been described. However, most trauma studies continue to limit experimental models to males to avoid the variable responses associated with hormonal fluctuation in proestrus/estrus females. In the present study, male and female (either diestrus or proestrus/estrus) Sprague-Dawley rats (250–325 g) were given a third-degree scald burn over 40% total body surface area and fluid resuscitated (4 ml/kg per %burn of lactated Ringer solution); sham burn males and diestrus as well as sham burn proestrus/estrus female rats were included to provide controls. Twenty-four hours postburn, hearts were either perfused to examine mechanical function (Langendorff, n = 8 to 9 hearts/group) or to prepare cardiomyocytes (collagenase digestion, n = 4 to 5 hearts/group). Left ventricular developed pressure and the positive and negative first derivative of left ventricular pressure responses to increases in preload were significantly lower in burned males compared with responses measured in either burned proestrus/estrus or burned diestrus females; burn trauma increased cardiomyocyte secretion of tumor necrosis factor-α, interleukin-1β, and nitric oxide to a lesser extent in proestrus/estrus females than levels secreted by either diestrus females or males. Similarly, myocytes from proestrus/estrus females accumulated significantly less sodium/calcium compared with values measured in males ( P < 0.05). Our data confirm gender-related differences in myocardial function and myocardial inflammatory responses to burn injury.

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