S-Methylisothiourea Inhibits Inducible Nitric Oxide Synthase and Improves Left Ventricular Performance after Acute Myocardial Infarction

Wildhirt, Stephen M.; Suzuki, Hiroshi; Wolf, Wolf-Peter; Dudek, R.; Horstman, Damian J.; Weismueller, Susanne; Reichart, Bruno

doi:10.1006/bbrc.1996.1509

Cited by 42 publications

(31 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…20,21 Although we do not have a good explanation for this discrepancy, we believe it may be related to the nonselectivity of L-NAME. Our group and others 23,24 have shown that iNOS is activated after myocardial infarction and that inhibition of iNOS with aminoguanidine or S-methylisothiourea (selective inhibitors of iNOS) reduces myocardial infarct size. Thus, if L-NAME protects the heart against ischemia/reperfusion injury, this may be due to inhibition of iNOS, not eNOS.…”

Section: Discussionmentioning

confidence: 94%

See 1 more Smart Citation

Endothelial Nitric Oxide Gene Knockout Mice

et al. 1999

View full text Add to dashboard Cite

Abstract-We tested the hypothesis that nitric oxide (NO) released by endothelial NO synthase (eNOS) is not only important in blood pressure regulation but also involved in cardiac function and remodeling and in the cardioprotective effect of angiotensin-converting enzyme inhibitors (ACEi). With the use of a 2D Doppler echocardiography system equipped with a 15-MHz linear transducer, we evaluated left ventricular (LV) morphology and function in conscious eNOS knockout mice (eNOS; nϭ15) and their wild-type littermates (eNOS ϩ/ϩ ; nϭ16). We also studied whether in eNOS Ϫ/Ϫ mice (1) myocardial ischemia/reperfusion injury is more severe and (2) the cardioprotective effect of ACEi is diminished or absent. In comparison with the wild type, eNOS Ϫ/Ϫ mice had significantly increased systolic blood pressure (128Ϯ3 versus 108Ϯ5 mm Hg; PϽ0.001) and decreased heart rate (531Ϯ22 versus 629Ϯ18 bpm; PϽ0.001) associated with increased LV posterior wall thickness (0.80Ϯ0.04 versus 0.64Ϯ0.02 mm; PϽ0.001) and LV mass (18.3Ϯ0.9 versus 13.1Ϯ0.5 mg/10 g body weight; PϽ0.01). Despite hypertension and LV hypertrophy, LV chamber dimension, shortening fraction and ejection fraction (indicators of LV contractility), and cardiac output did not differ between the 2 strains, which indicates that LV function in eNOS Ϫ/Ϫ mice is well compensated. We also found that in eNOS ϩ/ϩ mice, ACEi decreased the ratio of myocardial infarct size to area at risk from 62.7Ϯ3.9% to 36.3Ϯ1.6% (PϽ0.001), whereas in eNOS Ϫ/Ϫ mice this effect of ACEi was almost abolished: the ratio of myocardial infarct size to area at risk was 67.2Ϯ2.9% in the vehicle-treated group and 62.7Ϯ3.9% in mice treated with ACEi. Moreover, infarct size in vehicle-treated eNOS Ϫ/Ϫ mice was not significantly different from eNOS ϩ/ϩ mice given the same treatment. We concluded that (1) endothelium-derived NO plays an important role in the regulation of blood pressure homeostasis; (2) NO released under basal conditions has no significant impact on cardiac function; and (3) ACEi protect the heart against ischemia/reperfusion injury in mice and that this effect is mediated in part by endothelium-derived NO. (Hypertension. 1999;34:24-30.) Key Words: nitric oxide Ⅲ myocardial ischemia Ⅲ myocardial reperfusion injury Ⅲ mice, knockout Ⅲ angiotensin-converting enzyme inhibitors Ⅲ echocardiography N itric oxide (NO) is formed from L-arginine and oxygen by 3 isoenzymes collectively called nitric oxide synthase (NOS). [1][2][3] Those NO isoenzymes expressed constitutively in endothelial (eNOS) and neuronal cells (nNOS) are Ca 2ϩ -dependent and can be activated by elevated intracellular calcium concentration, 4,5 whereas the Ca 2ϩ -independent isoenzyme (iNOS) can be induced by cytokines in macrophages and vascular smooth muscle cells and produces an excessive amount of NO. 6,7 In the vasculature, endotheliumderived NO (EDNO) appears to play an important role in the regulation of blood pressure (BP), regional blood flow, and vascular tone, as well as receptor-mediated vasodilator responses to agonists ...

show abstract

Section: Discussionmentioning

confidence: 94%

“…The dose of L-NAME used in rabbits probably blocks not only eNOS but also iNOS. Our group and others 23,24 have recently shown that selective inhibition of iNOS reduced infarct size. Thus, it could be that NO produced by eNOS has a cardioprotective effect, whereas the excessive amount of NO released by iNOS may be detrimental to the heart.…”

mentioning

confidence: 79%

Endothelial Nitric Oxide Gene Knockout Mice

et al. 1999

View full text Add to dashboard Cite

show abstract

“…13 In contrast, Patel et al 14 found that pretreatment with the NOS inhibitor L-NAME reduced infarct size in a rabbit model of ischemia/reperfusion, but concluded that their results were possibly attributable to L-NAME-induced ischemia, which could act as a preconditioning mechanism. Thus, whether iNOS contributes to myocyte death and infarct size in the ischemic myocardium is unclear.…”

Section: [Tnf] Interleukin-1␤ [Il] and Interferon-␥ [Ifn]) And Bactmentioning

confidence: 97%

“…2,10,11 Inhibition of iNOS with S-methylisothiourea sulfate has been shown to improve left ventricular performance in rabbit hearts 3 days after MI without affecting infarct size, 12,13 whereas the cNOS inhibitor N--nitro-larginine had no beneficial effects. 13 In contrast, Patel et al 14 found that pretreatment with the NOS inhibitor L-NAME reduced infarct size in a rabbit model of ischemia/reperfusion, but concluded that their results were possibly attributable to L-NAME-induced ischemia, which could act as a preconditioning mechanism.…”

Section: [Tnf] Interleukin-1␤ [Il] and Interferon-␥ [Ifn]) And Bactmentioning

confidence: 99%

Reduction of myocardial infarct size by inhibition of inducible nitric oxide synthase

Wang

Yang

Liu

et al. 1999

American Journal of Hypertension

View full text Add to dashboard Cite

The inducible nitric oxide synthase isoform (iNOS) is upregulated by cytokines and endotoxins in many types of cells, including cardiac myocytes. Nitric oxide (NO) induced by cytokines can be cytotoxic, and has been implicated in the pathophysiology of myocardial infarction, cardiomyopathy, and septic shock. To examine the role of iNOS in the ischemic myocardium, we studied: 1) the time course of expression of iNOS mRNA after myocardial infarction (MI) in male Sprague-Dawley rat hearts and expression of iNOS protein in the infarcted region; 2) whether hypoxia in vitro is a potential mediator of the induction of iNOS mRNA; and 3) whether inhibition of iNOS by two different selective inhibitors (aminoguanidine and S-methylisothiourea sulfate) in vivo influences infarct size. Myocardial infarction was induced by ligation of the left anterior descending coronary artery (LAD), and tissue was collected at selected times thereafter from both ligated and sham-operated rats. iNOS mRNA was induced in the infarcted region of the left ventricle for 7 days; iNOS protein was also detected in the infarcted area. We next tested whether hypoxia would induce iNOS in vitro. In cultured neonatal ventricular myocytes, iNOS mRNA was slightly induced by 6 to 24 h of hypoxia; however, iNOS protein was only detected when the cytokine interleukin-1␤ was present. To study whether iNOS activity contributed to myocardial damage (eg, infarct size), we administered the first dose of the NOS inhibitors 24 h before LAD occlusion and then a second dose after surgery. Inhibition of iNOS activity with aminoguanidine reduced infarct size by 20% but had no effect on infiltration by neutrophils, whereas the more selective inhibitor S-methylisothiourea sulfate reduced infarct size by 41%. These data suggest that NO derived from the iNOS isoform contributes to some of the myocardial injury following MI, possibly by causing myocardial cell death in areas bordering the ischemic region of the heart. Am J Hypertens 1999;12:174 -182

show abstract

“…Increased expression of NOS2 and a consequent increase in tissue nitrite and nitrate (NO 2 Ϫ ϩ NO 3 Ϫ ) production occurs in cardiac, liver, and kidney ischemia-reperfusion (15)(16)(17)(18). In many instances, NOS2 inhibition by arginine analogs or ablation of NOS2 gene expression significantly limits tissue ischemia-reperfusion injury (19 -21).…”

mentioning

confidence: 99%

Nitric Oxide-dependent Generation of Reactive Species in Sickle Cell Disease

Aslan¹,

Ryan²,

Townes³

et al. 2003

Journal of Biological Chemistry

158

105

View full text Add to dashboard Cite

The intermittent vascular occlusion occurring in sickle cell disease (SCD) leads to ischemia-reperfusion injury and activation of inflammatory processes including enhanced production of reactive oxygen species and increased expression of inducible nitric-oxide synthase (NOS2). Appreciating that impaired nitric oxide-dependent vascular function and the concomitant formation of oxidizing and nitrating species occur in concert with increased rates of tissue reactive oxygen species production, liver and kidney NOS2 expression, tissue 3-nitrotyrosine (NO 2 Tyr) formation and apoptosis were evaluated in human SCD tissues and a murine model of SCD. Liver and kidney NOS2 expression and NO 2 Tyr immunoreactivity were significantly increased in SCD mice and humans, but not in nondiseased tissues. TdTmediated nick end-label (TUNEL) staining showed apoptotic cells in regions expressing elevated levels of NOS2 and NO 2 Tyr in all SCD tissues. Gas chromatography mass spectrometry analysis revealed increased plasma protein NO 2 Tyr content and increased levels of hepatic and renal protein NO 2 Tyr derivatives in SCD (21.4 ؎ 2.6 and 37.5 ؎ 7.8 ng/mg) versus wild type mice (8.2 ؎ 2.2 and 10 ؎ 1.2 ng/mg), respectively. Western blot analysis and immunoprecipitation of SCD mouse liver and kidney proteins revealed one principal NO 2 Tyr-containing protein of 42 kDa, compared with controls. Enzymatic in-gel digestion and MALDI-TOF mass spectrometry identified this nitrated protein as actin. Electrospray ionization and fragment analysis by tandem mass spectrometry revealed that 3 of 15 actin tyrosine residues are nitrated (Tyr 91 , Tyr 198 , and Tyr 240 ) at positions that significantly modify actin assembly. Confocal microscopy of SCD human and mouse tissues revealed that nitration led to morphologically distinct disorganization of filamentous actin. In aggregate, we have observed that the hemoglobin point mutation of sickle cell disease that mediates hemoglobin polymerization defects is translated, via inflammatory oxidant reactions, into defective cytoskeletal polymerization.

show abstract

S-Methylisothiourea Inhibits Inducible Nitric Oxide Synthase and Improves Left Ventricular Performance after Acute Myocardial Infarction

Cited by 42 publications

References 0 publications

Endothelial Nitric Oxide Gene Knockout Mice

Endothelial Nitric Oxide Gene Knockout Mice

Reduction of myocardial infarct size by inhibition of inducible nitric oxide synthase

Nitric Oxide-dependent Generation of Reactive Species in Sickle Cell Disease

Contact Info

Product

Resources

About