Biomedical subjects

Csaba Csonka

Publications and source records attributed to Csaba Csonka.

13 recordsLinked to original sources

PubMed2006

The role of peroxynitrite in chemical preconditioning with 3-nitropropionic acid in rat hearts.

OBJECTIVES: 3-Nitropropionic acid (3-NP), an irreversible inhibitor of succinate dehydrogenase, has been shown to protect against ischemic injury in the brain and in the heart via a preconditioning-like effect; however, the cellular mechanism is not known. The aim of the present study was to investigate if 3-NP pretreatment reduces infarct size and if altered metabolism of nitric oxide and reactive oxygen species are involved. METHODS: Hearts were assigned into 3 groups: 3 intermittent cycles of 5 min no-flow ischemia separated by 5 min aerobic perfusion protocol were used to induce ischemic preconditioning as a positive control; a time-matched non-preconditioning group served as control; and 3-NP (20 mg/kg, i.p.) was injected 3 h before the perfusion protocol to induce pharmacological preconditioning. Hearts from all groups were then subjected to 30 min global ischemia followed by 120 min reperfusion. RESULTS: Infarct size and lactate dehydrogenase release were significantly reduced after ischemia/reperfusion. While cardiac nitric oxide (NO) was increased, superoxide formation, nitrotyrosine level, and cardiac NADH oxidase and xanthine oxidase (XO) activities were markedly reduced by 3-NP administration. Cardiac activities of NO synthase and superoxide dismutase were not changed by 3-NP. CONCLUSION: This is the first demonstration in the rat myocardium that 3-NP induces pharmacological preconditioning, thereby limiting infarct size, and that this effect is associated with increased NO bioavailability and reduced peroxynitrite formation due to inhibition of superoxide formation by XO and NADH oxidase.

Animals↗

PubMed2006

Platelet activation and high tissue factor level predict acute stent thrombosis in pig coronary arteries: prothrombogenic response of drug-eluting or bare stent implantation within the first 24 hours.

Increased thrombogenicity of drug-eluting stents (DESs) has recently been reported. The aim of the present study was to investigate the prothrombogenic effect of DESs and Bare stents, and determine factors predictive of acute stent thrombosis (AST) in preclinical experiments using new stent design or coating. Circulating pre- and post-stenting parameters of platelet activation (mean platelet volume, MPV; platelet distribution width, platelet large cell ratio), thrombin activation (thrombin-antithrombin complex, TAT and prothrombin fragments, F1+2), tissue factor antigen (TF-ag) and -activity (TF-act) and plasminogen activator inhibitor-1 (PAI-1) were measured in 141 consecutive pigs. Stent implantations were performed after pretreatment with aspirin and clopidogrel with unfractionated heparin anticoagulation. Nineteen pigs (groups AST-DES, n = 12; and AST-Bare, n = 7) died mean 6.3 +/- 2.9 h after stent implantation from AST. The remaining 122 control (C) pigs (groups C-DES, n = 76, and C-Bare, n = 46) survived the 1-month follow-up. Non-significantly elevated levels of post-stent F1+2 and TAT were measured in AST groups. Post-stenting MPV was increased significantly in the groups ASTDES and AST-Bare as compared with the groups C-DES and C-Bare (11.73 +/- 1.12 and 11.6 +/- 0.68 vs. 8.85 +/- 0.78 and 9.04 +/- 0.81 fL; p < 0.001), similarly to TF-ag (189.1 +/- 87.5 and 127 +/- 34.9 vs. 42.5 +/- 24.6 and 35.3 +/- 37.6 pg/ml; p < 0.001, respectively), Tfact (3.23 +/- 0.95 and 2.73 +/- 1.68 vs. 1.43 +/- 1.12 and 1.61 +/- 1.31 pM; p < 0.01, respectively) and PAI-1 (99.1 +/- 15.8 and 99 +/- 14.7 vs.53.4 +/- 40.2 and 46.9 +/- 42.4 ng/ml;p < 0.01, respectively). Multivariate analysis revealed elevated post-stenting plasma levels of TF-ag (p = 0.016) and MPV (p = 0.001) as independent risk factors for developing AST within the first 24 h in a porcine coronary stent model.

Angiography↗

PubMed2005

Hyperlipidemia attenuates the infarct size-limiting effect of ischemic preconditioning: role of matrix metalloproteinase-2 inhibition.

Hyperlipidemia attenuates the cardioprotective effect of preconditioning via unknown mechanisms. We have reported previously that in normolipidemic rats, preconditioning decreased ischemia-induced activation and release of myocardial matrix metalloproteinase (MMP)-2 into the coronary perfusate. Here, we investigated whether hyperlipidemia interferes with the cardioprotective effect of preconditioning through modulation of MMP-2. Hearts isolated from male Wistar rats fed 2% cholesterol-enriched or control chow for 9 weeks were subjected to a preconditioning protocol (three intermittent periods of ischemia/reperfusion of 5-min duration each) or a time-matched nonpreconditioning protocol. This was followed by a test ischemia/reperfusion (30-min ischemia and 120-min reperfusion) in both groups. Preconditioning decreased infarct size in the control but not the cholesterol-fed group. Cardioprotection in the preconditioned control group but not in the cholesterol-fed group was associated with an 18 +/- 3% (p < 0.05) inhibition of test ischemia/reperfusion-induced activation and release of myocardial MMP-2 into the perfusate. Myocardial protein levels of tissue inhibitors of MMPs [tissue inhibitor of metalloproteinases (TIMP)-2 and TIMP-4] were not changed in either group. A reduction of infarct size in nonpreconditioned hearts from both control and cholesterol-fed group was produced by the MMP inhibitor ilomastat at 0.25 microM, a concentration producing MMP-2 inhibition comparable with that of preconditioning in the control group. We conclude that hyperlipidemia blocks preconditioning-induced cardioprotection, hyperlipidemia abolishes preconditioning-induced inhibition of myocardial MMP-2 activation and release, preconditioning-induced inhibition of MMP-2 activation and release is not mediated by TIMPs, and pharmacological inhibition of MMPs produces cardioprotection in both normal and hyperlipidemic rats.

Animals↗

PubMed2005

[Treatment of children's and adolescent's knee injuries].

INTRODUCTION: Authors made 162 knee arthroscopic operations due to hemarthrosis of the knee, acute knee blocking or acute developed instability on patients under 18 years after knee injury during a 12 years period. The retrospective analysis of patient reports shows, that in 61.7% of the cases they found chondral- or osteochondral fracture in the knee. MATERIAL AND METHODS: On three dimensional routine X-ray pictures they were performed after the injury, in 85% of the cases fractures were not seen. Fortunately the most part of the hyalin surface injuries was smaller than 0.5 cm or were situated on less weight-bearing area only hemarthrosis evacuation and removing of loose body were done. If the osteochondral fractures was bigger than 0.5 cm or was broken from the weight-bearing surface, they were fixed by KFI or Herbert-screws. When refixation of osteochondral fracture was not possible technically or in cases of chondral fractures, primary mosaic chondroplasty was used. The correct diagnosis and the early reconstruction of injured hyalin surface in childhood and teenagers is essential regarding to the function of the knee.

Adolescent↗

PubMed2004

Cholesterol diet-induced hyperlipidemia influences gene expression pattern of rat hearts: a DNA microarray study.

To profile gene expression patterns involved in the direct myocardial effect of cholesterol-enriched diet-induced hyperlipidemia, we monitored global gene expression changes by DNA microarray analysis of 3200 genes in rat hearts. Twenty-six genes exhibited significant up-regulation and 25 showed down-regulation in hearts of rats fed a 2% cholesterol-enriched diet for 8 weeks as compared to age-matched controls. The expression changes of 12 selected genes were also assessed by real-time quantitative polymerase chain reaction. Genes with altered expression in the heart due to hyperlipidemia included procollagen type III, cofilin/destrin, tensin, transcription repressor p66, synaptic vesicle protein 2B, Hsp86, chaperonin subunit 5epsilon, metallothionein, glutathione S-transferase, protein kinase C inhibitor, ATP synthase subunit c, creatine kinase, chloride intracellular channel 4, NADH oxidoreductase and dehydrogenase, fibronectin receptor beta chain, CD81 antigen, farnesyltransferase, calreticulin, disintegrin, p120 catenin, Smad7, etc. Although some of these genes have been suspected to be related to cardiovascular diseases, none of the genes has been previously shown to be involved in the mechanism of the cardiac effect of hyperlipidemia.

Animals↗

PubMed2003

Capsaicin-sensitive sensory neurons regulate myocardial nitric oxide and cGMP signaling.

We studied whether tissue levels of nitric oxide (NO) and cGMP are regulated by sensory nerves in normoxic and ischemic hearts. Wistar rats were treated with capsaicin to deplete neurotransmitters from capsaicin-sensitive sensory nerves. In separate experiments, capsaicin was applied perineurally to both vagus nerves for selective chemodenervation of vagal cardiac afferent nerves. Systemic capsaicin administration significantly decreased basal myocardial NO content assessed by electron spin resonance (ESR) spectroscopy, whereas, local treatment of vagus nerves did not change it. Both systemic and local capsaicin treatment decreased cardiac cGMP content measured by radioimmunoassay. In separate experiments, isolated hearts from control and systemic capsaicin-treated rats were subjected to 30-min global ischemia. NO signal intensity increased 10-fold after ischemia, whereas, cardiac cGMP decreased. Capsaicin pretreatment did not influence ischemic NO or cGMP content. These results suggest a major role for capsaicin-sensitive sensory neurons in the maintenance of basal but not ischemic myocardial NO and cGMP content. Vagal sensory nerves may be involved in the regulation of basal myocardial cGMP but not basal NO level. Consequently, basal NO content in the heart is regulated primarily by spinal afferent nerves.

Animals↗

PubMed2003

Hyperlipidemia induced by a cholesterol-rich diet leads to enhanced peroxynitrite formation in rat hearts.

OBJECTIVE: We investigated the influence of experimental hyperlipidemia on the formation of cardiac NO, superoxide, and peroxynitrite (ONOO(-)) in rat hearts. METHODS: Wistar rats were fed 2% cholesterol-enriched diet or normal diet for 8 weeks. Separate groups of normal and hyperlipidemic rats were injected twice intraperitoneally with 2 x 20 micromol/kg FeTPPS (5,10,15,20-tetrakis-[4-sulfonatophenyl]-porphyrinato-iron[III]), a ONOO(-) decomposition catalyst, 24 h and 1 h before isolation of the hearts. RESULTS: A cholesterol diet significantly decreased myocardial NO content, however, myocardial Ca(2+)-dependent and Ca(2+)-independent NO synthase activity and NO synthase protein level did not change. Myocardial superoxide formation and xanthine oxidase activity were significantly increased; however, cardiac superoxide dismutase activity did not change in the cholesterol-fed group. Dityrosine in the perfusate, a marker of cardiac ONOO(-) formation, and plasma nitrotyrosine, a marker for systemic ONOO(-) formation, were both elevated in hyperlipidemic rats. In cholesterol-fed rats, left ventricular end-diastolic pressure (LVEDP) was significantly elevated as compared to controls. Administration of FeTPPS normalized LVEDP in the cholesterol-fed group. CONCLUSION: We conclude that cholesterol-enriched diet-induced hyperlipidemia leads to an increase in cardiac ONOO(-) formation and a decrease in the bioavailability of NO which contributes to the deterioration of cardiac performance and may lead to further cardiac pathologies.

Animals↗

PubMed2003

Role of cholesterol-enriched diet and the mevalonate pathway in cardiac nitric oxide synthesis.

Cardiac stress adaptation is deteriorated in hyperlipidemia possibly due to deterioration of nitric oxide (NO) metabolism. However, inhibition of HMG-CoA reductase, a key enzyme in the mevalonate pathway, was shown to increase the level of endothelial NO-synthase (eNOS) mRNA. Here we studied the effect of dietary and pharmacologic modulation of the mevalonate pathway on cardiac NO synthesis. Rats were fed 2% cholesterol-enriched or normal diet for 8 weeks. Normal and cholesterol-fed animals were treated with farnesol, a major metabolite of the mevalonate pathway (2.2 mg/kg i.p.) or with the HMG-CoA reductase inhibitor lovastatin (3 x 5 mg/kg per os for 3 days, n = 5-6 in each group). Cardiac NO content was significantly decreased in cholesterol-fed rats as assessed by electron spin resonance spectroscopy, however, other treatments did not influence cardiac NO content. Cardiac activity of Ca(2+)-dependent NOS was unaffected by cholesterol-diet and by treatment with either farnesol or lovastatin, as assessed by (14)C-citrullin assay. Ca(2+)-independent NOS activity was negligible in all groups. Cardiac eNOS protein content measured by Western blotting was also unchanged in all groups. We conclude that cholesterol-diet decreases cardiac NO content, however, cholesterol diet-induced inhibition of the mevalonate pathway does not account for the decreased NO level in the heart, and that the mevalonate pathway does not influence cardiac NO biosynthesis.

Animals↗

PubMed2003

Defibrillatory action of glibenclamide is independent from ATP-sensitive K+ channels and free radicals.

This study investigated whether glibenclamide exerts a defibrillatory action and if this action is mediated by a blockade of ATP-sensitive K+ channels (K(ATP)) or by an anti-free radical mechanism. Aerobically perfused isolated rat hearts were subjected to 10 min of pacing-induced ventricular fibrillation (VF) followed by 10 min of perfusion without pacing (post-VF period), in the presence of solvent (controls), 1 microM K(ATP) blocker glibenclamide, 10 microM K(ATP) opener cromakalim, and their combination, respectively. In controls, pacing-induced VF caused a significant deterioration in cardiac function in the post-VF period. Spontaneous defibrillation was 42%. Glibenclamide improved post-VF cardiac function and resulted in 100% (P < 0.05) spontaneous defibrillation. Cromakalim did not significantly affect post-VF cardiac function and the incidence of spontaneous defibrillation as compared with controls. The combination of the compounds improved cardiac function and resulted in 83% (P < 0.05) spontaneous defibrillation. In separate experiments, 2,5-dihydroxybenzoic acid formation in the perfusate as a marker of hydroxyl radical formation was measured by high-performance liquid chromatography and cardiac superoxide production was assessed by lucigenin-enhanced chemiluminescence during pacing-induced VF. Glibenclamide did not affect hydroxyl radical generation or myocardial superoxide content during VF. The conclusion is that glibenclamide exerts a defibrillatory action and improves post-VF cardiac function in rat hearts and these effects are independent from K(ATP) and free radicals.

Adenosine Triphosphate↗

PubMed2003

Inhibition of interleukin-1beta convertase is associated with decrease of neointimal hyperplasia after coronary artery stenting in pigs.

Inhibition of IL-1beta convertase has been shown to decrease inflammation and apoptosis, which are features of the neointimal development after vascular interventions. The aim of our study was to reduce neointimal proliferation after stenting of the porcine coronary artery, using the irreversible IL-1beta convertase and caspase-1 inhibitor acetyl-tyrosinyl-valyl-alanyl-aspartyl-chloromethyl-ketone (Ac-YVAD-cmk). Before coronary stent implantation, 8 pigs received an intracoronary infusion of 50 mg Ac-YVAD-cmk into the left coronary artery (group 1, n = 8), while 8 animals served as untreated controls (group 2). After 4 weeks, coronary angiography and intracoronary ultrasound (IVUS) with 3D measurements were performed. IVUS revealed a smaller in-stent intimal volume (27.3 +/- 11.6 vs. 75.8 +/- 18.4 mm3, p < 0.005) and a decreased maximal percentage area stenosis (36.1 +/- 8.5 vs. 69.0 +/- 8.2%, p < 0.001) in group 1 vs. group 2. A smaller maximal neointimal thickness (0.63 +/- 0.28 vs. 1.75 +/- 0.94 mm, p < 0.005) and a decreased maximal neointimal area (2.14 +/- 1.29 vs. 5.03 +/- 1.92 mm2, p < 0.005), assessed by computerized planimetry, were found in group 1 vs. group 2. Lower apoptotic indices of the neointimal cells were observed in the treated animals (3.0 vs. 13.4% of total intimal cells, p < 0.05). The coronary arterial tissue IL-1beta level was significantly decreased in the animals treated with Ac-YVAD-cmk (0.254 +/- 0.162 vs. 0.463 +/- 0.307 pg/mg protein, p < 0.05), and exhibited a positive linear correlation (r = 0.581, p = 0.013) with the in-stent plaque volume. In conclusion, intracoronary administration of Ac-YVAD-cmk before coronary artery stenting results in significantly decreased neointimal hyperplasia due to the inhibition of local IL-1beta production and decreased neointimal apoptosis.

Amino Acid Chloromethyl Ketones↗

PubMed2003

Functional and structural characterization of anti-beta1-adrenoceptor autoantibodies of spontaneously hypertensive rats.

Eighteen month old spontaneously hypertensive rats (SHR-rats) showed myocardial dysfunction and autoantibodies directed against the beta1-adrenoceptor similarly as known in human dilated cardiomyopathy or Chagas' disease. The agonist-like antibodies were able to activate the beta1-adrenoceptor mediated signal transduction cascade in cultured rat cardiomyocytes and induced a long-lasting stimulatory effect resulting in a harmful adrenergic overdrive. The antibodies recognized an epitope of the second extracellular loop of the beta1-adrenoceptor identical to that epitope identified in Chagas' disease. In conclusion, our assumption is supported that old SHR-rat are an useful animal model for investigating the role of anti-beta1-adrenoceptor antibodies in the induction of human cardiomyopathy.

Adrenergic beta-Antagonists↗

PubMed2002

Preconditioning decreases ischemia/reperfusion-induced release and activation of matrix metalloproteinase-2.

Release and activation of matrix metalloproteinases (MMPs) significantly contribute to myocardial stunning injury immediately after ischemia and reperfusion, however, their role in preconditioning remains unknown. We therefore examined the effects of preconditioning and subsequent ischemia/reperfusion on MMP activity in isolated rat hearts. Hearts were subjected to a preconditioning protocol (three consecutive 5-min periods of global ischemia interspersed with 5 min of reperfusion) followed by 30 min ischemia and 5 min reperfusion. To measure MMP release, coronary effluent was collected: (a) during aerobic perfusion, (b) in reperfusion following each preconditioning ischemia, and (c) during the final reperfusion following test ischemia. MMP-2 activities could be detected by gelatin zymography in the ventricles and coronary effluent samples from the perfused hearts. The levels of MMP-2 activity in the effluent were markedly increased in effluent following test ischemia from control hearts without preconditioning. This was accompanied by a decrease in corresponding tissue MMP activities. Preconditioning significantly decreased the MMP-2 activity in the coronary effluent following test ischemia/reperfusion and preserved the MMP-2 protein content and activity in the myocardium. Our results demonstrate that classic preconditioning inhibits ischemia/reperfusion induced release and activation of MMP-2. These results suggest that preconditioning may exert part of its cardioprotective effects through the reduction of MMP-2 release.

Animals↗

PubMed2002

Hyperlipidemia induced by high cholesterol diet inhibits heat shock response in rat hearts.

We examined whether heat shock response is affected by experimental hyperlipidemia in rat hearts. Therefore, isolated hearts of male Wistar rats fed a 2% cholesterol-enriched diet or standard diet for 12 weeks were subjected to either 20 min heat stress at 42 degrees C or global normothermic ischemia followed by 120 min normothermic, normoxic perfusion. Both heat stress and ischemia resulted in a significant increase in cardiac mRNA and protein levels of the inducible member of the 70-kDa heat shock protein family (HSP70) when compared to time-matched controls as assessed by reverse transcriptase polymerase chain reaction and Western blotting in hearts of normal rats. However, in hyperlipidemic groups, increase in cardiac hsp70 mRNA and HSP70 protein in response to heat stress and ischemia was markedly attenuated. We further observed that the basal level of hsp70 mRNA was significantly higher in the hyperlipidemic group when compared to normal controls; however, the HSP70 protein level was not different. This is the first demonstration that hyperlipidemia inhibits cardiac heat shock response. We further conclude that basal HSP70 expression might be downregulated at a posttranscriptional level in hyperlipidemia.

Animals↗