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1.
J Pharmacol Exp Ther ; 352(3): 429-37, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25512369

RESUMEN

Thrombopoietin confers immediate protection against injury caused by ischemia/reperfusion in the rat heart. Eltrombopag is a small molecule agonist of the thrombopoietin receptor, the physiologic target of thrombopoietin. However, the ability of eltrombopag and thrombopoietin to protect human cardiac myocytes against injury and the mechanisms underlying myocyte protection are not known. Human cardiac myocytes (n = 6-10/group) were treated with eltrombopag (0.1-30.0 µM) or thrombopoietin (0.1-30.0 ng/ml) and then subjected to 5 hours of hypoxia (95% N2/5% CO2) and 16 hours of reoxygenation to determine their ability to confer resistance to myocardial injury. The thrombopoietin receptor c-Mpl was detected in unstimulated human cardiac myocytes by Western blotting. Eltrombopag and thrombopoietin confer immediate protection to human cardiac myocytes against injury from hypoxia/reoxygenation by decreasing necrotic and apoptotic cell death in a concentration-dependent manner, with an optimal concentration of 3 µM for eltrombopag and 1.0 ng/ml for thrombopoietin. The extent of protection conferred with eltrombopag is equivalent to that of thrombopoietin. Eltrombopag and thrombopoietin activate multiple prosurvival pathways; inhibition of Janus kinase-2, proto-oncogene tyrosine-protein kinase, protein kinase B/phosphatidylinositol-3 kinase, p44/42 mitogen-activated protein kinase (MAPK), and p38 MAPK abolished cardiac myocyte protection by eltrombopag and thrombopoietin. Eltrombopag and thrombopoietin may represent important and potent agents for immediately and substantially increasing protection of human cardiac myocytes, and may offer a long-lasting benefit through activation of prosurvival pathways during ischemia.


Asunto(s)
Benzoatos/farmacología , Cardiotónicos/farmacología , Hidrazinas/farmacología , Miocitos Cardíacos/fisiología , Pirazoles/farmacología , Receptores de Trombopoyetina/agonistas , Receptores de Trombopoyetina/fisiología , Transducción de Señal/fisiología , Hipoxia de la Célula/efectos de los fármacos , Hipoxia de la Célula/fisiología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Células Cultivadas , Relación Dosis-Respuesta a Droga , Humanos , Miocitos Cardíacos/efectos de los fármacos , Proto-Oncogenes Mas , Transducción de Señal/efectos de los fármacos , Trombopoyetina/farmacología
2.
J Biol Chem ; 288(1): 737-46, 2013 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-23148226

RESUMEN

The ability to interact with cell surface glycosaminoglycans (GAGs) is essential to the cell migration properties of chemokines, but association with soluble GAGs induces the oligomerization of most chemokines including CXCL12. Monomeric CXCL12, but not dimeric CXCL12, is cardioprotective in a number of experimental models of cardiac ischemia. We found that co-administration of heparin, a common treatment for myocardial infarction, abrogated the protective effect of CXCL12 in an ex vivo rat heart model for myocardial infarction. The interaction between CXCL12 and heparin oligosaccharides has previously been analyzed through mutagenesis, in vitro binding assays, and molecular modeling. However, complications from heparin-induced CXCL12 oligomerization and studies using very short oligosaccharides have led to inconsistent conclusions as to the residues involved, the orientation of the binding site, and whether it overlaps with the CXCR4 N-terminal site. We used a constitutively dimeric variant to simplify the NMR analysis of CXCL12-binding heparin oligosaccharides of varying length. Biophysical and mutagenic analyses reveal a CXCL12/heparin interaction surface that lies perpendicular to the dimer interface, does not involve the chemokine N terminus, and partially overlaps with the CXCR4-binding site. We further demonstrate that heparin-mediated enzymatic protection results from the promotion of dimerization rather than direct heparin binding to the CXCL12 N terminus. These results clarify the structural basis for GAG recognition by CXCL12 and lend insight into the development of CXCL12-based therapeutics.


Asunto(s)
Quimiocina CXCL12/metabolismo , Oligosacáridos/química , Receptores CXCR4/metabolismo , Animales , Sitios de Unión , Biofisica/métodos , Cardiotónicos/química , Quimiocinas/metabolismo , Dimerización , Glicosaminoglicanos/química , Heparina/química , Humanos , Concentración 50 Inhibidora , Cinética , Espectroscopía de Resonancia Magnética/métodos , Modelos Moleculares , Conformación Molecular , Infarto del Miocardio/metabolismo , Perfusión , Estructura Terciaria de Proteína , Ratas
3.
FASEB J ; 26(4): 1727-35, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22247331

RESUMEN

Signals from the intestinal microbiota are important for normal host physiology; alteration of the microbiota (dysbiosis) is associated with multiple disease states. We determined the effect of antibiotic-induced intestinal dysbiosis on circulating cytokine levels and severity of ischemia/reperfusion injury in the heart. Treatment of Dahl S rats with a minimally absorbed antibiotic vancomycin, in the drinking water, decreased circulating leptin levels by 38%, resulted in smaller myocardial infarcts (27% reduction), and improved recovery of postischemic mechanical function (35%) as compared with untreated controls. Vancomycin altered the abundance of intestinal bacteria and fungi, measured by 16S and 18S ribosomal DNA quantity. Pretreatment with leptin (0.12 µg/kg i.v.) 24 h before ischemia/reperfusion abolished cardioprotection produced by vancomycin treatment. Dahl S rats fed the commercially available probiotic product Goodbelly, which contains the leptin-suppressing bacteria Lactobacillus plantarum 299v, also resulted in decreased circulating leptin levels by 41%, smaller myocardial infarcts (29% reduction), and greater recovery of postischemic mechanical function (23%). Pretreatment with leptin (0.12 µg/kg i.v.) abolished cardioprotection produced by Goodbelly. This proof-of-concept study is the first to identify a mechanistic link between changes in intestinal microbiota and myocardial infarction and demonstrates that a probiotic supplement can reduce myocardial infarct size.


Asunto(s)
Intestinos/microbiología , Metagenoma/efectos de los fármacos , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/prevención & control , Animales , Antibacterianos/farmacología , Citocinas/sangre , Agua Potable , Humanos , Intestinos/efectos de los fármacos , Leptina/sangre , Leptina/farmacología , Daño por Reperfusión Miocárdica/fisiopatología , Probióticos/uso terapéutico , Ratas , Ratas Endogámicas Dahl , Vancomicina/farmacología
4.
Cardiovasc Res ; 77(1): 44-53, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18006466

RESUMEN

AIMS: Thrombopoietin (Tpo) is known for its ability to stimulate platelet production. However, it is currently unknown whether Tpo plays a physiological function in the heart. METHODS AND RESULTS: We assessed the potential protective role of Tpo in vitro and in vivo in two rat models of myocardial ischaemia/reperfusion. Tpo receptor (c-mpl) message was detected in the heart using RT-PCR, and the Tpo receptor protein was detected using western blotting and immunohistochemistry. Tpo treatment immediately before ischaemia reduced myocardial necrosis, apoptosis, and decline in ventricular function following ischaemia/reperfusion in the rat in a concentration- and dose-dependent manner with an optimal concentration of 1.0 ng/mL in vitro and an optimal dose of 0.05 microg/kg iv in vivo. Tpo also reduced infarct size when given after the onset of ischaemia or at reperfusion. Tpo activated JAK-2 (Janus kinase-2) and p44 MAPK (mitogen-activated protein kinase) during reperfusion but not prior to ischaemia. Inhibition of JAK-2 (AG-490), p42/44 MAPK (PD98059), mitochondrial K(ATP) channels (5-HD), and sarcolemmal K(ATP) channels (HMR 1098) abolished Tpo-induced resistance to injury from myocardial ischaemia/reperfusion. AG-490, PD98059, 5-HD, and HMR1098 alone had no effect on cardioprotection. Treatment with a single dose of Tpo (0.05 or 1.0 microg/kg iv) did not result in the elevation of platelet count or haematocrit over a 16-day period. CONCLUSION: A single treatment of Tpo confers cardioprotection through JAK-2, p42/44 MAPK, and K(ATP) channels, suggesting a potential therapeutic role of Tpo in the treatment of injury resulting from myocardial ischaemia and reperfusion.


Asunto(s)
Apoptosis/efectos de los fármacos , Infarto del Miocardio/tratamiento farmacológico , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Aturdimiento Miocárdico/tratamiento farmacológico , Trombopoyetina/uso terapéutico , Animales , Quinasas MAP Reguladas por Señal Extracelular/fisiología , Humanos , Técnicas In Vitro , Janus Quinasa 2/fisiología , Canales KATP/fisiología , Masculino , Infarto del Miocardio/patología , Ratas , Ratas Sprague-Dawley , Factor de Transcripción STAT3/fisiología , Trombopoyetina/farmacología , Factores de Tiempo
5.
J Mol Cell Cardiol ; 44(2): 345-51, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18083188

RESUMEN

The lanthanide cation, gadolinium (Gd) attenuates post-ischemic myocardial stunning. This study tests the hypothesis that Gd also preconditions the myocardium against infarction following ischemia-reperfusion (IR) and explores potential mechanisms underlying Gd-induced cardioprotection. Regional myocardial infarction was induced in rats by occluding the left anterior descending artery for 30 min and reperfusing for 120 min. Rats (n=6/group) were administered intravenous Gd (1 to 100 micromol/kg) 15 min prior to ischemia. Hearts were excised after reperfusion to determine infarct size (IS) and area at risk (AAR). The ratio IS/AAR (%) was reduced by Gd in a "U"-shaped, dose-dependent manner. The minimum dose that reduced IS/AAR was 5 micromol/kg (52+/-5% vs. 64+/-4%), while the dose that reduced IS/AAR maximally was 20 micromol/kg (44+/-4%). Gd also reduced IS/AAR when given 1 min before reperfusion (47+/-3%) but not when given 10 s after reperfusion (60+/-3%). Cardioprotection was maintained if IR was delayed 24-72 h after Gd administration. Cardioprotection by Gd was abolished by inhibition of JAK-2 with AG-490, of p42/44 MAPK with PD98059 or of K(ATP) channels with glibenclamide. None of these agents given alone altered IS/AAR compared with controls. Inhibition of JAK-2 also blocked Gd-induced delayed cardioprotection. Gd may have broad potential roles in IR, as it conferred immediate cardioprotection when given prior to ischemia or prior to reperfusion and delayed cardioprotection for up to 72 h after administration. The mechanism underlying Gd-induced preconditioning appears to be multi-factorial, involving JAK-2, STAT-3 and p44 MAPK pathways, as well as K(ATP) channels.


Asunto(s)
Gadolinio/farmacología , Infarto del Miocardio/prevención & control , Animales , Cardiotónicos/farmacología , Relación Dosis-Respuesta a Droga , Hemodinámica/efectos de los fármacos , Técnicas In Vitro , Janus Quinasa 2/metabolismo , Masculino , Infarto del Miocardio/enzimología , Infarto del Miocardio/fisiopatología , Isquemia Miocárdica , Canales de Potasio/metabolismo , Ratas , Ratas Sprague-Dawley , Factores de Transcripción STAT/metabolismo , Factores de Tiempo
6.
J Pharmacol Exp Ther ; 324(3): 1045-54, 2008 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-18055876

RESUMEN

Harnessing endogenous cardioprotectants is a novel therapeutic strategy to combat ischemia/reperfusion (I/R) injury. Thrombin causes I/R injury, whereas exogenous adenosine prevents I/R injury. We hypothesized that blocking thrombin receptor activation with a protease-activated receptor (PAR) 4 antagonist would unmask the cardioprotective effects of endogenous adenosine. The protective role of two structurally unrelated PAR4 antagonists, trans-cinnamoyl-YPGKF-amide (tc-Y-NH(2)) and palmitoyl-SGRRYGHALR-amide (P4pal10), were evaluated in two rat models of myocardial I/R injury. P4pal10 (10 microg/kg) treatment before ischemia significantly decreased infarct size (IS) by 31, 21, and 19% when given before, during, and after ischemia in the in vivo model. tc-Y-NH(2) (5 microM) treatment before ischemia decreased IS by 51% in the in vitro model and increased recovery of ventricular function by 26%. To assess whether the cardioprotective effects of PAR4 blockade were due to endogenous adenosine, isolated hearts were treated with a nonselective adenosine receptor blocker, 8-sulfaphenyltheophylline (8-SPT), and tc-Y-NH(2) before ischemia. 8-SPT abolished the protective effects of tc-Y-NH(2) but did not affect IS when given alone. Adenosine-mediated survival pathways were then explored. The cardioprotective effects of tc-Y-NH(2) were abolished by inhibition of Akt (wortmannin), extracellular signal-regulated kinase 1/2 [PD98059 (2'-amino-3'-methoxyflavone)], nitric-oxide synthase [N(G)-monomethyl-l-arginine (l-NMA)], and K(ATP) channels (glibenclamide). PD98059, l-NMA, and glibenclamide alone had no effect on cardioprotection in vitro. Furthermore, inhibition of mitochondrial K(ATP) channels [5-hydroxydecanoic acid (5-HD)] and sarcolemmal K(ATP) channels (sodium (5-(2-(5-chloro-2-methoxybenzamido)ethyl)-2-methoxyphenylsulfonyl)(methylcarbamothioyl)amide; HMR 1098) abolished P4pal10-induced cardioprotection in vivo. Thrombin receptor blockade by PAR4 inhibition provides protection against injury from myocardial I/R by unmasking adenosine receptor signaling and supports the hypothesis of a coupling between thrombin receptors and adenosine receptors.


Asunto(s)
Adenosina/metabolismo , Daño por Reperfusión Miocárdica/prevención & control , Receptores de Trombina/antagonistas & inhibidores , Transducción de Señal/fisiología , Animales , Cardiotónicos/farmacología , Cardiotónicos/uso terapéutico , Corazón/efectos de los fármacos , Corazón/fisiología , Masculino , Daño por Reperfusión Miocárdica/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Trombina/metabolismo , Transducción de Señal/efectos de los fármacos
7.
Cardiovasc Res ; 72(1): 143-51, 2006 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-16930572

RESUMEN

OBJECTIVE: The relative contributions of the fraction of inspired oxygen (FIO2) and atmospheric pressure (ATM) to cardioprotection are unknown. We determined whether the product of FIO2 x ATM (oxygen partial pressure) controls the extent of hyperoxic+hyperbaric-induced cardioprotection and involves activation of nitric oxide synthase (NOS). METHODS: Adult Sprague Dawley rats (n = 10/gp) were treated for 1 h with (1) normoxia+normobaria (21% O2 at 1 ATM), (2) hyperoxia+normobaria (100% O2 at 1 ATM), (3) normoxia+hyperbaria (21% O2 at 2 ATM) and (4) hyperoxia+hyperbaria (100% O2 at 2 ATM). RESULTS: Infarct size following 25 min ischemia and 180 min reperfusion was decreased following hyperoxia+normobaria and normoxia+hyperbaria compared with normoxia+normobaria and further decreased following hyperoxia+hyperbaria treatment. l-NAME (200 microM) reversed the cardioprotective effects of hyperoxia+hyperbaria. Nitrite plus nitrate content was increased 2.2-fold in rats treated with normoxia+hyperbaria and hyperoxia+hyperbaria. NOS3 protein increased 1.2-fold and association of hsp90 with NOS3 four-fold in hyperoxic+hyperbaric rats. CONCLUSIONS: Cardioprotection conferred by hyperoxia+hyperbaria is directly dependent on oxygen availability and mediated by NOS.


Asunto(s)
Oxigenoterapia Hiperbárica , Daño por Reperfusión Miocárdica/prevención & control , Miocardio/química , Óxido Nítrico Sintasa de Tipo III/metabolismo , Animales , Activación Enzimática , Proteínas HSP90 de Choque Térmico/metabolismo , Hemo-Oxigenasa 1/metabolismo , Masculino , Isquemia Miocárdica/metabolismo , Reperfusión Miocárdica , Daño por Reperfusión Miocárdica/metabolismo , Nitratos/análisis , Óxido Nítrico/metabolismo , Oxígeno/metabolismo , Perfusión , Ratas , Ratas Sprague-Dawley
8.
Circ Res ; 91(4): 300-6, 2002 Aug 23.
Artículo en Inglés | MEDLINE | ID: mdl-12193462

RESUMEN

Chronic hypoxia increases endothelial nitric oxide synthase (eNOS) production of nitric oxide (*NO) and cardioprotection in neonatal rabbit hearts. However, the mechanism by which this occurs remains unclear. Recent studies suggest that heat shock protein 90 (hsp90) alters eNOS function. In the present study, we examined the role of hsp90 in eNOS-dependent cardioprotection in neonatal rabbit hearts. Chronic hypoxia increased recovery of postischemic left ventricular developed pressure (LVDP). Geldanamycin (GA), which inhibits hsp90 and increases oxidative stress, decreased functional recovery in normoxic and hypoxic hearts. To determine if a loss in *NO, afforded by GA, decreased recovery, GA-treated hearts were perfused with S-nitrosoglutathione (GSNO) as a source of *NO. GSNO increased recovery of postischemic LVDP in GA-treated normoxic and hypoxic hearts to baseline levels. Although chronic hypoxia decreased phosphorylated eNOS (S1177) levels by approximately 4- to 5-fold and total Akt and phosphorylated Akt by 4- and 5-fold, it also increased hsp90 association with eNOS by more than 3-fold. Using hydroethidine (HEt), a fluorescent probe for superoxide, we found that hypoxic hearts contained less ethidine (Et) staining than normoxic hearts. Normoxic hearts generated 3 times more superoxide by an N(omega)-nitro-L-arginine methyl ester (L-NAME)-inhibitable mechanism than hypoxic hearts. Taken together, these data indicate that the association of hsp90 with eNOS is important for increasing *NO production and limiting eNOS-dependent superoxide anion generation. Such changes in eNOS function appear to play a critical role in protecting the myocardium against ischemic injury.


Asunto(s)
Proteínas HSP90 de Choque Térmico/metabolismo , Hipoxia/metabolismo , Isquemia Miocárdica/metabolismo , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico/metabolismo , Proteínas Serina-Treonina Quinasas , Animales , Animales Recién Nacidos , Benzoquinonas , Western Blotting , Enfermedad Crónica , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Colorantes Fluorescentes , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Hipoxia/complicaciones , Técnicas In Vitro , Lactamas Macrocíclicas , Isquemia Miocárdica/complicaciones , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III , Estrés Oxidativo/efectos de los fármacos , Fosforilación/efectos de los fármacos , Unión Proteica , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-akt , Quinonas/farmacología , Conejos , Recuperación de la Función/efectos de los fármacos , Serina/metabolismo , Superóxidos/metabolismo , Función Ventricular Izquierda/efectos de los fármacos
9.
PLoS One ; 11(8): e0160840, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27505423

RESUMEN

Intestinal microbiota determine severity of myocardial infarction in rats. We determined whether low molecular weight metabolites derived from intestinal microbiota and transported to the systemic circulation are linked to severity of myocardial infarction. Plasma from rats treated for seven days with the non-absorbed antibiotic vancomycin or a mixture of streptomycin, neomycin, polymyxin B and bacitracin was analyzed using mass spectrometry-based metabolite profiling platforms. Antibiotic-induced changes in the abundance of individual groups of intestinal microbiota dramatically altered the host's metabolism. Hierarchical clustering of dissimilarities separated the levels of 284 identified metabolites from treated vs. untreated rats; 193 were altered by the antibiotic treatments with a tendency towards decreased metabolite levels. Catabolism of the aromatic amino acids phenylalanine, tryptophan and tyrosine was the most affected pathway comprising 33 affected metabolites. Both antibiotic treatments decreased the severity of an induced myocardial infarction in vivo by 27% and 29%, respectively. We then determined whether microbial metabolites of the amino acids phenylalanine, tryptophan and tyrosine were linked to decreased severity of myocardial infarction. Vancomycin-treated rats were administered amino acid metabolites prior to ischemia/reperfusion studies. Oral or intravenous pretreatment of rats with these amino acid metabolites abolished the decrease in infarct size conferred by vancomycin. Inhibition of JAK-2 (AG-490, 10 µM), Src kinase (PP1, 20 µM), Akt/PI3 kinase (Wortmannin, 100 nM), p44/42 MAPK (PD98059, 10 µM), p38 MAPK (SB203580, 10 µM), or KATP channels (glibenclamide, 3 µM) abolished cardioprotection by vancomycin, indicating microbial metabolites are interacting with cell surface receptors to transduce their signals through Src kinase, cell survival pathways and KATP channels. These inhibitors have no effect on myocardial infarct size in untreated rats. This study links gut microbiota metabolites to severity of myocardial infarction and may provide future opportunities for novel diagnostic tests and interventions for the prevention of cardiovascular disease.


Asunto(s)
Microbioma Gastrointestinal , Infarto del Miocardio/metabolismo , Infarto del Miocardio/microbiología , Animales , Antibacterianos/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Metabolómica , Fenotipo , Ratas , Vancomicina/farmacología
10.
Circulation ; 106(2): 239-45, 2002 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-12105165

RESUMEN

BACKGROUND: Many infants who undergo heart surgery have a congenital cyanotic defect in which the heart is chronically perfused with hypoxic blood. However, the signaling pathways by which infant hearts adapt to chronic hypoxia and resist subsequent surgical ischemia is unknown. METHODS AND RESULTS: We determined the activation and translocation of protein kinase C (PKC) isoforms and mitogen activated protein kinases (MAP kinases) in 15 infants with cyanotic (SaO2<85%) or acyanotic (SaO2>95%) heart defects undergoing surgical repair and in 80 rabbits raised from birth in a hypoxic (SaO2<85%) or normoxic (SaO2>95%) environment. Tissues from infant human and rabbit hearts were processed for Western and in vitro kinase analysis. In human infants with cyanotic heart defects, PKCepsilon, p38 MAP kinase, and JUN kinase but not p42/44 MAP kinase were activated and translocated from the cytosolic to the particulate fraction compared with acyanotic heart defects. In rabbit infants there was a parallel response for PKCepsilon, p38 MAP kinase, and JUN kinase similar to humans. In infant rabbit hearts inhibition of PKCepsilon with chelerythrine, p38 MAP kinase, with SB203580 and JUN kinase with curcumin abolished the cardioprotective effects of chronic hypoxia but had no effects on normoxic hearts. CONCLUSIONS: Infant human and rabbit hearts adapt to chronic hypoxia through activation of PKCepsilon, p38 MAP kinase, and JUN kinase signal transduction pathways. These pathways may be responsible for cardioprotection in the chronically hypoxic infant rabbit heart.


Asunto(s)
Cardiopatías Congénitas/complicaciones , Hipoxia/enzimología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Miocardio/enzimología , Proteína Quinasa C/metabolismo , Factor de Transcripción Activador 2 , Transporte Activo de Núcleo Celular , Adaptación Fisiológica , Animales , Cardiotónicos/metabolismo , Núcleo Celular/metabolismo , Enfermedad Crónica , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Activación Enzimática , Femenino , Atrios Cardíacos/enzimología , Cardiopatías Congénitas/cirugía , Ventrículos Cardíacos/enzimología , Humanos , Hipoxia/etiología , Lactante , Recién Nacido , Masculino , Isquemia Miocárdica/etiología , Técnicas de Cultivo de Órganos , Fosforilación , Conejos , Factores de Transcripción/metabolismo
11.
Pharmacol Res Perspect ; 3(3): e00145, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26171225

RESUMEN

The ability of simvastatin to mitigate the increases in risk factors for and the occurrence of cardiac disease after 10 Gy total body irradiation (TBI) was determined. This radiation dose is relevant to conditioning for stem cell transplantation and threats from radiological terrorism. Male rats received single dose TBI of 10 Gy. Age-matched, sham-irradiated rats served as controls. Lipid profile, heart and liver morphology and cardiac mechanical function were determined for up to 120 days after irradiation. TBI resulted in a sustained increase in total- and LDL-cholesterol (low-density lipoprotein-cholesterol), and triglycerides. Simvastatin (10 mg/kg body weight/day) administered continuously from 9 days after irradiation mitigated TBI-induced increases in total- and LDL-cholesterol and triglycerides, as well as liver injury. TBI resulted in cellular peri-arterial fibrosis, whereas control hearts had less collagen and fibrosis. Simvastatin mitigated these morphological injuries. TBI resulted in cardiac mechanical dysfunction. Simvastatin mitigated cardiac mechanical dysfunction 20-120 days following TBI. To determine whether simvastatin affects the ability of the heart to withstand stress after TBI, injury from myocardial ischemia/reperfusion was determined in vitro. TBI increased the severity of an induced myocardial infarction at 20 and 80 days after irradiation. Simvastatin mitigated the severity of this myocardial infarction at 20 and 80 days following TBI. It is concluded simvastatin mitigated the increases in risk factors for cardiac disease and the extent of cardiac disease following TBI. This statin may be developed as a medical countermeasure for the mitigation of radiation-induced cardiac disease.

12.
Radiat Res ; 180(3): 247-58, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23919311

RESUMEN

The objective of this study was to determine whether radiation-induced injury to the heart after 10 Gy total body irradiation (TBI) is direct or indirect. Young male WAG/RijCmcr rats received a 10 Gy single dose using TBI, upper hemi-body (UHB) irradiation, lower hemi-body (LHB) irradiation, TBI with the kidneys shielded or LHB irradiation with the intestines shielded. Age-matched, sham-irradiated rats served as controls. The lipid profile, kidney injury, heart and liver morphology and cardiac function were determined up to 120 days after irradiation. LHB, but not UHB irradiation, increased the risk factors for cardiac disease as well as the occurrence of cardiac and kidney injury in a way that was quantitatively and qualitatively similar to that observed after TBI. Shielding of the kidneys prevented the increases in risk factors for cardiac disease. Shielding of the intestines did not prevent the increases in risk factors for cardiac disease. There was no histological evidence of liver injury 120 days after irradiation. Injury to the heart from irradiation appears to be indirect, supporting the notion that injury to abdominal organs, principally the kidneys, is responsible for the increased risk factors for and the occurrence of cardiac disease after TBI and LHB irradiation.


Asunto(s)
Corazón/efectos de la radiación , Dosis de Radiación , Traumatismos Experimentales por Radiación/etiología , Irradiación Corporal Total , Animales , Secuencia de Bases , Cartilla de ADN , Intestinos/efectos de la radiación , Riñón/efectos de la radiación , Masculino , Ratas , Factores de Riesgo
13.
Cardiovasc Res ; 83(2): 325-34, 2009 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-19380418

RESUMEN

AIMS: Thrombin activates protease-activated receptor 1 by proteolytic cleavage of the N-terminus. Although much research has focused on the activated receptor, little is known about the 41-amino acid N-terminal peptide (parstatin). We hypothesized that parstatin would protect the heart against ischaemia-reperfusion injury. METHODS AND RESULTS: We assessed the protective role of parstatin in an in vivo and in vitro rat model of myocardial ischaemia-reperfusion injury. Parstatin treatment before, during, and after ischaemia decreased infarct size by 26%, 23%, and 18%, respectively, in an in vivo model of ischaemia-reperfusion injury. Parstatin treatment immediately before ischaemia decreased infarct size by 65% and increased recovery in ventricular function by 23% in an in vitro model. We then assessed whether parstatin induced cardioprotection by activation of a Gi-protein-dependent pathway. Gi-protein inactivation by pertussis toxin completely abolished the cardioprotective effects. The cardioprotective effects were also abolished by inhibition of nitric oxide synthase (NOS), extracellular signal-regulated kinases 1/2 (ERK1/2), p38 mitogen-activated protein kinase (p38 MAPK), and K(ATP) channels in vitro. Furthermore, parstatin increased coronary flow and decreased perfusion pressure in the isolated heart. The vasodilatory properties of parstatin were confirmed in rat coronary arterioles. CONCLUSION: A single treatment of parstatin administered prior to ischaemia confers immediate cardioprotection by recruiting the Gi-protein activation pathway including p38 MAPK, ERK1/2, NOS, and K(ATP) channels. Parstatin exerts effects on both the cardiomyocytes and the coronary circulation to induce cardioprotection. This suggests a potential therapeutic role of parstatin in the treatment of cardiac injury resulting from ischaemia and reperfusion.


Asunto(s)
Cardiotónicos/farmacología , Infarto del Miocardio/prevención & control , Daño por Reperfusión Miocárdica/prevención & control , Fragmentos de Péptidos/farmacología , Receptor PAR-1/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Circulación Coronaria/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/metabolismo , Guanilato Ciclasa/metabolismo , Frecuencia Cardíaca/efectos de los fármacos , Canales KATP/efectos de los fármacos , Canales KATP/metabolismo , Masculino , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/fisiopatología , Miocardio/metabolismo , Miocardio/patología , Óxido Nítrico Sintasa de Tipo III/metabolismo , Bloqueadores de los Canales de Potasio/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Citoplasmáticos y Nucleares/metabolismo , Transducción de Señal/efectos de los fármacos , Guanilil Ciclasa Soluble , Factores de Tiempo , Vasodilatación/efectos de los fármacos , Función Ventricular Izquierda/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
14.
Protein Sci ; 18(7): 1359-69, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19551879

RESUMEN

The chemokine stromal cell-derived factor-1 (SDF-1/CXCL12) directs leukocyte migration, stem cell homing, and cancer metastasis through activation of CXCR4, which is also a coreceptor for T-tropic HIV-1. Recently, SDF-1 was shown to play a protective role after myocardial infarction, and the protein is a candidate for development of new anti-ischemic compounds. SDF-1 is monomeric at nanomolar concentrations but binding partners promote self-association at higher concentrations to form a typical CXC chemokine homodimer. Two NMR structures have been reported for the SDF-1 monomer, but only one matches the conformation observed in a series of dimeric crystal structures. In the other model, the C-terminal helix is tilted at an angle incompatible with SDF-1 dimerization. Using a rat heart explant model for ischemia/reperfusion injury, we found that dimeric SDF-1 exerts no cardioprotective effect, suggesting that the active species is monomeric. To resolve the discrepancy between existing models, we solved the NMR structure of the SDF-1 monomer in different solution conditions. Irrespective of pH and buffer composition, the C-terminal helix remains tilted at an angle with no evidence for the perpendicular arrangement. Furthermore, we find that phospholipid bicelles promote dimerization that necessarily shifts the helix to the perpendicular orientation, yielding dipolar couplings that are incompatible with the NOE distance constraints. We conclude that interactions with the alignment medium biased the previous structure, masking flexibility in the helix position that may be essential for the distinct functional properties of the SDF-1 monomer.


Asunto(s)
Cardiotónicos/química , Quimiocina CXCL12/química , Animales , Cardiotónicos/metabolismo , Cardiotónicos/farmacología , Quimiocina CXCL12/metabolismo , Quimiocina CXCL12/farmacología , Dimiristoilfosfatidilcolina/metabolismo , Modelos Animales de Enfermedad , Corazón/efectos de los fármacos , Histidina/química , Concentración de Iones de Hidrógeno , Micelas , Modelos Moleculares , Infarto del Miocardio/tratamiento farmacológico , Reperfusión Miocárdica , Resonancia Magnética Nuclear Biomolecular , Fosfatos/química , Éteres Fosfolípidos/metabolismo , Multimerización de Proteína , Ratas , Electricidad Estática
15.
Int J Radiat Biol ; 85(12): 1089-100, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19995235

RESUMEN

PURPOSE: To determine the impact of 10 Gy total body irradiation (TBI) or local thorax irradiation, a dose relevant to a radiological terrorist threat, on lipid and liver profile, coronary microvasculature and ventricular function. MATERIALS AND METHODS: WAG/RijCmcr rats received 10 Gy TBI followed by bone marrow transplantation, or 10 Gy local thorax irradiation. Age-matched, non-irradiated rats served as controls. The lipid profile and liver enzymes, coronary vessel morphology, nitric oxide synthase (NOS) isoforms, protease activated receptor (PAR)-1 expression and fibrinogen levels were compared. Two-dimensional strain echocardiography assessed global radial and circumferential strain on the heart. RESULTS: TBI resulted in a sustained increase in total and low density lipoprotein (LDL) cholesterol (190 +/- 8 vs. 58 +/- 6; 82 +/- 8 vs. 13 +/- 3 mg/dl, respectively). The density of small coronary arterioles was decreased by 32%. Histology revealed complete blockage of some vessels while cardiomyocytes remained normal. TBI resulted in cellular peri-arterial fibrosis whereas control hearts had symmetrical penetrating vessels with less collagen and fibroblasts. TBI resulted in a 32 +/- 4% and 28 +/- 3% decrease in endothelial NOS and inducible NOS protein, respectively, and a 21 +/- 4% and 35 +/- 5% increase in fibrinogen and PAR-1 protein respectively, after 120 days. TBI reduced radial strain (19 +/- 8 vs. 46 +/- 7%) and circumferential strain (-8 +/- 3 vs. -15 +/- 3%) compared to controls. Thorax-only irradiation produced no changes over the same time frame. CONCLUSIONS: TBI with 10 Gy, a dose relevant to radiological terrorist threats, worsened lipid profile, injured coronary microvasculature, altered endothelial physiology and myocardial mechanics. These changes were not manifest with local thorax irradiation. Non-thoracic circulating factors may be promoting radiation-induced injury to the heart.


Asunto(s)
Enfermedad de la Arteria Coronaria/etiología , Rayos gamma/efectos adversos , Corazón/fisiopatología , Corazón/efectos de la radiación , Miocardio/patología , Dosis de Radiación , Irradiación Corporal Total/efectos adversos , Animales , Trasplante de Médula Ósea , Colágeno/metabolismo , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/patología , Modelos Animales de Enfermedad , Fibrinógeno/metabolismo , Fibroblastos/metabolismo , Lípidos/sangre , Masculino , Óxido Nítrico Sintasa/química , Óxido Nítrico Sintasa/metabolismo , Ratas , Ratas Wistar , Receptor PAR-1/metabolismo , Factores de Riesgo
16.
Basic Res Cardiol ; 102(4): 350-8, 2007 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-17468933

RESUMEN

Myocardial ischemia/reperfusion (I/R) injury is partly mediated by thrombin. In support, the functional inhibition of thrombin has been shown to decrease infarct size after I/R. Several cellular responses to thrombin are mediated by a G-protein coupled protease-activated receptor 1 (PAR1).However, the role of PAR1 in myocardial I/R injury has not been well characterized. Therefore, we hypothesized that PAR1 inhibition will reduce the amount of myocardial I/R injury. After we detected the presence of PAR1 mRNA and protein in the rat heart by RT-PCR and immunoblot analysis,we assessed the potential protective role of SCH 79797, a selective PAR1 antagonist, in two rat models of myocardial I/R injury. SCH 79797 treatment immediately before or during ischemia reduced myocardial necrosis following I/R in the intact rat heart. This response was dose-dependent with the optimal dose being 25 microg/kg IV. Likewise, SCH 79797 treatment before ischemia in the isolated heart model reduced infarct size and increased ventricular recovery following I/R in the isolated heart model with an optimal concentration of 1 microM. This reduction was abolished by a PAR1 selective agonist. SCH 79797-induced resistance to myocardial ischemia was abolished by wortmannin, an inhibitor of PI3 kinase; L-NMA, a NOS inhibitor; and glibenclamide, a nonselective K(ATP) channel blocker. PAR1 activating peptide,wortmannin, L-NMA and glibenclamide alone had no effect on functional recovery or infarct size. A single treatment of SCH 79797 administered prior to or during ischemia confers immediate cardioprotection suggesting a potential therapeutic role of PAR1 antagonist in the treatment of injury resulting from myocardial ischemia and reperfusion.


Asunto(s)
Cardiotónicos/farmacología , Infarto del Miocardio/prevención & control , Daño por Reperfusión Miocárdica/prevención & control , Pirroles/farmacología , Quinazolinas/farmacología , Receptor PAR-1/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Trombina/metabolismo , Androstadienos/farmacología , Animales , Cardiotónicos/uso terapéutico , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Gliburida/farmacología , Hirudinas/farmacología , Masculino , Infarto del Miocardio/genética , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Daño por Reperfusión Miocárdica/genética , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/fisiopatología , Miocardio/metabolismo , Miocardio/patología , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Oligopéptidos/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio/metabolismo , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pirroles/uso terapéutico , Quinazolinas/uso terapéutico , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor PAR-1/genética , Receptor PAR-1/metabolismo , Proteínas Recombinantes/farmacología , Proyectos de Investigación , Trombina/antagonistas & inhibidores , Factores de Tiempo , Función Ventricular Izquierda/efectos de los fármacos , Wortmanina , omega-N-Metilarginina/farmacología
17.
J Mol Cell Cardiol ; 43(4): 437-44, 2007 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-17765919

RESUMEN

Reduction of nitrite to nitric oxide during ischemia protects the heart against injury from ischemia/reperfusion. However the optimal dose of nitrite and the mechanisms underlying nitrite-induced cardioprotection are not known. We determined the ability of nitrite and nitrate to confer protection against myocardial infarction in two rat models of ischemia/reperfusion injury and the role of xanthine oxidoreductase, NADPH oxidase, nitric oxide synthase and K(ATP) channels in mediating nitrite-induced cardioprotection. In vivo and in vitro rat models of myocardial ischemia/reperfusion injury were used to cause infarction. Hearts (n=6/group) were treated with nitrite or nitrate for 15 min prior to 30 min regional ischemia and 180 min reperfusion. Xanthine oxidoreductase activity was measured after 15 min aerobic perfusion and 30 min ischemia. Nitrite reduced myocardial necrosis and decline in ventricular function following ischemia/reperfusion in the intact and isolated rat heart in a dose- or concentration-dependent manner with an optimal dose of 4 mg/kg in vivo and concentration of 10 microM in vitro. Nitrate had no effect on protection. Reduction in infarction by nitrite was abolished by the inhibition of flavoprotein reductases and the molybdenum site of xanthine oxidoreductase and was associated with an increase in activity of xanthine dehydrogenase and xanthine oxidase during ischemia. Inhibition of nitric oxide synthase had no effect on nitrite-induced cardioprotection. Inhibition of NADPH oxidase and K(ATP) channels abolished nitrite-induced cardioprotection. Nitrite but not nitrate protects against infarction by a mechanism involving xanthine oxidoreductase, NADPH oxidase and K(ATP) channels.


Asunto(s)
Cardiotónicos/farmacología , Canales KATP/fisiología , Infarto del Miocardio/prevención & control , NADPH Oxidasas/fisiología , Nitritos/farmacología , Xantina Deshidrogenasa/fisiología , Animales , Relación Dosis-Respuesta a Droga , Masculino , Nitratos/farmacología , Óxido Nítrico/fisiología , Ratas , Ratas Sprague-Dawley , Factores de Tiempo
18.
J Cardiovasc Pharmacol ; 50(5): 497-502, 2007 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-18030058

RESUMEN

Chronic hypoxia increases resistance to myocardial ischemia in infants. Activation of the mitochondrial big conductance Ca(2+) -sensitive K channel (mitoBKCa) has been shown to be protective in adult hearts; however, its role in infant hearts is unknown. Hearts from normoxic or hypoxic infant rabbits were perfused with a mitoKCa opener, NS1619, or blocker Paxilline before ischemia and reperfusion. Hypoxic hearts were more resistant to ischemia than normoxic hearts as manifested by a reduction in infarct size (9 +/- 5% versus 14 +/- 5%) and an increase in recovery of left ventricular developed pressure (LVDP) (69 +/- 7% versus 51 +/- 2%). NS1619 decreased infarct size in normoxic hearts from 14 +/- 5% to 10 +/- 5% and increased recovery of LVDP from 51 +/- 2% to 65 +/- 4%, but it had no effect on hypoxic hearts. Paxilline did not affect normoxic or hypoxic hearts. Activation of mitoBKCa protects normoxic infant rabbit hearts; however, cardioprotection by chronic hypoxia in infant rabbits does not appear involve mitoBKCa.


Asunto(s)
Canales de Potasio de Gran Conductancia Activados por el Calcio/metabolismo , Mitocondrias/metabolismo , Daño por Reperfusión Miocárdica/prevención & control , Miocardio/metabolismo , Animales , Animales Recién Nacidos , Bencimidazoles/farmacología , Circulación Coronaria/efectos de los fármacos , Corazón/efectos de los fármacos , Corazón/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Hipoxia/metabolismo , Hipoxia/fisiopatología , Indoles/farmacología , Precondicionamiento Isquémico Miocárdico , Subunidades alfa de los Canales de Potasio de Gran Conductancia Activados por Calcio/metabolismo , Canales de Potasio de Gran Conductancia Activados por el Calcio/agonistas , Canales de Potasio de Gran Conductancia Activados por el Calcio/antagonistas & inhibidores , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Infarto del Miocardio/prevención & control , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/fisiopatología , Miocardio/patología , Perfusión , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio/agonistas , Conejos , Función Ventricular/efectos de los fármacos
19.
Basic Res Cardiol ; 100(3): 187-97, 2005 May.
Artículo en Inglés | MEDLINE | ID: mdl-15611843

RESUMEN

The immediate protective effect of erythropoietin (EPO) against ischemia in heart suggests a role beyond hematopoiesis and the treatment of anemia. We determined the role of JAK/STAT and Ras/Rac/MAPK in the protective effect of EPO against ischemia-reperfusion injury in infant rabbit heart. EPO (1.0 U/ml) administered 15 minutes prior to 30-minutes global ischemia and 35 minutes reperfusion resulted in increased recovery of postischemic ventricular developed pressure in rabbit hearts. EPO exerted its immediate cardioprotective effect via activation of multiple signaling pathways by: 1) phosphorylation and activation of JAK1/2, STAT3 and STAT5A but not of STAT1alpha and STAT5B, 2) phosphorylation and activation of PI(3) kinase and its downstream kinases Akt and Rac, 3) activation of PKCepsilon, Raf, MEK1/2, p42/44 MAPK and p38 MAPK. Pretreatment with Wortmannin abolished EPO-induced Akt activation and phosphorylation. Pretreatment with Chelerythrine followed by EPO treatment resulted in partial inhibition of Raf activation, and abolished PKCepsilon and p38 MAPK activation without any effect on Akt, MEK1/2 and p42/44 MAPK. PD98059 abolished MEK1/2 and p42/44 MAPK activation with no effect on Akt, Raf and p38 MAPK activation. SB203580 inhibited only p38 MAPK activation by EPO. We can conclude EPO increases immediate cardioprotection through the activation of multiple signal transduction pathways.


Asunto(s)
Cardiotónicos/farmacología , Eritropoyetina/farmacología , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/prevención & control , Transducción de Señal/efectos de los fármacos , Factores de Edad , Animales , Cardiotónicos/metabolismo , Eritropoyetina/metabolismo , Factor 3 de Genes Estimulados por el Interferón/metabolismo , Janus Quinasa 1 , Janus Quinasa 2 , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Miocardio/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Conejos , Transducción de Señal/fisiología , Quinasas raf/metabolismo
20.
Am J Physiol Heart Circ Physiol ; 288(1): H175-84, 2005 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-15388508

RESUMEN

We determined whether isoflurane can confer delayed cardioprotection in the adult rat by triggering increased production of reactive oxygen (ROS) and nitrogen species (RNS). Our objectives were to determine 1) the concentration of isoflurane that confers delayed cardioprotection in the adult rat, 2) the role of ROS and RNS in the induction of delayed cardioprotection, and 3) the cellular sources of ROS and RNS responsible for induction of delayed cardioprotection by isoflurane. Male Sprague-Dawley rats at 8 wk of age (n = 8 rats/group) were exposed to 0.5%, 0.8%, 1%, and 2% (vol/vol) isoflurane-100% oxygen for 2 h. Isoflurane conferred delayed cardioprotection 24 h later at a concentration of 0.8% (vol/vol). Administration of manganese (III) tetrakis (4-benzoic acid)porphyrin chloride (MnTBAP), a superoxide scavenger (15 mg/kg ip), or N(G)-nitro-L-arginine methyl ester (L-NAME), a general nitric oxide synthase inhibitor (15 mg/kg ip), 15 min before isoflurane treatment abolished the delayed cardioprotective effects of isoflurane. MnTBAP and L-NAME had no effect on delayed cardioprotection in untreated hearts. Perfusion of isolated hearts with hydroethidine, a fluorescent probe for superoxide, after isoflurane treatment resulted in a twofold increase in ethidine staining of isoflurane-treated hearts compared with untreated controls, which was attenuated by myxothiazol, an inhibitor of the mitochondrial electron transport chain (0.2 mg/kg ip) and L-NAME (15 mg/kg ip). Nitrite and nitrate content in isoflurane-treated hearts was 1.5-fold higher than in untreated hearts, whereas myocardial reduced glutathione levels were decreased by 13% in 0.8% but not in 1.0% isoflurane-treated hearts. We conclude that isoflurane confers delayed cardioprotection in the adult rat, triggered by ROS and RNS.


Asunto(s)
Anestésicos por Inhalación/farmacología , Citoprotección , Corazón/efectos de los fármacos , Isoflurano/farmacología , Miocardio/metabolismo , Especies de Nitrógeno Reactivo/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Animales , Gases/sangre , Glutatión/metabolismo , Masculino , Miocardio/citología , Óxido Nítrico/biosíntesis , Óxido Nítrico Sintasa/metabolismo , Oxidación-Reducción/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Superóxido Dismutasa/metabolismo , Factores de Tiempo
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