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Mol Cell Biochem ; 391(1-2): 259-66, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24639125


The aim of this study is to investigate the dynamic alterations of cardiac connexin 43 (Cx43), matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-2 (TIMP-2) in the setting of different ventricular fibrillation (VF) duration. In this study, thirty-two dogs were randomly divided into sham control group, 8-min VF group, 12-min VF group, and 30-min VF group. Cx43 and phosphorylated Cx43 (p-Cx43) in tissues were detected by western blot and immunofluorescence analysis. MMP-2 and TIMP-2 were detected by western blot and immunohistochemistry analysis. The results showed that Cx43 levels in three VF groups were significantly decreased compared with sham control group. p-Cx43 levels in 12-min and 30-min VF groups were significantly reduced compared with sham control group. The ratio of p-Cx43/Cx43 was also decreased in VF groups. Compared with sham controls, no significant difference was observed between the sham control group and 8-min VF group in MMP-2 level, but MMP-2 level increased in 12-min and 30-min VF groups. The ratios of MMP-2/TIMP-2 were higher in VF groups, and were correlated with the duration of VF. A remarkable correlation was observed between the ratio of p-Cx43/Cx43 and MMP-2/TIMP-2 (r = -0.93, P < 0.01). In conclusion, the alteration of Cx43 and/or p-Cx43 levels and the imbalance of MMP-2 and TIMP-2 may contribute to the initiation and/or persistence of VF. Maneuvers managed to modulate Cx43 level or normalize the balance of MMP-2/TIMP-2 are promising to ameliorate prognosis of VF.

Conexina 43/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Fibrilação Ventricular/enzimologia , Animais , Western Blotting , Modelos Animais de Doenças , Cães , Imunofluorescência , Fosforilação
Tex Heart Inst J ; 39(6): 784-91, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23304014


In ventricular fibrillation, the uncoupling of gap junctions slows conduction velocity and increases action-potential dispersion, which slows and diminishes defibrillation. We studied how the peptide ZP123, a gap-junction enhancer, might lower defibrillation-energy requirements during ventricular fibrillation in live pigs. We randomly assigned 33 pigs into 3 groups: ZP123 (receiving a 1-µg/kg bolus and 10 µg/kg/hr of ZP123), control (receiving saline solution), and sham (undergoing a sham operation). After a 30-min administration of agents, ventricular fibrillation was induced and left untreated for 8 min. Biphasic defibrillation of 50 J was increased by 50-J increments as necessary. Defibrillation-energy requirements were defined as the lowest energy required to achieve defibrillation. Electrocardiographic values were obtained before and after the administration of agents. Western blot and immunofluorescence analyses were performed on ventricular myocardial samples. All but one pig survived. The ZP123 treatment did not alter electrocardiographic variables. In the ZP123 group, the average required defibrillation energy was lower than that in the control group (327.28±269.6 vs 610±192.64 J; P=0.015), and the cumulative percentage of successful defibrillation at upper energy levels was higher (P<0.05). Supraventricular rhythm occurred more often in the ZP123 group than in the control group (72.7% vs 50%, P=0.042). Western-blot and immunofluorescence results showed that ZP123 did not alter the total amount of connexin43 but did prevent its dephosphorylation. We conclude that ZP123 can reduce defibrillation-energy requirements by preventing connexin43 remodeling during prolonged ventricular fibrillation.

Conexina 43/metabolismo , Cardioversão Elétrica/métodos , Eletrocardiografia/efeitos dos fármacos , Oligopeptídeos/farmacologia , Fibrilação Ventricular/terapia , Remodelação Ventricular/fisiologia , Animais , Modelos Animais de Doenças , Feminino , Masculino , Suínos , Resultado do Tratamento , Fibrilação Ventricular/fisiopatologia
Am J Emerg Med ; 30(7): 1202-9, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22030200


AIMS: This study aimed to determine whether (a) there was an imbalance between matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1) after cardiopulmonary resuscitation (CPR) in a canine model of prolonged ventricular fibrillation (VF); (b) with the duration of VF, the degree of the imbalance would be greater; and (c) there was a relationship between the level of MMP-9 or TIMP-1 and the cardiac function. METHODS AND RESULTS: Ventricular fibrillation was electrically induced in 24 dogs. The animals were randomly divided into 3 groups (sham control, n = 8; 8-minute VF, n = 8; 12-minute VF, n = 8). Echocardiographic measurement and hemodynamic variables were recorded before VF and after return of spontaneous circulation. Tissue inhibitor of metalloproteinase 1 (TIMP-1) and MMP-9 were analyzed by Western blot and immunohistochemistry. Compared with sham controls, dogs under VF and CPR showed significantly decreased level of TIMP-1 (P < .001), and with the duration of VF, the level of TIMP-1 declined (P < .01). The level of MMP-9 did not achieve statistical significance in the 3 groups (P > .05); however, they were higher in VF and longer duration VF groups. The ratios of TIMP-1/MMP-9 were lower in VF groups (P < .05). There was a negative correlation between TIMP-1 and left atrium dimension and left ventricular diastolic dimensions (r = -0.83 and r = -0.96, respectively; P < .01) and a positive correlation between TIMP-1 and left ventricular ejection fraction (r = 0.85; P < .01). CONCLUSIONS: There was an imbalance between TIMP-1 and MMP-9 after CPR. It may partly contribute to the postresuscitation cardiac dysfunction.

Reanimação Cardiopulmonar , Metaloproteinase 9 da Matriz/sangue , Inibidor Tecidual de Metaloproteinase-1/sangue , Animais , Western Blotting , Modelos Animais de Doenças , Cães , Feminino , Coração/fisiopatologia , Masculino , Metaloproteinase 9 da Matriz/fisiologia , Fatores de Tempo , Inibidor Tecidual de Metaloproteinase-1/fisiologia , Fibrilação Ventricular/sangue , Fibrilação Ventricular/fisiopatologia , Fibrilação Ventricular/terapia
Cardiology ; 118(3): 147-52, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21606647


OBJECTIVES: It was the aim of this study to investigate the effect of ZP123 on prolonged ventricular fibrillation (VF) in swine. METHODS: VF was electrically induced in 20 pigs. The animals randomly received either ZP123 or saline control infusion before VF. After 8 min of untreated VF, cardiopulmonary resuscitation and biphasic defibrillation shocks were applied. VF mean frequency (VF(mf)) and mean amplitude (VF(ma)), hemodynamics, outcome of defibrillation and the rate of return of spontaneous circulation (ROSC) were analyzed. RESULTS: Compared with the control group, VF(mf) was higher but VF(ma) lower during the 8 min of VF in the drug group (11.8 ± 2.1 vs. 10.4 ± 2.0 Hz and 0.24 ± 0.10 vs. 0.31 ± 0.16 mV, respectively; p < 0.05). Hemodynamic variables in the 2 groups were comparable (p > 0.05). The defibrillation threshold was lower and the rate of successful defibrillation was higher in the drug group compared with the control group (92.2 ± 26.4 vs. 133.3 ± 28.9 J and 90 vs. 30%, respectively; p < 0.05). The rate of ROSC was not different between the 2 groups (40 vs. 30%; p > 0.05). CONCLUSION: In prolonged VF, ZP123 could decrease the defibrillation threshold and improve the rate of successful defibrillation. However, it could not improve the rate of ROSC - which may be due to its side effect of decreasing VF(ma).

Oligopeptídeos/uso terapêutico , Fibrilação Ventricular/tratamento farmacológico , Animais , Pressão Sanguínea , Modelos Animais de Doenças , Cardioversão Elétrica , Feminino , Junções Comunicantes , Masculino , Sus scrofa , Suínos , Fatores de Tempo , Fibrilação Ventricular/etiologia , Fibrilação Ventricular/fisiopatologia
Zhongguo Wei Zhong Bing Ji Jiu Yi Xue ; 22(10): 595-8, 2010 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-20977841


OBJECTIVE: To observe changes in connexin 43 (Cx43) after ventricular fibrillation (VF) and the effects of rotigaptide (ZP123) on Cx43. METHODS: Thirty domestic pigs were randomly assigned to three groups (10 in each group): sham group, model group and ZP123 group. VF was induced by an 80 V AC transthoracic shock for 5 seconds with the use of subcutaneous needles. Before the induction of VF, animals in ZP123 group were administered with ZP123 (1 µg/kg bolus+10 µg×kg(-1)×h(-1) dissolved in 50 ml normal saline and pumped for 15 minutes ). Those in model group received 50 ml normal saline pumped for 15 minutes. For pigs in sham group VF was not induced and no fluid was given. After 8 minutes of VF, animals were euthanized and myocardial tissues were harvested along the long axis of each left ventricular free wall. Immunofluorescence combined with laser scanning confocal microscope was used to detect the distribution of Cx43. Western blotting was used for quantitative determination of Cx43 protein expression. RESULTS: Immunofluorescence signals for Cx43 in sham group were strong and regularly distributed. In model group, Cx43 signals were weak and distributed in heterogeneity, while in ZP123 group, Cx43 signals were enhanced and their distribution were much more orderly. Compared with sham group, the percentage area and the optical densities (A value) of Cx43 fluorescence signals and Cx43 protein expression were significantly decreased in model group [the percentage area: (0.64±0.36)% vs.(1.27±0.19)%, A value: 15 201± 2 613 vs. 30 634±4 975, Cx43 protein expression: 0.72±0.08 vs. 0.97±0.07, all P<0.05]. The level of Cx43 expression in ZP 123 group [the percentage area (0.96±0.16)%, A value 22 100±4 404, Cx43 protein expression 0.82±0.04] was much higher than model group (all P<0.05). CONCLUSION: During VF, down-regulation of myocardial Cx43 expression occurred, which could be attenuated by administration of ZP123.

Conexina 43/metabolismo , Miocárdio/metabolismo , Fibrilação Ventricular/metabolismo , Animais , Modelos Animais de Doenças , Oligopeptídeos/farmacologia , Suínos