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Qi Wu,
Hai-Yan Wang,
Juan Li,
Peng Zhou,
Qiu-Lin Wang,
Lei Zhao,
Rong Fan,
Yue-Min Wang,
Xue-Zeng Xu,
Ding-Hua Yi,
Shi-Qiang Yu, Jian-Ming Pei
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ABSTRACT: The present study was designed to investigate the effect of κ-opioid receptor stimulation with U50,488H on endothelial function and underlying mechanism in rats with hypoxic pulmonary hypertension (HPH). Chronic hypoxia-induced HPH was simulated by exposing the rats to 10% oxygen for 2 wk. After hypoxia, mean pulmonary arterial pressure (mPAP), right ventricular pressure (RVP) and right ventricular hypertrophy index (RVHI) were measured. Relaxation of pulmonary artery in response to acetylcholine (ACh) was determined. Expression and activity of endothelial nitric oxide (NO) synthase (eNOS) and inducible NO synthase (iNOS) with NO production, total antioxidant capacity (T-AOC), gp91(phox) expression and nitrotyrosine content were measured. The effect of U50,488H administration during chronic hypoxia was investigated. Administration of U50,488H significantly decreased mPAP and right ventricular hypertrophy as evidenced by reduction in RVP and RVHI. These effects were mediated by κ-opioid receptor. In the meantime, treatment with U50,488H significantly improved endothelial function as evidenced by enhanced relaxation in response to ACh. Moreover, U50,488H resulted in a significant increase in eNOS phosphorylation, NO content in serum, and T-AOC in pulmonary artery of HPH rats. In addition, the activity of eNOS was enhanced, but the activity of iNOS was attenuated in the pulmonary artery of chronic hypoxic rats treated with U50,488H. On the other hand, U50,488H markedly blunted HPH-induced elevation of gp91(phox) expression and nitrotyrosine content in pulmonary artery, and these effects were blocked by nor-BNI, a selective κ-opioid receptor antagonist. These data suggest that κ-opioid receptor stimulation with U50,488H improves endothelial function in rats with HPH. The mechanism of action might be attributed to the preservation of eNOS activity, enhancement of eNOS phosphorylation, downregulation of iNOS activity and its antioxidative/nitrative effect.
PLoS ONE 01/2013; 8(5):e60850. · 4.09 Impact Factor
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Juan Li,
Quan-Xing Shi,
Rong Fan,
Li-Jun Zhang,
Shu-Miao Zhang,
Hai-Tao Guo,
Yue-Min Wang,
Aaron Joshua Kaye,
Alan David Kaye,
Franklin Rivera Bueno,
Xue-Zeng Xu,
Shi-Qiang Yu,
Ding-Hua Yi, Jian-Ming Pei
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ABSTRACT: Impairment of pulmonary endothelium function in the pulmonary artery is a direct result of chronic hypoxia. This study is to investigate the vasculoprotective effects of U50,488H (a selective κ-opioid receptor agonist) and its underlying mechanism in hypoxia-induced pulmonary artery endothelial functional injury. Chronic hypoxia was simulated by exposing the rats to 10% oxygen for two weeks. After hypoxia, right ventricular pressure (RVP) and right ventricular hypertrophy index (RVHI) were measured. The pulmonary vascular dysfunction, effect of nitric oxide synthase inhibitor (L-NAME) on the relaxation of U50,488H and level of nitric oxide (NO) were determined. In vitro, the signaling pathway involved in the anti-apoptotic effect of U50,488H was investigated. Cultured endothelial cells were subjected to simulated hypoxia, and cell apoptosis was determined by TUNEL staining. U50,488H (1.25 mg/kg) significantly reduced RVP and RVHI in hypoxia. U50,488H markedly improved both pulmonary endothelial function (maximal vasorelaxation in response to ACh: 74.9±1.8%, n =6, P <0.01 vs. hypoxia for 2 wk group) and increased total NO production (1.65 fold). U50,488H relaxed the pulmonary artery rings of the hypoxic rats. This effect was partly abolished by L-NAME. In cells, U50,488H both increased NO production and reduced hypoxia-induced apoptosis. Moreover, pretreatment with nor-BNI (nor-binaltorphimine, a selective κ-opioid receptor antagonist), PI3K inhibitor, Akt inhibitor or L-NAME almost abolished anti-apoptotic effect exerted by U50,488H. U50,488H resulted in increases in Akt and eNOS phosphorylation. These results demonstrate that pretreatment with U50,488H attenuates hypoxia-induced pulmonary vascular endothelial dysfunction in an Akt-dependent and NO-mediated fashion.
Journal of Applied Physiology 11/2012; · 3.75 Impact Factor
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Yue-Min Wang,
Rong Fan,
Juan Li,
Li-Jun Zhang,
Quan-Xing Shi,
Xu-Zeng Xu,
Shi-Qiang Yu,
Ding-Hua Yi,
Aaron Joshua Kaye,
Franklin Rivera Bueno,
Alan David Kaye, Jian-Ming Pei
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ABSTRACT: In addressing the challenge of the low survival rates of rats with myocardial ischaemia, we developed a novel respiratory mask. We tested this mask on the rat model. We gave attention to several features of the mask: (1) shape, (2) size, (3) inlet, (4) outlet, (5) compatibility between rat head and the mask, (6) connection between mask and ventilator. We found certain features, especially to influence mask efficacy. These features include: mask shape, mask inlet and outlet, mask connection to the respiratory machine, mask mount on the rat head. We examined the rat mask in a model of chronic myocardial ischaemia; our model was the ligation of the coronary artery. The rats with the masks experienced an increase in survival by a factor of 50-90% compared with rats deprived of the masks. Towards the examination of myocardial ischaemia, our new mask may offer a platform replete with both efficiency and stability.
Laboratory Animals 10/2012; 46(4):293-8. · 1.21 Impact Factor
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Quan-Xing Shi,
Li-Jun Zhang,
Yuan Yao,
Quan-Yu Zhang,
Wei Wang,
Juan Li,
Yu-Long Shang,
Hui Bi,
Shu-Miao Zhang,
Hai-Tao Guo,
Yue-Min Wang,
Shi-Qiang Yu,
Ding-Hua Yi,
Franklin Rivera Bueno,
Alan David Kaye, Jian-Ming Pei
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ABSTRACT: κ-opioid receptor (κ-OR) activation with U50,488H, a selective κ-OR agonist, has been previously demonstrated to prevent against cardiac arrhythmias via stabilizing the synthesis and degradation of an integral membrane protein, Cx43, in gap junctions. However, the exact prevention mechanism remains unclear. The present study tested the hypothesis that the kappa OR agonist U50,488H mediates the prevention of arrhythmia through the regulation of intracellular calcium leading to the preservation of Cx43 protein. By performing electrocardiogram monitoring and immunoblotting in isolated Langendorff-perfused rat hearts, high concentrations of calcium-perfused rat hearts exhibited increased cardiac arrhythmias. Diminished expression of Cx43 protein was observed. The utilization of a whole-cell patch clamp technique revealed that U50,488H inhibited L-type calcium current in single ventricular myocytes in a dose-dependent manner. These effects were blocked by nor-binaltorphimine, potent and selective κ-OR antagonists. Administration of U50,488H before myocardial ischemia resulted in an attenuated of total arrhythmia scores. The attenuation effect was blocked by nor-binaltorphimine. The attenuation effect was antagonized both by Bay K8644, a L-type calcium channel agonist, and also by the Cx43 uncoupler heptanol. Finally, immunoblotting data demonstrated that the preservation of Cx43 protein conferred by U50,488H was reversed in the presence of Bay K8644. In summary, the present study demonstrates κ-OR activation with U50,488H may confer antiarrhythmic effects via modulation of the calcium-Cx43 pathway.
American journal of therapeutics 09/2012;
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ABSTRACT: To investigate the effect of compound nutrients on Th1/Th2 imbalance caused by changes in cytokines of Th cell subsets, interleukin (IL)-2, IL-6 and TNF-α, in rats with acute immobilization and cold water-immersion stress.
Male SD rats were randomly assigned to three groups including normal control group (C), acute stress group (S) and acute stress+compound nutrients group (S+CN). Stress procedure was the acute immobilization and cold water-immersion. The stress rats were fed water (Group S) or compound nutrient liquid (Group S+CN) by a feeding needle 1 week before acute stress, and then restrained and immersed in cold water for 30 min. The control rats were given water in the same way without stress stimulation. The rats were killed and blood samples were collected 0, 30, 60 and 120 min after stress, respectively. Serum was separated by centrifugation and stored at -70 DegreesCelsius until assayed. The serum levels of IL-2, IL-6 and TNF-α were analyzed by an enzyme-linked immunosorbent assay (ELISA) kit.
Acute immobilization and cold water-immersion stress reduced IL-2 level, and increased IL-6 and TNF-α level at different time points (0, 30, 60 and 120 min) after stress, which was most obvious at 30 min. Oral administration (gavage) of compound nutrients was found to moderate the acute immobilization and cold water-immersion stress-induced changes in serum IL-2, IL-6 and TNF-α, which was also most significant at 30 min after stress.
Complex nutrients can significantly alleviate the changes of Th1/Th2 cytokines in stress rats, including IL-2, IL-6 and TNF-α, which suggests that compound nutrients can improve the immune regulation function of stress rats and restore Th1/Th2 balance. Compound nutrients might enhance the body's anti-stress ability and lighten the stress-related damage, thus being a possible candidate for the therapeutic modulation of stress.
Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 06/2012; 28(6):601-3.
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ABSTRACT: This study was designed to investigate whether Resveratrol (Res) could be a prophylactic factor in the prevention of I/R injury and to shed light on its underlying mechanism. Primary culture of neonatal rat cardiomyocytes were randomly distributed into three groups: the normal group (cultured cardiomyocytes were in normal conditions), the I/R group (cultured cardiomyocytes were subjected to 2 h simulated ischemia followed by 4 h reperfusion), and the Res+I/R group (100 µmol/L Res was administered before cardiomyocytes were subjected to 2 h simulated ischemia followed by 4 h reperfusion). To test the extent of cardiomyocyte injury, several indices were detected including cell viability, LDH activity, Na(+)-K(+)-ATPase and Ca(2+)-ATPase activity. To test apoptotic cell death, caspase-3 activity and the expression of Bcl-2/Bax were detected. To explore the underlying mechanism, several inhibitors, intracellular calcium, SOD activity and MDA content were used to identify some key molecules involved. Res increased cell viability, Na(+)-K(+)-ATPase and Ca(2+)-ATPase activity, Bcl-2 expression, and SOD level. While LDH activity, capase-3 activity, Bax expression, intracellular calcium and MDA content were decreased by Res. And the effect of Res was blocked completely by either L-NAME (an eNOS inhibitor) or MB (a cGMP inhibitor), and partly by either DS (a PKC inhibitor) or Glybenclamide (a K(ATP) inhibitor). Our results suggest that Res attenuates I/R injury in cardiomyocytes by preventing cell apoptosis, decreasing LDH release and increasing ATPase activity. NO, cGMP, PKC and K(ATP) may play an important role in the protective role of Res. Moreover, Res enhances the capacity of anti-oxygen free radical and alleviates intracellular calcium overload in cardiomyocytes.
PLoS ONE 01/2012; 7(12):e51223. · 4.09 Impact Factor
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ABSTRACT: The aim of this study was to evaluate the cardiovascular and renal activities of a newly designed natriuretic peptide (NP). Here, we engineered a novel 28-amino acid chimeric peptide, termed AC-NP that combined the 17-amino acid ring of C type natriuretic peptide (CNP) with the 6-amino acid N-terminus and 5-amino acid C-terminus of atrial natriuretic peptide (ANP). Both in vitro and in vivo experiments were performed to determine the actions of AC-NP. In normal rats, AC-NP proved to be more potentially diuretic, natriuretic and hypotensive compared with other NPs, such as ANP, CNP and vasonatrin peptide (VNP), which is another man-made NP. In relaxation of isolated abdominal aorta from rat, AC-NP was equally effective to ANP, CNP and VNP. Elevated levels of 3',5'-guanosine monophosphate (cGMP) in plasma and urine cGMP excretion indicated the participation of cGMP in the functions of AC-NP. Taken together, innovative designed AD-NP might be a new candidate therapeutic peptide against cardiorenal disorders.
PLoS ONE 01/2011; 6(5):e20477. · 4.09 Impact Factor
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Quan-Yu Zhang,
Wei Wang,
Quan-Xing Shi,
Yu-Long Li,
Jing-Hui Huang,
Yuan Yao,
Juan Li,
Shu-Miao Zhang,
Rong Fan,
Jing-Jun Zhou,
Hai-Tao Guo,
Yue-Min Wang,
Wen Yin, Jian-Ming Pei
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ABSTRACT: Acute myocardial ischemia induces electrical and chemical uncoupling of gap junctions, which contributes to conduction abnormalities and re-entrant arrhythmias. We tested the hypothesis that structure and function of Connexin43 may vibrate during acute myocardial ischemia and reperfusion and κ-opioid receptor stimulation may stabilize the alteration of Connexin43.
An animal intervention study was conducted with comparison to a control group.
University preclinical research laboratory.
Age-, weight-, and sex-matched Sprague-Dawley rats.
Adult rat hearts were subjected to ischemia or ischemia/reperfusion, which was induced by temporary occlusion of the left main coronary artery. U50488H was given 10 mins before tissue specimens were taken or before ischemia (1.5 mg/kg, intravenous) and nor-BNI was given 15 mins before tissue specimens were taken or before ischemia (2 mg/kg, intravenous). Tissue samples came from left ventricular myocardium of the rat hearts.
Electrocardiogram, immunohistochemistry, immunoblotting, and reverse transcription-polymerase chain reaction were used to measure changes of arrhythmias, protein, and gene expression of Connexin43, respectively. κ-opioid receptor activation with U50 decreased arrhythmia in a model of myocardial ischemia and reperfusion. In normal hearts, immunohistochemical data showed reduced amount and lateralization of Connexin43 induced by κ-opioid receptor activation, whereas immunoblotting data demonstrated no significant changes between control and U50 group. During ischemia, however, Connexin43 protein underwent dephosphorylation and degradation, and Connexin43 mRNA was upregulated. These alterations were significantly attenuated on κ-opioid receptor stimulation. During ischemia and reperfusion, Connexin43 protein underwent dephosphorylation and degradation and recovered slowly during reperfusion. Activation of κ-opioid receptor accelerated recovery of phosphorylated and total Connexin43.
In normal rat hearts, Connexin43 translocates from intercellular junctions to intracellular locations on κ-opioid receptor activation. In rat hearts experiencing acute myocardial ischemia and reperfusion, protein and gene expression of Connexin43 undergo vibration. This phenomenon is stabilized when κ-opioid receptor is activated and by the fact that κ-opioid receptor produces antiarrhythmic effects.
Critical care medicine 09/2010; 38(12):2365-76. · 6.37 Impact Factor
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Yan Cui,
Shu-Miao Zhang,
Quan-Yu Zhang,
Rong Fan,
Juan Li,
Hai-Tao Guo,
Hui Bi,
Yue-Min Wang,
Yu-Zhen Hu,
Qi-Jun Zheng,
Chun-Hu Gu,
Shi-Qiang Yu,
Ding-Hua Yi,
Zhi-Chao Li, Jian-Ming Pei
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ABSTRACT: Modulation of intracellular calcium ([Ca(2+)](i)) transient in response to beta-adrenoceptor stimulation in the hearts of hindlimb unweighted (HLU) rats during simulated weightlessness has not been reported. In the present study, we adopted the rat tail suspension for 4 wk to simulate weightlessness. Effects of simulated microgravity on beta-adrenoceptor responsiveness were then studied. Mean arterial blood pressure, left ventricular pressure (LVP), systolic function [maximum positive change in pressure over time (+dP/dt(max))], and diastolic function [maximum negative change in pressure over time (-dP/dt(max))] were monitored during the in vivo experiment. beta-Adrenoceptor density was quantitated by radioactive ligand binding. Single rat ventricular myocyte was obtained by enzymatic dissociation method. +/-dP/dt(max), myocyte contraction, intracellular [Ca(2+)](i) transient, and L-type calcium current in response to beta-adrenoceptor stimulation with isoproterenol were measured. Compared with the control group, no significant changes were found in heart weight, body weight, and mean arterial blood pressure, whereas LVP and +/-dP/dt(max) were significantly reduced. LVP and +/-dP/dt(max) were significantly attenuated in the HLU group in response to isoproterenol administration. In the in vitro study, the beta-adrenoceptor density was unchanged. Effects of isoproterenol on electrically induced single-cell contraction and [Ca(2+)](i) transient in myocytes of ventricles in HLU rats were significantly attenuated. The enhanced L-type Ca(2+) current elicited by isoproterenol in cardiomyocytes was significantly decreased in the HLU group. The above results indicate that impaired function of L-type Ca(2+) current and decreased [Ca(2+)](i) transient cause the depressed responsiveness of the beta-adrenoceptor stimulation, which may be partially responsible for the depression of cardiac function.
Journal of Applied Physiology 04/2010; 108(4):838-44. · 3.75 Impact Factor
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Fan Rong,
Zhang Peng,
Ming-Xiang Ye,
Quan-Yu Zhang,
Yin Zhao,
Shu-Miao Zhang,
Hai-Tao Guo,
Bi Hui,
Yue-Min Wang,
Cheng Liang,
Chun-Hu Gu,
Chen Tao,
Qin Cui,
Shi-Qiang Yu,
Ding-Hua Yi, Jian-Ming Pei
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ABSTRACT: It remains unclear whether U50488H (a selective kappa-opioid receptor agonist) produces anti-apoptotic effect during ischemia and reperfusion (I/R). Therefore, the effect of U50488H on myocardial apoptosis was investigated in the present study.
Rats were subjected to 45min coronary artery occlusion and 180min of reperfusion. U50488H (1.5mg/kg IV) was given prior to occlusion. Nor-Binaltorphimine (nor-BNI) (2mg/kg IV), a selective kappa-opioid receptor antagonist, was given 10min prior to U50488H. Cardiac apoptosis was evaluated by terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end labeling (TUNEL) assay and in situ identification of nuclear DNA fragmentation.
The ultrastructure injury of myocardium, myocardial infarct size, and plasma CK and LDH were reduced significantly with administration of U50488H before I/R, whereas the effects of U50488H were abolished by nor-BNI. DNA fragments were visualized by agarose electrophoresis, and clear DNA ladder formation was observed in myocardial tissue from hearts subjected to I/R. Administration of U50488H before ischemia exerted a significant anti-apoptotic effect as evidenced by markedly weaker DNA ladder formation. TUNEL staining showed U50488H treatment before I/R significantly reduced the percentage of apoptotic cells, which was blocked by 5-HD, a mitochondrial k(ATP) channel blocker. In accordance, U50488H treatment significantly inhibited I/R-induced elevated activities of caspase-3 and caspase-9. U50488H also produced an increase in Bcl-2 and a decrease in Bax protein expression in the I/R heart, and the anti-apoptotic effects of U50488H were all blocked by nor-BNI.
U50488H reduces myocardial necrosis and apoptosis after I/R and activation of kappa-opioid receptor may mediate a role in U50488H-induced myocardial protection.
Archives of medical research 06/2009; 40(4):227-34. · 1.88 Impact Factor
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ABSTRACT: The present study evaluated the distribution of κ-opioid receptors (κ-ORs) in pulmonary arteries (PAs) in rats and investigated whether κ-ORs are altered in PAs during hypoxia. An animal model of hypobaric/hypoxic pulmonary hypertension and a pulmonary artery smooth muscle cell (PASMC) model of hypoxia were utilized. Distribution of κ-ORs was determined by fluorescence immunohistochemistry and changes in κ-ORs expression in PAs and PASMCs were determined by fluorescence immunohistochemistry or Western blot techniques. The κ-ORs were primarily distributed in the smooth muscle layer of the PAs and in the nucleus of PASMCs. The expression of the κ-ORs were increased in PAs of rats subjected to hypoxia for 1–4 week (P < 0.01). Accordingly, the expression of κ-ORs in PASMCs were also increased when subjected to hypoxia for 12–36 hr (P < 0.05). The present study has provided evidence for the first time of the precise location of κ-ORs in PAs and PASMCs of rats and that hypoxia upregulates expression of κ-ORs. Anat Rec, 2009. © 2009 Wiley-Liss, Inc.
The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology 05/2009; 292(7):1062 - 1067. · 1.47 Impact Factor
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ABSTRACT: The present study evaluated the distribution of kappa-opioid receptors (kappa-ORs) in pulmonary arteries (PAs) in rats and investigated whether kappa-ORs are altered in PAs during hypoxia. An animal model of hypobaric/hypoxic pulmonary hypertension and a pulmonary artery smooth muscle cell (PASMC) model of hypoxia were utilized. Distribution of kappa-ORs was determined by fluorescence immunohistochemistry and changes in kappa-ORs expression in PAs and PASMCs were determined by fluorescence immunohistochemistry or Western blot techniques. The kappa-ORs were primarily distributed in the smooth muscle layer of the PAs and in the nucleus of PASMCs. The expression of the kappa-ORs were increased in PAs of rats subjected to hypoxia for 1-4 week (P < 0.01). Accordingly, the expression of kappa-ORs in PASMCs were also increased when subjected to hypoxia for 12-36 hr (P < 0.05). The present study has provided evidence for the first time of the precise location of kappa-ORs in PAs and PASMCs of rats and that hypoxia upregulates expression of kappa-ORs.
The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology 05/2009; 292(7):1062-7. · 1.47 Impact Factor
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Juan Li,
Peng Zhang,
Quan-Yu Zhang,
Shu-Miao Zhang,
Hai-Tao Guo,
Hui Bi,
Yue-Min Wang,
Xin Sun,
Jin-Cheng Liu,
Liang Cheng,
Qin Cui,
Shi-Qiang Yu,
Alan David Kaye,
Ding-Hua Yi, Jian-Ming Pei
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ABSTRACT: The aim of the present study was to determine whether U50,488H, a selective kappa-opioid receptor agonist, inhibits the remodeling of the pulmonary artery (PA). In addition, changes in the concentrations of nitric oxide (NO), endothelin (ET) and angiotensin II (AngII) in hypoxic pulmonary hypertensive (HPH) rats were investigated to explore the mechanisms underlying the effects of U50, 488H on HPH. We found that intraperitoneal administration of U50,488H (every other day) during hypoxia depressed mean pulmonary arterial pressure (mPAP) and attenuated right ventricular pressure (RVP) and right ventricular hypertrophy, at the same time it inhibited remodeling of the PA compared with hypoxia for 2 wk. Moreover, U50,488H also inhibited proliferation of the pulmonary arterial smooth muscle cells (PASMCs) induced by hypoxia for 48 h in a dose-dependent manner. Compared with the 2 wk hypoxia group, U50,488H increased the concentration of NO and decreased the production of ET and AngII (P<0.01). In addition, acute intravenous administration of U50,488H after hypoxia for 4 wk decreased mPAP. Our results suggest that effects of anti-remodeling of the PA and anti-proliferation of the PASMC, and regulation of the vasomotor factors in both blood and pulmonary tissues of HPH rats may be critical mechanisms underlying the preventive and therapeutic effects of U50,488H in HPH rats.
Vascular Pharmacology 04/2009; 51(2-3):72-7. · 1.99 Impact Factor
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Wen Yin,
Peng Zhang,
Jing Hui Huang,
Quan Yu Zhang,
Rong Fan,
Juan Li,
Jing Jun Zhou,
Yu Zhen Hu,
Hai Tao Guo,
Shu Miao Zhang,
Yue Min Wang,
Alan David Kaye,
Chun Hu Gu,
Jin Cheng Liu,
Liang Cheng,
Qin Cui,
Ding Hua Yi, Jian Ming Pei
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ABSTRACT: The aim of the present study was to determine whether U50,488H (a selective kappa-opioid receptor agonist) inhibits cardiac hypertrophy and fibrosis induced by beta-adrenoceptor stimulation in a rat model. Cardiac hypertrophy and fibrosis were developed by intraperitoneal administration of isoprenaline (ip. 3.0 mg/kg/day,14 days). In the isoprenaline-treated group, heart weight and heart-to-body ratio increased significantly. Hypertrophic alterations were observed in light micrographs of tissue and transmission electron micrographs of myocardial ultra structures. Increases in heart weight, heart-to-body ratio, diameter of cardiomyocytes, and morphological hypertrophic alterations induced by isoprenaline were significantly attenuated by U50,488H(i.p. 1.25 mg/kg/day). Growth of cardiomyocytes was induced by incubating with isoprenaline (10(-6) mol/l), which resulted in an increase in optical density (OD) values. The increased OD value was attenuated by U50,488H(10(-7) mol/l-10(-5) mol/l) in a dose dependent manner. Animals receiving administration of isoprenaline displayed significant fibrosis. The extent of isoprenaline induced left ventricular fibrosis was dramatically reduced in U50,488H treated animals. Increased cardiac fibroblast proliferation and collagen synthesis induced by isoprenaline, as evidenced by increased OD value, (3)H-thymidine, and (3)H-proline incorporation, were significantly reduced in the U50,488H treated group. The specific extracellular matrix proteins, including type I, type III collagen and fibronectin, which increased after administration of isoproterenol, were also attenuated by U50,488H. The abovementioned effects of U50,488H were completely abolished by nor-BNI (nor-binaltorphimine), a selective kappa-opioid receptor antagonist. The enhanced intracellular Ca(2+) transient and L-type Ca(2+) current elicited by isoprenaline in cardiomyocytes were significantly inhibited by U50,488H. This study provides the first morphological evidence of the inhibitory effect of U50,488H on isoprenaline-induced cardiac hypertrophy and fibrosis via kappa-opioid receptor stimulation.
European journal of pharmacology 03/2009; 607(1-3):135-42. · 2.59 Impact Factor
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ABSTRACT: To determine whether insulin administration modulates the systemic inflammatory response in infants undergoing cardiac surgery with cardiopulmonary bypass, 60 infants undergoing cardiopulmonary bypass were randomly assigned into a routine therapy group or to an intensive insulin therapy group with 30 infants in each group. Plasma IL-1beta, IL-6, IL-10, and TNF-alpha levels were determined before anesthesia, at the initiation of cardiopulmonary bypass, and at 0, 6, 12, 24, and 48 h after cardiopulmonary bypass. Nuclear factor-kappaBp65 expression and IkappaB expression in peripheral blood mononuclear cells were also measured by Western blot analysis. TNF-alpha, IL-1beta, IL-6, and IL-10 levels were all elevated after the initiation of cardiopulmonary bypass. However, TNF-alpha, IL-1beta, and IL-6 levels were significantly attenuated in the intensive insulin therapy group compared to those in the routine therapy group after initiation of cardiopulmonary bypass (p<0.05 or <0.01). Meanwhile, plasma IL-10 levels were significantly higher in the intensive insulin therapy group than in the routine therapy group after initiation of cardiopulmonary bypass (p<0.05 or <0.01). Accordingly, Nuclear factor-kappaBp65 expression and IkappaB expression were significantly increased after initiation of cardiopulmonary bypass in both groups (p<0.05 or <0.01). The expression of Nuclear factor-kappaBp65, which induces the transcription of pro-inflammatory cytokines was significantly attenuated in the intensive insulin therapy group (p<0.05 or <0.01). Meanwhile, the expression of IkappaB, an inhibitor of NF-kappaB, was significantly higher in the intensive insulin therapy group (p<0.05 or <0.01). These results suggested that intensive insulin therapy may attenuate the systemic inflammatory response in infants undergoing cardiopulmonary bypass.
Cytokine 10/2008; 44(1):96-100. · 3.02 Impact Factor
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ABSTRACT: To investigate the mechanism of rosiglitazone (RSG, the activator of peroxisome proliferators activated receptor lambda) for inhibiting endothelin-1 (ET-1)-induced neonatal rat cardiac myocyte hypertrophy and the role of protein kinase C (PKC) and c-fos.
In vitro cultured neonatal rat cardiac myocytes were treated with ET-1, phorbol ester (PMA, the PKC activator), ET-1+RSG, ET-1+chelerythrine (che, the PKC inhibitor), PMA+RSG, or without treatment (control), respectively. The effects of RSG on the protein content, (3)H-leucine incorporation, PKC activity and C-fos protein expression were observed in the cardiac myocytes stimulated with ET-1 or PMA.
After two days of culture, the intracellular protein content in ET-1 group and PMA group were increased by 15% (339-/+15 microg/ml) and 13% (329-/+14 microg/ml) as compared with the control cells (290-/+13 microg/ml), respectively (P<0.01). Compared with the ET-1 group, cells treated with ET-1+10(-8) mol/L RSG, ET-1+10(-7) mol/L RSG, and ET-1+che showed decreased intracellular protein content by 10% (303-/+14 microg/ml, P<0.05), 12% (292-/+11 microg/ml, P<0.05), and 13% (291-/+12 microg/ml, P<0.01), respectively. The intracellular protein content in PMA+10(-7) mol/LRSG group was decreased by 10% (P<0.05) in comparison with the PMA group. RSG inhibited protein synthesis enhancement and increased (3)H-leucine incorporation induced by ET-1 and PMA, and antagonized the effects of ET-1 and PMA in promoting PKC activity and c-fos protein expression in the myocytes.
The inhibitory effect of RSG on ET-1- or PMA-induced myocyte hypertrophy is associated with PKC-c-fos pathway.
Nan fang yi ke da xue xue bao = Journal of Southern Medical University 06/2008; 28(6):1056-60.
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Wen Yin,
Jin-Cheng Liu,
Rong Fan,
Xi-Qing Sun,
Jin Ma,
Na Feng,
Quan Yu Zhang,
Zhao Yin,
Shu-Miao Zhang,
Hai-Tao Guo,
Hui Bi,
Yue-Min Wang,
Xin Sun,
Liang Cheng,
Qin Cui,
Shi-Qiang Yu,
Ding-Hua Yi, Jian-Ming Pei
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ABSTRACT: The modulation of beta-adrenoceptor signaling in the hearts of hindlimb unweighting (HU) simulated weightlessness rats has not been reported. In the present study, we adopted the rat tail suspension for 4 wk to simulate weightlessness; then the effects of simulated microgravity on beta-adrenoceptor signaling were studied. Mean arterial blood pressure (ABP), left ventricular pressure (LVP), systolic function (+dP/dtmax), and diastolic function (-dP/dtmax) were monitored in the course of the in vivo experiment. Single rat ventricular myocyte was obtained by the enzymatic dissociation method. Hemodynamics, myocyte contraction, and cAMP production in response to beta-adrenoceptor stimulation with isoproterenol or adenylyl cyclase stimulation with forskolin were measured, and Gs protein was also determined. Compared with the control group, no significant changes were found in heart weight, body weight and ABP, while LVP and +/-dP/dtmax were significantly reduced. The ABP decrease, LVP increase, and +/-dP/dtmax in response to isoproterenol administration were significantly attenuated in the HU group. The effects of isoproterenol on electrically induced single-cell contraction and cAMP production in myocytes of ventricles in the HU rats were significantly attenuated. The biologically active isoform, Gsalpha (45 kDa) in the heart, was unchanged. Both the increased electrically induced contraction and cAMP production in response to forskolin were also significantly attenuated in the simulated weightlessness rats. Above results indicated that impaired function of adenylyl cyclase causes beta-adrenoceptor desensitization, which may be partly responsible for the depression of cardiac function.
Journal of Applied Physiology 06/2008; 105(2):569-74. · 3.75 Impact Factor
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ABSTRACT: Multiple sclerosis (MS) is a chronic disease characterized by loss of myelin. However, data indicate that autoimmune cells could directly impair neuronal cell bodies and myelin sheath is lacking. The aim of the present study was to determine morphological evidence of the direct impairment of neurons by autoreactive lymphocytes and to further identify the subtypes of these lymphocytes.
Lymphocytes activated by myelin basic protein (MBP) 83-99 and neurons of human brain were co-cultured for 24 h.
Observations through scanning electron microscope showed that MBP-specific lymphocytes (CD4+, CD8+ cells, and NK cells) aggregated in the vicinity of the neuronal cell bodies and the myelin sheaths and attacked them directly, resulting in the degeneration of both neurons.
Our studies provide morphological evidences of the direct impairment of neuronal cell bodies and myelin sheaths by MBP-specific lymphocytes. Our studies also suggest that MBP-specific CD4+, CD8+, and NK cells might be involved in this process. These processes may play a role in the direct impairment of neurons and myelin sheaths in early stages of MS and provide evidences for the application of immunosuppressant therapy of MS.
Archives of Medical Research 02/2008; 39(1):45-51. · 1.88 Impact Factor
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ABSTRACT: Angelica and ChuanXiong are used to cure ischemic heart disease in China. Previous studies found that these two herbs could increase myocardial blood flow, oxygen-supply and keep myocardial oxygen balance, etc. However, the mechanisms of angiogenic effects of these two herbs are not well-known. The purpose of this study was to assess the effects of Angelica and ChuanXiong on vascular endothelial growth factor (VEGF) expression in rat myocardial infarction, on endothelial cell proliferation and quantity of vessels on chick embryo chorioallantoic membrane (CAM). In this study, rats were divided randomly into either pre-treatment or acute-treatment group and sacrificed at the end of the treatments. VEGF expression using Western blot analysis was significantly increased in the groups pre-treated with ChuanXiong and Angelica when compared to the control group (p < 0.05). There was significant increase in VEGF expression in the rats treated acutely with Angelica (p < 0.05). In the contrary, the rats treated with ChuanXiong showed a decrease in VEGF expression when compared to the acute-treatment control group (p < 0.05). Similar results were observed in immunohistochemistry of VEGF expression in the myocardia. Our study also demonstrated that these two herbs significantly enhanced endothelial cell proliferation (p < 0.05) and revascularity in CAM (p < 0.05). The data showed that Angelica and ChuanXiong could affect VEGF expression in rat myocardial infarction, promote endothelial cell proliferation and stimulate quantity of vessels on CAM model. The results suggest that Angelica and ChuanXiong have angiogenic effects, and may provide some mechanisms for the treatment of myocardial infarction and peripheral ischemia.
The American Journal of Chinese Medicine 01/2008; 36(3):541-54. · 1.98 Impact Factor
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ABSTRACT: The pathogenesis of myocardial stunning caused by brief ischemia and reperfusion remains unclear. The aim of the present study was to investigate the underlying mechanism of myocardial stunning. An isolated cell model of myocardial stunning was firstly established in isolated rat ventricular myocytes exposed to 8 min of simulated ischemia and 30 min of reperfusion, the cardiomyocyte contractile function was used to evaluate myocardial stunning. A diastolic Ca(2+) overload without significant changes in systolic Ca(2+) and the amplitude of Ca(2+) transient during the first 10 min of reperfusion played an important role in the occurrence of myocardial stunning. Decreasing Ca(2+) entry into myocardial cells with low Ca(2+) reperfusion was a very efficient way to prevent myocardial stunning. Diastolic Ca(2+) overload was closely related to the reverse mode of Na(+)/Ca(2+) exchanger (NCX) rather than L-type Ca(2+) channel. The activity of the reverse mode of NCX was found significantly higher at the initial time of reperfusion, and KB-R7943, a selective inhibitor of the reverse mode of NCX, administered at first 10 min of reperfusion rather than at the time of ischemia significantly attenuated myocardial stunning. In addition, NCX inhibition also attenuated the Ca(2+) oscillation and cardiac dysfunction when field stimulus was stopped at first 10 min of reperfusion. These data suggest that one of the important mechanisms of triggering myocardial stunning is diastolic Ca(2+) overload caused by activation of the reverse mode of NCX of cardiomyocytes during the initial period of reperfusion following brief ischemia.
European Journal of Pharmacology 11/2007; 572(1):1-11. · 2.52 Impact Factor
