Effects of spironolactone on atrial structural remodeling in rabbit model of chronic atrial fibrillation

AIM: To evaluate the effects and potential mechanism of spironolactone (SP) on atrial structural remodeling in rabbit model of chronic atrial fibrillation (AF). METHODS: The sternotomy was performed and the pacing electrodes were fixed to the left atria of New Zealand white rabbits. The animals were randomly divided into 3 groups. The rabbits were subjected to rapid atrial pacing (RAP) for 3 weeks in RAP group (intragastric administration with placebo) and RAP+SP group (intragastric administration with spironolactone at 20 mg·kg^-1·d^-1), respectively. The rabbits in sham group did not receive RAP and drugs. Before and after RAP, the structure and function of the atria were evaluated and AF inducibility was tested. After RAP, the atrial fibrosis was evaluated, and the expression levels of collagen I, collagen Ⅲ, matrix metalloproteinase (MMP)-2 and MMP-9 were determined. RESULTS: After 3 weeks of RAP, compared with sham group, obvious left atrial enlargement and dysfunction were observed in RAP group and RAP+SP group, but those had no significant differences in these 2 groups. Sustained AF was induced in 7, 5, and 0 rabbits in RAP group, RAP+SP group, and sham group, respectively. Compared with sham group, atrial interstitial fibrosis and the protein expression levels of collagen Ⅰ, collagen Ⅲ, MMP-2 and MMP-9 were all significantly increased in RAP group and RAP+SP group(P<0.05). Compared with RAP group, the the above indexes were all decreased in RAP+SP group(P<0.05). CONCLUSION: Spironolactone suppresses the atrial interstitial fibrosis and collagen expression, thus preventing atrial structural remodeling in rabbit model of chronic AF. The effect of spironolactone on reducing atrial MMP-2 and MMP-9 levels may be the potential mechanism.     

Effects of atorvastatin on atrial electrical remodeling in a rabbit model of chronic atrial fibrillation

AIM: To evaluate the effects of atorvastatin (ATO) on atrial electrical remodeling in a rabbit mo-del of chronic atrial fibrillation (AF) produced by 3 weeks of rapid atrial pacing (RAP). METHODS: The sternotomy was performed and the pacing and testing electrodes were fixed to the left atria of 24 New Zealand white rabbits. The animals were randomly divided into 3 groups. The rabbits in model group and ATO group were subjected to RAP for 3 weeks, and then were treated with placebo and ATO (2.5 mg·kg^-1·d^-1), respectively. The rabbits in sham group did not receive RAP and drugs. Electrophysiological examination was performed to test heart rate, P-wave duration, atrial effective refractory period (AERP) and AF inducibility. The protein expression levels of Cav1.2, Kv4.3 and myeloperoxidase (MPO) were detected by Western blot. RESULTS: Sustained AF was induced in 5 and 4 rabbilts in model group and atorvastatin group and no rabbits in sham group was found. After 3 weeks of RAP, compared with sham group, heart rate and P-wave duration were increased and AERP was shortened in model group and ATO group (P<0.05). Compared with model group, AERP was increased in ATO group (P<0.05), while heart rate and P-wave duration had no difference between these 2 groups. Compared with sham group, the protein levels of Cav1.2 and Kv4.3 were decreased, and protein level of MPO was increased in model group and ATO group (P<0.05). Compared with model group, Cav1.2 was increased and MPO was decreased in ATO group (P<0.05), while Kv4.3 had no difference between these 2 groups. CONCLUSION: Atorvastatin suppresses the down-regulation of atrial Cav1.2 protein level and the shortening of AERP, thus preventing atrial electrical remodeling in a rabbit model of chronic AF. The effect of atrovastatin on reducing atrial MPO level may be the potential mechanism.     

Effect of simvastatin on function of mouse pancreatic beta cells and its mechanisms

AIM: To observe the influence of simvastatin on insulin secretion function of mouse pancreatic beta cell line MIN6 and to explore its possible mechanisms.
METHODS: MIN6 cells were randomly divided into normal control group and low-, middle-and high-concentration simvastatin treatment groups, which were cultured for 48 h with high-glucose DMEM containing 15% fetal bovine serum plus 0, 2, 5 and 10 μmol/L simvastatin, respectively. The insulin secretion of MIN6 cells was measured by radioimmunoassay. The content of ATP in MIN6 cells was measured by biochemiluminescence method. The mRNA and protein expression levels of inwardly rectifying potassium channel 6.2 (Kir6.2), voltage-dependent calcium channel 1.2 (CaV1.2) and glucose transporter 2 (GLUT2) were detected by real-time fluorescence quantitative PCR and Western blotting, respectively.
RESULTS: Compared with normal control group, middle-and high-concentration simvastatin treatment markedly decreased the synthesis and secretion of insulin in MIN6 cells (P<005). The content of ATP in MIN6 cells was markedly decreased in simvastatin treatment groups (P<005). The mRNA expression level of Kir6.2 in MIN6 cells was significantly up-regulated in simvastatin treatment groups (P<001), while the mRNA expression levels of CaV1.2 and GLUT2 were significantly down-regulated in middle-and high-concentration simvastatin treatment groups (P<001). The protein expression of Kir6.2 was significantly increased but that of CaV1.2 was significantly decreased in middle-and high-concentration simvastatin treatment groups (P<001), and the protein expression level of GLUT2 was markedly decreased in high-concentration simvastatin treatment group (P<001).
CONCLUSION: Simvastatin inhibits insulin synthesis and secretion in mouse pancreatic beta cell line MIN6 via suppressing ATP production, up-regulating the expression of Kir6.2 and down-regulating the expression of CaV1.2 and GLUT2.     

Effect of pioglitazone on glucose metabolism and PPAR-γ expression in lipid-infused rats

AIM: To investigate the effect of pioglitazone (Pio) on glucose metabolism and peroxisome proliferators-activated receptor (PPAR)-γ expression in free fatty acid (FFA) -induced insulin resistance in rats. METHODS: A hyperinsulinaemic-euglycaemic clamp and ［3-3H］-glucose tracing technique were used in awake rats. Glucose metabolism in vivo and PPAR-γ in adipose tissue expression were assessed with elevation FFA by lipid infusion over 4 h in rats pretreated with or without Pio.RESULTS: During steady-state of clamp, there was a significant increase in plasma FFA in two lipid-infused groups, compared to control rats (P<0.01). The glucose infusion rates (GIR) in Pio-treated rats (P/L group), compared with controls, were significantly reduced ［(20.6±0.4) mg·kg^-1·min^-1 vs (33.6±0.6)mg·kg^-1· min^-1, P<0.01］, whereas the GIR was lower in the lipid group (L group) than that in the P/L group［(12.6±0.8) mg·kg^-1·min^-1 vs (20.6±0.4) mg·kg^-1·min^-1, P<0.01］. The hepatic glucose production (HGP) was significantly suppressed (85%) ［(18.3±2.1)mg· kg^-1·min^-1 (basal) vs (2.7±2.4)mg· kg^-1·min^-1, and (17.5±2.6) mg· kg^-1·min^-1 vs (2.6±1.0)mg· kg^-1·min^-1］, all P<0.01 during clamp in control and P/L groups. The suppressive effect of insulin on HGP was significantly blunted in L group［(17.3±2.1)mg· kg^-1·min^-1 vs (15.8±1.5)mg· kg^-1·min^-1］. The rate of glucose disappearance (GRd) was significantly reduced in two lipid-infused rats compared with controls［(26.6±1.6)mg· kg^-1·min^-1 and (23.2±0.9)mg· kg^-1·min^-1 vs (37.7±2.6)mg·kg^-1·min^-1,P<0.01］. The PPAR-γ expression of adipose tissue in P/L group was significantly upregulated. CONCLUSION: Lipid-infusion induces an acute insulin-resistance in vivo. Pio treatment upregulates the PPAR-γ of adipose tissue and suppresses HGP. Pio can protect partly against lipid-induced insulin resistance.     

Effects of DEHP on testosterone synthesis in fetal Leydig cells of newborn male rats

AIM: To observe the effects of diethylhexylphthalate(DEHP) on testosterone synthesis in fetal Leydig cells(FLC) of newborn male rats.METHODS: The pregnant rats were exposed to DEHP at dose of 10 mg·kg^-1·d^-1, 100 mg·kg^-1·d^-1 or 750 mg·kg^-1·d^-1(body weight) by gavage from gestation 12 days(GD 12) to postnatal 1 day(PND 1) respectively. The serum level of testosterone was detected by chemiluminescence. The morphology of FLC from the testes was observed under light microscope and transmission electron microscope. The mRNA expression of steroidogenic acute regulatory protein(StAR) and insulin-like growth factor I(IGF-I) was detected by real-time PCR(ΔΔCT). RESULTS: The serum testosterone level in low dose group was significantly higher than that in control, middle and high dose groups. The serum testosterone level in middle and high dose groups was significantly lower than that in control group(P<0.05). Light microscopy showed the aggregative cluster distribution of FLCs in low dose group, while manifested as tumor-like hyperplasia of FLCs in middile dose group and high dose group. Under electron microscope, the FLC in low dose group showed oval-shape or long spindle-shape, the lipid particles were decreased, but smooth endoplasmic reticulum and mitochondria were increased in cytoplasm. In middle and high dose group, the FLC were spindle or oval-shaped, showed large or small, nuclear large, round, rich in cytoplasm and cell aggregation, the cytoplasm was rich lipid particles with deep-stained, smooth endoplasmic reticulum and mitochondria were expanded. Compared to control group, the mRNA expression of StAR in low, middle and high dose group was decreased. The mRNA expression of StAR in high dose group was decreased more significantly(P<0.01) as compared to that in control group, while the mRNA expression of IGF-I in low dose group and middle dose group was increased, but that only in low dose group was increased more significantly as compared to control group(P<0.01). CONCLUSION: DEHP has toxic effect on FLC and changes the morphology and steroidogenic capacity in testicular FLC. The low dose of DEHP elevates the gene expression of IGF-I, and IGF-I stimulates the production of testosterone by FLC. The high dose of DEHP may inhibit the gene expression of StAR to reduce the serum levels of testosterone.     

Protective effects of tongxinluo,carvedilol and valsartan on microvascular endothelial function and integrity after late reperfused AMI in rabbits

AIM:To compare the protective effects of tongxinluo, a Chinese medicine, and carvedilol and valsartan on myocardium microvascular endothelial function and integrity after late reperfusion of acute myocardial infarction (AMI) in rabbits. METHODS:Forty-eight rabbits were randomly assigned to the following groups:(1) sham operated rabbits;(2) ischemia-reperfusion (I-R) controls;(3) tongxinluo (1.0 g·kg^-1·d^-1);(4) carvedilol (5 mg·kg^-1·d^-1);(5) valsartan (10 mg·kg^-1·d^-1) and (6) ticlopidine + aspirine (30 and 20 mg·kg^-1·d^-1, respectively) groups. After 3 d of drug treatment, the left coronary artery in the rabbit was ligated for 2 h and loosed subsequently for another 2 h. The serum levels of nitric oxide (NO₂^-/NO₃^-) and endothelin (ET) at baseline before AMI, 2 h after both AMI and reperfusion were examined. Also, the number of circulating endothelial cells (CEC), MI size and percentage myocardium focal bleeding incidence were determined 2 h after reperfusion. RESULTS:(1) The baseline level of NO₂^-/NO₃^- was significantly higher in tongxinluo group than that in other groups (all P<0.01), whereas the content of ET was not significantly different among the groups. 2 h after both AMI and reperfusion, NO₂^-/NO₃^- was significantly reduced (P<0.05, P<0.01) and ET was significantly increased in each group as compared with their baseline (P<0.05, P<0.01). Yet among the groups, NO₂^-/NO₃^- was still significantly higher and ET was significantly lower in tongxinluo-treated group than that in the other groups (P<0.05, P<0.01). (2) CEC number was significantly increased in I-R controls as compared with sham group (P<0.01), and was significantly reduced in the tongxinluo-treated groups as compared with I-R controls (P<0.05). (3) MI size was significantly reduced in the four treatment groups as compared with I-R controls (all P<0.01). (4) The percentage of myocardium focal bleeding incidence was significantly lower in tongxinluo and valsartan-treated groups than that in I-R controls (P<0.05, P<0.01). CONCLUSION:Tongxinluo as well as valsartan effectively protectsmyocardium endothelial function and integrity during AMI and late reperfusion,with the effects of tongxinluo being superior.     

Calcineurin signal transduction pathway involves in cardiomyocyte hypertrophy induced by prostaglandin F2α

AIM: To study the role of prostaglandin F₂α (PGF₂α) in cardiac hypertrophy and its relation with calcineurin (CaN) signal transduction pathway in vitro. METHODS: The cultured neonatal rat cardiomyocyte was used to observe the hypertrophic effect of PGF2α, and the hypertrophic response was assayed by measuring the cell diameter, protein content and atrial natriuretic factor (ANF) mRNA expression. For mechanism studies, the intracellular free calcium concentration (［Ca²⁺］_i) in cultured cardiomyocytes was measured by using Fura-2/AM as a fluorescent indicator. ANF and CaN mRNA expressions, and the expressions of CaN and its downstream effectors, NFAT₃ and GATA₄ proteins were assayed by RT-PCR and Western blotting, respectively.RESULTS: In cultured cardiomyocytes, PGF₂α induced profound hypertrophic morphology change, the significant increase in cell diameter and protein content in a concentration-dependent manner compared with those in vehicle control (P<0.01). The same result was found in measuring the ［Ca²⁺］_i in cardiomyocytes (P<0.01). PGF₂α at concentration of 10-7 mol/L significantly promoted ANF and CaN mRNA expressions and the protein expressions of CaN/NFAT₃/GATA₄ compared with those in the vehicle control (P<0.05). Cyclosporin A, a CaN inhibitor, markedly inhibited the myocyte hypertrophy (P<0.01), reduced the increased ［Ca²⁺］_i(P<0.01) and decreased the expressions of CaN mRNA and CaN/NFAT₃/GATA₄ proteins (P<0.05) compared with those of only PGF₂α　10^-7 mol/L treatment. CONCLUSION: Cardiomyocyte hypertrophy induced by PGF2α may be, at least in part, mediated by CaN signal transduction pathway activated by increasing ［Ca²⁺］_i.     

Expression of MPO,MMP-2 and MMP-9 in atrial myocardium of rabbit atrial fibrillation model

ATM: To investigate the expression of myeloperoxidase (MPO), matrix metalloproteinase (MMP)-2 and MMP-9 in the atrial myocardium, and their potential effects on atrial structural remodeling in a rabbit atrial fibrillation (AF) model. METHODS: The sternotomy was performed and the pacing electrode was fixed to the left atria of 20 New Zealand white rabbits. The animals were randomly divided into 2 groups:rapid atrial pacing (RAP) group and sham group. The rabbits in RAP group were subjected to RAP for 3 weeks. The structure and function of the atria and ventricle were analyzed by echocardiography. Atrial burst stimulation was performed to test AF inducibility. The atrial fibrosis was evaluated by Masson trichrome-staining. The mRNA and protein levels of MPO, MMP-2 and MMP-9 were detected by RT-qPCR and Western blot. RESULTS: After 3 weeks of RAP, obvious left atrial enlargement and dysfunction were observed, but almost no change of left ventricular diameter and function was found in RAP group compared with sham group. AF inducibility, atrial interstitial fibrosis and the mRNA and protein levels of MPO, MMP-2 and MMP-9 were all significantly increased in RAP group compared with sham group. CONCLUSION: Obvious atrial structural remodeling is found in the rabbit AF model induced by sustained RAP, and the up-regulation of MPO, MMP-2 and MMP-9 may be the potential molecular mechanism of atrial structural remodeling.     

Therapeutic effect of sodium arsenite on rheumatoid arthritis in rats

AIM:To study the molecular mechanism of rheumatoid arthritis (RA) and the effects of sodium arsenite on AP-1 and MIP-1. METHODS:32 Wistar female rats were randomly divided into 4 groups: normal control (C), arthritis (A), low concentration of sodium arsenite (LSA) and high concentration of sodium arsenite group (HSA).The LSA group and the HSA group were treated with sodium arsenite (0.5 mg·kg^-1·d^-1 and 1.0 mg·kg^-1·d^-1) through abdominal cavity injection for 20 days. The normal control group and the model group were treated with saline (0.2 mL/d). The AP-1 and MIP-1α expression of synovium in four groups were determined by immunohistochemistry. Light microscope was used to observe the synovium with HE staining. RESULTS:Compared with C group, the expression of AP-1 and MIP-1α in the synovium up-regulated in A group (P<0.01) and were inhibited by sodium arsenite treatment (P<0.05), especially in HSA group. CONCLUSION:The activated AP-1 and MIP-1α play an important role in the development of rheumatoid arthritis. Sodium arsenite down-regulated the expression of AP-1 and MIP-1α and may have some therapeutic effects in RA.     

The experimental study on mouse pristine hepatic fibrosis induced by different doses of alcohol

AIM: To explore the difference on formation mechanism and the pathology in the process of early liver fibration induced by two dose of ethanol. METHODS: 24 male KM mice were randomly divided into 3 groups which are control group, low dose of alcohol group and high dose of alcohol group, respectively. The mice treated with 8 g·kg^-1·d^-1 ethanol, 3 g·kg^-1·d^-1 ethanol by oral were killed 30 days later. The liver histomorphology,inflammation grade and fibration staging were observed and the areas of collagen per high power field were calculated by hematoxylin-feosin (HE) and Masson staining; the expression of Toll like receptor-4(TLR-4), α-smooth muscle actin (α-SMA) and content of transforming growth factor-β (TGF-β), nuclear factor-kappa B (NF-кB) protein, BMP and activin membrane-bound inhibitor (Bambi) mRNA were measured using immunohistochemistry, Western blotting, real-time quantitative polymerase chain reaction, respectively; apoptosis cell number was calculated by In Situ Nick-End Labeling (TUNEL). RESULTS: Different degree of fibration mice induced by ethanol appeared (P<0.01) and hepatic stellate cells (HSCs) in these mice liver were activated, meanwhile the apoptosis cell number increased too (P<0.01). The liver fibration at high dose group was more serious than that at low dose group mice, and the number of apoptosis cells showed the same trend as fibration, but the content of Bambi mRNA in high dose group down regulated compared to that in low dose group (P<0.05). On the other hand, the expression of TLR-4 enhanced in low dose group while decreased in high dose group compared to control group (P<0.01). CONCLUSION: The mechanism of early mouse liver fibration induced by two dose of alcohol is different. Apoptosis may be more responsible for the liver fibration induced by high dose alcohol than TLR-4 pass way, and there is a TLR-4 independent pathway to down-regulate the Bambi that probably is one of the reasons that the fibrosis is more serious in the high dose group.     

Electrophysiological characters in a noble model of atrial fibrillation induced by left atrium pacing after right atrial infarction

AIM: To explore a noble chronic atrial fibrillation model induced by left atrium pacing after right atrial infarction and to investigate the atrial electrophysiological characters of the model. METHODS: 24 rabbits were randomly divided into 3 groups: control group (C group, n=8), pacing group (P group, n=8), artial infarction+pacing group (I group, n=8). C group: a pacing pole was fixed under adventitia of the left atrium without pacing; P group: a pacing pole was fixed under adventitia of the left atrium with 1 000 beats/min of pacing; I group: the animals were placed under 1 000 beats/min of left atrial pacing after ligating the atrial branch of right coronary artery. The technique of programmed stimulating was used to measure electrophysiological indexes of atrial in the groups. RESULTS: (1) After 3 weeks pacing AF was induced with a higher rates, and reached to 100% in I group. (2) At driving cycle length of 200 ms, ERPA was (115.0±7.6) ms in C group, (81.3±12.5) ms in P group and (87.5±12.8) ms in I group, which were statistically shorter in the later two groups compared to control group (both P<0.01). (3) I group and P group showed a significantly poor performance of frequency adaptability compared to control group after 3 week stimulation (P<0.01, P<0.05, respectively). (4) 3 weeks after pacing, the interval of P-wave in I group was significantly prolonged compared to P group and C group (P<0.05, P<0.01, respectively). (5) ERPA was obviously shortened and RRPA was prolonged significantly in I group compared to control group (P<0.01, respectively). Inter-atrial conduction defect (IACD) was significantly prolonged in I group compared to C group and P group after 1 h to 3 week stimulation (P<0.01, respectively). CONCLUSION: Compared to the traditional AF model induced by pacing only, a noble model of left atrium pacing after right atrial infarction has a higher AF incidence. The apparent electrophysiological changes of the AF model include: shortening of ERPA, the frequency inadaptability, extension of P-wave interval and prolonged RRPA as well as IACD.     

Effect of tissue kallikrein gene treatment on blood pressure in type 2 diabetic rats and its mechanism

AIM:To study the effect of tissue kallikrein gene (HK) treatment on blood pressure in type 2 diabetic rats and its mechanism. METHODS:Male Wistar rats were injected with low dose streptozotocin and fed with diets enriched in fat and sugar to form type 2 diabetic model. Recombinant adeno-associated viral vectors (rAAV)-mediated HK gene (HK group) or LacZ gene (LacZ group) was introduced to the diabetic rats. The systolic blood pressure was measured every 2 weeks. The acetylcholine (Ach)-dependent vasodilation response, the synthesis of nitric oxide (NO), the expression of endothelin-1 (ET-1) and endothelin-A receptor (ETA-R) in the aorta were detected. RESULTS:(1) Systolic blood pressure was significantly higher in diabetic rats than that in normal control rats. In HK group, systolic blood pressure was significantly reduced within 2 weeks after injection with rAAV·HK, reached near normal levels at 4 weeks and kept until the experiments ended (16 weeks). (2) In LacZ group, Ach-dependent vasodilation response of isolated aorta was markedly decreased than that in HK group (P<0.01). (3) The concentration of NO in the aorta of HK group were significantly higher than those in LacZ group. The expression of ET-1 and ETA-R mRNA were significantly decreased in HK group compared with those in LacZ group (P<0.01). CONCLUSION:rAAV-mediated HK gene delivery efficiently lowed blood pressure and attenuated the endothelial function partly through increasing the concentration of NO and inhibiting the expression of ET-1 and ETA-R of aorta in type 2 diabetic rats.     

Effects of bilirubin on oxygen free radicals and caspase-3 in acute lung injury rats

AIM:To investigate the mechanisms by which bilirubin inhibits acute lung injury (ALI). METHODS:30 female Wistar rats were divided into normal group, ALI group and bilirubin treatment group. ALI was induced by intravenous injection of LPS. The contents of OH^-, H₂O₂ and O₂^· in the lung as well as the expression of caspase-3 in the lungs were investigated. RESULTS:(1) The contents of OH^-, H₂O₂ and O₂^· in the lung homogenate and the expression of caspase-3 in the lungs in ALI group increased compared with those in normal group (P<0.05). (2) The contents of OH^-, H₂O₂ and O₂^· in the lung homogenate and the expression of caspase-3 in the lungs in bilirubin treatment group increased compared with those in normal group, but decreased compared with those in ALI models (P<0.05). CONCLUSION:(1) Bilirubin was shown to be able to ameliorate apoptosis in ALI rats. (2) The increase in the contents of OH^-, H₂O₂, O₂^· in ALI group indicated the development of oxidative lung injury, which was ameliorated by bilirubin. (3) Expression of caspase-3 confirmed that the model made by LPS was associated with apoptosis, which was reduced by bilirubin.     

Effects of different doses of L-dopa on rotational behavior and amounts of cells expressing D2 receptors in hemiparkinsonian rats

AIM：To observe the effects of different doses of L-dopa on the rotational behavior and amounts of cells expressing D₂ receptors in striatum in hemiparkinsonian rats.METHODS：A hemiparkinsonian model was established in rats by pretreatment with 6-hydroxydopamine.The D₂ receptor expression were detected by immunohistochemical staining.The numbers of rotations induced by apomorphine was counted within 30 min before and after L-dopa (10 mg·kg^-1·d^-1,50 mg·kg^-1·d-^-1 or 100 mg·kg^-1·d^-1,ip) was introduced to Parkinson’s disease (PD) model rats for 15 days.RESULTS：In successful PD model rats,the increased percentage of D₂ receptor in lesioned side compared with intact side was associated linearly with the numbers of rotations within 30 min (r=0.927,P<0.01).After high dose of L-dopa intervention to PD model,the numbers of rotations decreased significantly (P<0.05),the amounts of cells expressing D₂ receptor at the lesioned side striatum decreased significantly (P<0.01).CONCLUSION：After high dose of L-dopa intervention,rotation behavior of PD rats improves,and D₂ receptor is down-regulated significantly.     

Mutation of ATP-sensitive K+ channels and neonatal diabetes iDEND syndrome

Activating mutation in the KCNJ11 gene encoding Kir6.2 subunit of adenosine triphosphate (ATP)-sensitive potassium (K_ATP) channel gives rise to intermediate developmental delay, epilepsy and neonatal diabetes (iDEND) syndrome, a rare hereditary endocrine metabolic disorder characterized by neonatal diabetes accompanied by developmental delay and muscle weakness, but no epilepsy. The Kir6.2 Val⁵⁹→Met⁵⁹ (V59M) activating mutation is the common cause of iDEND syndrome (>50%). Activating mutation causes iDEND syndrome by inhibiting normal closure of ATP-sensitive K⁺ channel, which leads to reduce insulin secretion. Most of such patients are more sensitive to sulfonylurea. High blood-brain barrier permeability and sulfonylurea receptor 1 (SUR1)-specific drugs are expected to become a major therapy.     

Effect of hypercholesterolemia on the ionic currents in cardiac ventricular myocytes of rats

AIM: To determine whether chronic hypercholesterolemia affects ionic currents on cardiac ventricular myocytes of rats. METHODS: Whole-cell patch-clamp technique was used to record the ionic currents in single cardiac myocytes isolated from normal cholesterolemia and hypercholesterolemia rats. RESULTS: In the hypercholesterol group (group Ⅱ), serum total-cholesterol level was significantly higher than that of normal group (group Ⅰ) ［(3.10±0.62)mmol·L-1 vs (1.18±0.37)mmol·L-1, P<0.01, n=20］. The serum triglyceride content of group II was remarkably higher than that of group Ⅰ ［(1.51±0.30)mmol·L-1 vs (0.43±0.15)mmol·L-1, P<0.01, n=20］. In ventricular myocytes of rats, 50% repolarization of action potential duration (APD50) prolonged from (70.86±8.12)ms (group Ⅰ) to (116.16±6.90)ms (group Ⅱ) (n=10 in each group, P<0.01); APD90 prolonged from (95.10±7.27)ms (group Ⅰ) to (144.04±7.39)ms (group Ⅱ) (n=10 in each group, P<0.01); at the test potential of -120 mV, Ik1 increased from (-16.98±4.54) pA/pF(group Ⅰ) to (-19.92±4.08) pA/pF (group Ⅱ) (n=12 in each group, P<0.05); at the test potential of 0 mV, ICa-L decreased from (-8.56±1.29) pA/pF (group Ⅰ) to (-5.24±0.90) pA/pF (group Ⅱ) (n=10 in each group, P<0.01); at the test potential of +60 mV, Ito decreased from (13.20±1.97) pA/pF (group Ⅰ) to (10.30±1.97) pA/pF (group Ⅱ) (n=8 in each group, P<0.05). CONCLUSION: Hypercholesterolemia affects the ionic currents on cardiomyocytes of rats greatly, which may be the ionic mechanism of cardiac toxicity induced by hypercholesterolemia.     

Effect of angelica on myocardial fibrosis post myocardial infarction in rats

AIM: To investigate 1) the role of transforming growth factor-β₁ (TGF-β₁) and macrophage infiltration during the development of myocardial fibrosis (MF) in rats after myocardial infarction (MI);and 2) mechanisms of MF post-MI and the inhibitory effect of angelica.METHODS: Sprague-Dawley (SD) rats were subjected to MI by ligating the left anterior descending coronary artery.The animals were randomly divided into three groups: sham, MI and MI+angelica.After 24 hours of ligation, rats received angelica (20 mL·kg^-1·d^-1, ip) or saline.Left ventricular hemodynamics were measured and rats were killed at week 1, week 2 and week 4, respectively.Collagen content, macrophage infiltration and TGF-β₁ expression were examined in the non-infarcted area.RESULTS: ① In MI group, the numbers of macrophage and TGF-β₁ expression were significantly upregulated compared to sham at week 1 post-MI and remained elevated at week 4 (P<0.01).Angelica significantly decreased macrophage infiltration and TGF-β₁ expression (P<0.01 vs MI).② Collagen content was increased significantly in MI group compared to sham at week 2 and week 4 (P<0.01), and decreased in MI+angelica group (P<0.05 vs MI).③ Cardiac function was markedly decreased post-MI in MI group (P<0.01), and improved at week 4 in MI+angelica group (P<0.05).CONCLUSION: In MF post-MI, angelica may have an antifibrotic effect by decreasing macrophage infiltration and TGF-β₁ expression, by which reactive myocardial fibrosis is reduced, and cardiac function is improved.