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Objective To investigate the role and molecular mechanism of Sirt1 in renal injury in diabetic mice under acute inflammatory state.Methods Forty SPF grade C57BL/6J male mice,8 weeks old,weighing 20-25 g were selected.The mice were divided into five groups by random number table meth-od:control group(group C),diabetic group(group D),lipopolysaccharide(LPS)+diabetic group(group L),LPS+diabetic+Sirt1 blocker EX527 group(group E),and LPS+diabetic+Sirt1 agonist ginkgoflavone sapogenins group(group G),8 mice in each group.After successful preparation of the diabet-ic mouse model,group L was injected intraperitoneally with LPS 10 mg/kg.Group E was injected intraper-itoneally with EX527 5 mg/kg(dissolved in DMSO 0.2 ml)1 hour before giving LPS treatment to diabetic mice.Group G was injected intraperitoneally with 200 mg/kg of ginkgoflavone sapogenins(dissolved in DMSO 0.2 ml)1 hour before LPS treatment was given to diabetic mice,groups C and D underwent an in-traperitoneal injection of 2％DMSO 0.15 ml at the same time point.24-hours urine volume was collected and 24-hours urinary protein concentration was determined,and blood was taken from the posterior eyes to detect serum Scr and BUN concentrations.After kidney tissues were removed,IL-1βand IL-18 concentra-tions were measured by ELISA,nitrate reductase assay for nitric oxide(NO)content in kidney,iron ion an-tioxidant capacity assay for total antioxidant capacity(T-AOC),qPCR and Western blot assay for Sirtl,caspase-1,NLRP3,and ASC mRNA expression and protein content.The acetylated FoxO3a protein content was detected by immunoprecipitation,the reactive oxygen species(ROS)content was calculated by di-hydroethidium staining,the pyroptosis rate was calculated by immunofluorescence double staining,HE stai-ning was performed,and the pathological results were observed under light microscope.Results Compared with group C,24-hours urine volume,urine protein concentration,serum Scr and BUN concentration,con-centrations of renal tissue IL-1β,IL-18,and NO,NLRP3,caspase-1,and ASC mRNA expressions and protein contents,ROS content and pyroptosis rate were significantly increased,T-AOC activity was signifi-cantly decreased in groups D,L,E,and G(P＜0.05).Compared with group D,24-hours urine volume,urine protein concentration,serum Scr and BUN concentration,concentrations of renal tissue IL-1 β,IL-18,and NO,NLRP3,caspase-1,and ASC mRNA expressions and protein contents,ROS content and pyroptosis rate were significantly increased,T-AOC activity was significantly decreased in groups L,E,and G(P＜0.05).Compared with group L,24-hours urine volume,urine protein concentration,serum Scr and BUN concentration,concentrations of renal tissue IL-1β,IL-18,and NO,NLRP3,caspase-1,and ASC mRNA expressions and protein contents,acetylated FoxO3a protein content,ROS content,and pyroptosis rate were significantly increased,T-AOC activity,Sirt1 mRNA expression and protein content,and FoxO3a mRNA expression were significantly decreased in group E(P＜0.05),24-hours urine volume,urine pro-tein concentration,serum Scr and BUN concentration,concentrations of renal tissue IL-1β,IL-18,and NO,NLRP3,caspase-1,and ASC mRNA expressions and protein contents,acetylated FoxO3a protein con-tent,ROS content and pyroptosis rate were significantly decreased,T-AOC activity,Sirt1 mRNA expression and protein content were significantly increased in group G(P＜0.05).Compared with group E,24-hours urine volume,urinary protein concentration,serum Scr and BUN concentration,concentrations of renal tissue IL-1β,IL-18,and NO,NLRP3,caspase-1,and ASC mRNA expressions and protein contents,acetylated FoxO3a protein content,ROS content,and pyroptosis rate were significantly decreased,T-AOC activity,Sirt1 mRNA expression and protein content were significantly increased in group G(P＜0.05).Conclusion In diabetic mice under acute inflammatory state,elevated Sirt1 reduces kidney injury by de-creasing acetylated FoxO3a protein content,reduced urine volume,urine protein concentration,serum Scr and BUN concentration,inflammatory factor concentrations and apoptosis levels in renal tissue,and attenua-ted oxidative stress and inflammation levels.
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Objective:To evaluate the relationship between Sestrin2 and mitochondrial DNA (mtDNA)-NOD-like receptor associated protein 3 (NLRP3) inflammasome pathway during endotoxin-induced myocardial injury in mice.Methods:One hundred and eighty-four clean-grade healthy male ICR mice, aged 8-12 weeks, weighing 20-25 g, were used in this study. One hundred and sixty-eight mice were divided into 7 groups ( n=24 each) using the random number table method: normal control group (N group), lipopolysaccaride(LPS) group (L group), mtDNA group, LPS+ mtDNA group (M group), normal control+ negative control adeno-associated virus (AAV-NC)group (NC group), LPS+ mtDNA+ AAV-NC group (MC group), and LPS+ mtDNA+ Sestrin2 overexpression adeno-associated virus (AAV-Sestrin2) group (MSgroup). Another 10 mice were used to detect the transfection effect of AAV-Sestrin2, and the left 6 mice were used for mtDNA extraction. The model of endotoxemia was developed by intraperitoneal injection of LPS 10 mg/kg. mtDNA 5 mg/kg was intraperitoneally injected in mtDNA group, and mtDNA 5 mg/kg was intraperitoneally injected at 30 min after LPS injection in M group.AAV-Sestrin2 150 μl was injected via the tail vein in MS group, and the equal volume of AAV-NC was injected via the tail vein in MC and NC groups. Four weeks after virus injection, LPS 10 mg/kg was intraperitoneally injected and 30 min later mtDNA 5 mg/kg was intraperitoneally injected in MS and MC groups. Blood samples were collected at 24 h after LPS injection for determination of serum creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) activities (by biochemical assay), concentrations of serum cardiac troponin I (cTnI), interleukin-18 (IL-18) and interleukin-1beta (IL-1β)(by enzyme-linked immunesorbent assay), and expression of mtDNA (by quantitative real-time polymerase chain reaction). The animals were sacrificed after the end of blood sampling and myocardial tissues were obtained for determination of the contents of reactive oxygen species (ROS), total antioxidant capacity (T-AOC), and adenosine triphosphate (ATP) and expression of NOD-like receptor associated protein 3 (NLRP3), active subunit p20 of caspase-1 (caspase-1p20) and apoptosis-associated microprotein (ASC) in myocardial tissues (by Western blot) and for microscopic examination of the pathological changes after HE staining (with a light microscope). Results:Compared with N group, the levels of CK-MB, LDH, cTnI, IL-1β and IL-18 in serum were significantly increased, the expression of mtDNA was up-regulated, the ROS content in myocardial tissues was increased, the T-AOC and ATP contents in myocardial tissues were decreased, the expression of NLRP3, caspase-1p20 and ASC in the myocardial tissues was up-regulated( P<0.05), and the pathological changes of myocardial tissues were aggravated in L group and mtDNA group.Compared with L group and mtDNA group, the levels of CK-MB, LDH, cTnI, IL-1β and IL-18 in serum were significantly increased, the expression of mtDNA was up-regulated, the ROS content in myocardial tissues was increased, the T-AOC and ATP contents in myocardial tissues were decreased, the expression of NLRP3, caspase-1p20 and ASC in the myocardial tissues was up-regulated( P<0.05), and the pathological changes of myocardial tissues were aggravated in M group. Compared with M group, the levels of CK-MB, LDH, cTnI, IL-1β and IL-18 in serum were significantly decreased, the expression of mtDNA was down-regulated, the ROS content in myocardial tissues was decreased, the T-AOC and ATP contents in myocardial tissues were increased, the expression of NLRP3, caspase-1p20 and ASC in the myocardial tissues was down-regulated( P<0.05), and the pathological changes of myocardial tissues were significantly attenuated in MS group. Conclusions:Sestrin2 can reduce endotoxin-induced myocardial injury in mice by alleviating mitochondrial damage, inhibiting oxidative stress, protecting mtDNA from oxidative damage, and then inhibiting mtDNA-NLRP3 inflammasome pathway.
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Objective:To evaluate the role of silencing regulatory protein (SIRT1) and its associated microRNAs (miRNAs) in dexmedetomidine-induced attenuation of renal damage in diabetic mice.Methods:SPF grade C57 male mice, aged 8 weeks, in which diabetes mellitus model was developed by intraperitoneal injection of 1% streptozotocin, were used.Thirty mice in which the model was successfully developed were divided into 5 groups ( n=6 each) using the random number table method: diabetes mellitus group (D group), diabetes mellitus + dexmedetomidine group (DD group), diabetes mellitus + dexmedetomidine + EX527 group (DDE group), diabetes mellitus + dexmedetomidine + miR-34a-3p-agomir group (DDH group), and diabetes mellitus + dexmedetomidine + miR-34a-3p-agomirNC group (DDC group). Six normal mice were selected as control group (C group). Dexmedetomidine 40 μg/kg was intraperitoneally injected once every 2 h, 3 times in total in DD, DDE, DDH and DDC groups.miR-34a-3p-agomir and miR-34a-3p-agomirNC 2.5 mmol were intraperitoneally injected via the tail vein at 72 h before dexmedetomidine administration once every 3 days, 2 times in total in DDH and DDC groups, respectively.SIRT1 inhibitor EX527 10 mg/kg was intraperitoneally injected at 1 h before dexmedetomidine administration in group DDE.At 24 h after the end of administration, serum concentrations of IL-6, IL-18, Cr and BUN, contents of nitric oxide (NO) and total antioxidant capacity (T-AOC), ROS activity, and expression of SIRT1, FoxO3a and P53 protein and mRNA, and expression of miR-217, miR-138 and miR-34a in renal tissues were determined. Results:Compared with group C, the serum IL-6, IL-18, Cr and BUN concentrations, contents of T-AOC and NO, and ROS activity were significantly increased, the expression of P53 protein and mRNA, miR-34a, miR-217 and miR-138 was up-regulated, and the expression of SIRT1 and FoxO3a protein and mRNA was down-regulated in group D ( P<0.05). Compared with group D, serum IL-6, IL-18, Cr and BUN concentrations, ROS activity and NO content were significantly decreased, T-AOC content was increased, the expression of SIRT1 and FoxO3a protein and mRNA was up-regulated, and the expression of miR-34a was down-regulated in group DD ( P<0.05). Compared with group DD, the serum IL-6, IL-18, Cr and BUN concentrations, NO content and ROS activity were significantly increased, T-AOC content was decreased, and the expression of SIRT1 and FoxO3a protein and mRNA was down-regulated in group DDE and group DDH ( P<0.05), no significant change was found in the expression of P53 protein and mRNA, miR-217, miR-34a and miR-138 in group DDE ( P>0.05), and the expression of P53 protein and mRNA and miR-34a was significantly up-regulated in group DDH ( P<0.05). Conclusions:The mechanism by which dexmedetomidine attenuates renal injury may be related to down-regulation of miR-34a expression, which further up-regulates SIRT1/FoxO3 expression and decreases oxidative stress in diabetic mice.
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OBJECTIVE： To analyze the clinical manifestations and characteristics of adverse drug reactions （ADR） induced by osimertinib mesylate， and to provide reference for clinical safe use of drugs. METHODS： Retrieved from PubMed， Wanfang database， CNKI and VIP during database establishment-Aug. 2018， ADR cases of osimertinib mesylate were analyzed retrospectively in respects of patient’s age， gender， nationality， usage and dosage of osimertinib mesylate， occurrence time of ADR， clinical manifestations， treatment measures and outcome， etc. RESULTS： A total of 20 articles were included， involving 21 patients. The age of the patients was 32-82 years old， and the proportion of patients aged 57-79 was the largest （80.9％）. The female with ADR （14 cases） were more than the male. The patients were from 5 countries， in which Japan took the most ratio （13 cases， 61.9％）. The dose of osimertinib mesylate was 160 mg/d in a patient and commonly recommended dose 80 mg/d for other patients. The most ADR cases （16 cases， 76.2％） occurred within 3 months， and no reports of ADR occurred more than 12 months. Organs/systems involved in ADRs were mainly respiratory system （11 case times， 45.8％） and digestive system （6 cases， 25.0％）， in addition， ADR also occurred in cardiovascular system， hematological system， systemic reactions， skin and eyes. Among 21 patients， 3 cases were mild ADR so that they were given same dose with same frequency. A patient suffered from interstitial pneumonia and was given medicine every other day and symptomatic treatment； the symptoms of the patient were relieved. Other 17 cases were relieved after drug withdrawal and symptomatic treatment， but 2 patients died of tumor progression. CONCLUSIONS： In clinical application of osimertinib mesylate， attention should be paid to ADR monitoring， especially short-term ADR， especially ADR of respiratory， digestive system.
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Objective To evaluate the changes in the expression of Cx45 and Cx40 in the sinoatrial node during dexmedetomidine-induced sinus bradycardia in rats. Methods Forty healthy Sprague-Dawley rats, weighing 250-300 g, were divided into 5 groups ( n=8 each) using a random number table method:control group ( group C) , low-dose dexmedetomidine group ( group D1 ) , high-dose dexmedetomidine group ( group D2 ) , low-dose dexmedetomidine plus atropin group ( group D1 A) , and high-dose dexmedetomidine plus atropin group (group D2A). Normal saline was intravenously infused in group C. Dexmedetomidine was intravenously infused for 10 min as a loading dose of 20 and 120 μg∕kg, followed by an infusion of 10 and 60 μg·kg-1 ·h-1 for 110 min in D1 and D2 groups, respectively. In D1 A and D2 A groups, dexme-detomidine was correspondingly given according to the method previously described in D1 and D2 groups, and in addition atropin 0. 5 mg was intravenously injected at the end of infusing the loading dose of dexme-detomidine. Heart rate ( HR ) , mean arterial pressure ( MAP ) and SpO2 were recorded before giving dexmedetomidine and at 10, 60 and 120 min after giving dexmedetomidine, and the development of brady-cardia was recorded. The sinoatrial node tissues were obtained at the end of administration for determination of the expression of Cx45 and Cx40 protein and mRNA by Western blot and real-time polymerase chain reac-tion, respectively. Results The incidence of bradycardia was 100％ in D1 and D2 groups and 0 after using atropin in D1 A and D2 A groups. Compared with group C, HR and MAP were significantly decreased in the other four groups, the expression of Cx45 protein and mRNA was up-regulated, and the expression of Cx40 protein and mRNA was down-regulated in D1 and D2 groups (P<0. 05), and no significant change was found in the expression of Cx45 and Cx40 protein and mRNA in D1A and D2A groups (P>0. 05). Com-pared with group D1 , HR and MAP were significantly increased, the expression of Cx45 protein and mRNA was down-regulated, and the expression of Cx40 protein and mRNA was up-regulated in group D1 A ( P<0. 05) . Compared with group D2 , HR and MAP were significantly increased, the expression of Cx45 pro-tein and mRNA was down-regulated, and the expression of Cx40 protein and mRNA was up-regulated in group D2 A ( P<0. 05) . Conclusion The mechanism by which dexmedetomidine induces sinus bradycardia may be related to up-regulated expression of Cx45 and down-regulated expression of Cx40, and the auto-nomic nervous activity is involved in dexmedetomidine-induced regulation of Cx45 and Cx40 expression in rats.
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Objective To evaluate the role of A1 adenosine receptor ( A1 AR) within the nucleus tractus solitarii ( NTS ) in dexmedetomidine-induced increase in baroreflex sensitivity ( BRS ) in rats. Methods Thirty-two clean-grade healthy male Sprague-Dawley rats, weighing 240-280 g, were divided in-to 4 groups ( n=8 each) using a random number table method: control group ( group C) , solvent control group ( group S) , dexmedetomidine group ( group D) , and dexmedetomidine plus 8-cyclopentyl-1,3-diprop-ylxanthine (DPCPX, a highly selective A1AR blocker) group (group DD). After the rats were anesthe-tized, 1 μl drug liquid was injected into the right NTS with a brain stereotaxic apparatus. Oneμl normal sa-line was injected into the right NTS in C and D groups, 1 μl dimethyl sulfoxide in group S, and 1 μl DPCPX in group DD. After catheters were implanted into the femoral vein, dexmedetomidine was intrave-nously infused as a bolus of 100μg/kg over 15 min followed by an infusion of 50μg·kg-1 ·h-1 for 105 min in D and DD groups. The equal volume of normal saline was given instead of dexmedetomidine in C and S groups. BRS was measured using phenylephrine immediately before intravenous infusion (T0) and at 60 and 120 min after beginning of infusion ( T1,2 ) . Results Compared with C and S groups, the BRS was signifi-cantly increased at T1,2 in D and DD groups ( P＜0. 05) . Compared with group D, the BRS was significantly decreased at T1,2 in group DD ( P＜0. 05) . Conclusion A1 AR within the NTS is involved in dexmedetomi-dine-induced increase in BRS in rats.
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Objective To investigate the changes of cardiac sinus node connexin 45 (Cx45), connexin 31.9(Cx31.9) of gap junction in rabbits'' sinus bradycardia model caused by dexmedetomidine, and to discuss whether the negative frequency and negative conduction caused by Dexmedetomidine are related to the expression changes of connexin.Methods Forty-eight healthy adult New Zealand rabbits were divided into three groups (n=16).Sinus bradycardia rabbits were prepared by intravenous injecting Dexmedetomidine through ear vein.After rabbits were anesthetized by sodium pentobarbital, basic procedures were quickly completed in order to monitor MAP and ECG.Rabbits in group C were injected with normal saline.Rabbits in group D1 were injected a loading dose of dexmedetomidine 10 μg/kg for 10 min, and then continuously pumped 5 μg·kg-1·h-1 for 50 min.Rabbits in group D2 were pumped a loading dose of dexmedetomidine 60 μg/kg for 10 min, and then continuously pumped 30 μg·kg-1·h-1 for 50 min.After observation hearts were quickly removed and sinus node tissue was dissected.The average optical density of sinus node Cx45, Cx31.9 were detected by immunohistochemistry, and the genes expression were detected by real-time quantitative.Results Cx45 gene expression of group D2 showed remarkable increase than groups C and D1(P<0.05), there were no significant differences between groups D1 and C, Cx45 average optical density change were consistent with the gene expression.Cx31.9 gene expression of group D1 showed a more remarkable increase than group C(P<0.05), there were no significant differences between groups D2 and C,D1 and D2, Cx31.9 average optical density changes were consistent with the gene expression.Conclusion Dexmedetomidine increases the expression of low electrical conductivity Cx45, Cx31.9 of gap junction on rabbits'' sinus node, which is one of the possibly reasons that slow down cardiac conduction velocity in sinus node.
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Aim To investigate the effects of dioscin ( Dio) on rat myocardial contractility. Methods Left ventricular contractile function was measured using the Langendorff non-recirculating mode of isolated rat heart perfusion. Effects of low, middle and high concentra-tion of Dio were investigated by measuring left ventricu-lar systolic pressure ( LVSP ) and left ventricular end diastolic pressure ( LVEDP) . Also, peak rates of rise/fall of left ventricular pressure ( ± dp/dtmax ) of isolated rat heart were calculated. Effects of Dio on intracellu-lar free calcium concentration in rat H9 c2 cells were measured by using the confocal microscopy. Mitochon-drial membrane potential was detected with multifunc-tional microplate reader. Results With 0. 1, 1 μmol · L-1 Dio, LVSP were significantly enhanced from (11. 55 ± 0. 52), (10. 53 ± 0. 28) kPa to (13. 08 ± 0. 72), (12. 53 ±0. 64) kPa(P<0. 01); +dp/dtmax were dramatically increased from ( 0. 38 ± 0. 10 ) , (0. 40 ± 0. 07) kPa·ms-1 to (0. 42 ± 0. 11), (0. 43 ± 0. 02) kPa·ms-1(P<0. 05). With the 10μmol· L-1 Dio, LVSP and + dp/dtmax were both decreased from (12. 13 ± 0. 33) kPa and (0. 42 ± 0. 04) kPa· ms-1 to ( 9. 46 ± 0. 77 ) kPa and ( 0. 24 ± 0. 04 ) kPa ·ms-1 (P <0. 01). With 0. 1, 1, 10 μmol·L-1 Dio, the relative fluorescence intensity of intracellular free calcium concentrations was increased significantly from (16. 62 ± 0. 89) to (21. 48 ± 0. 80), (25. 68 ± 0. 69) and (19. 84 ± 0. 66)(P <0. 01)respectively. 0. 1, 1μmol·L-1 Dio showed no significant effects on the mitochondrial membrane potential of rat H9 c2 cells, while with effects of 10 μmol·L-1 Dio, the ra-tio of JC-1 monomer and J-aggregates was changed from (1. 14 ± 0. 03) to (1. 35 ± 0. 06)(P<0. 01), indica-ting a decrease in the mitochondrial membrane poten-tial. Conclusion Low and middle concentrations of Dio show a positive inotropic effect on isolated rat heart, as the LVSP and + dp/dtmax are enhanced, which may concern with the increase of the intracellu-lar concentration of Ca2+. It will not cause the calcium overload while the intracellular concentration of Ca2+ is increased by low and middle concentration of Dio in the myocytes except high concentration of Dio.
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Objective To evaluate the effects of different doses of dexmedetomidine on atrioventricular node (AVN) conduction function in the healthy volunteers.Methods Sixteen healthy volunteers of both sexes,aged 18-30 yr,with body mass index of 19-26 kg/m2,were included in the study.Dexmedetomidine was infused in a loading dose of 1.0 μg/kg over 10 min,followed by an infusion of 0.5 μg · kg-1 · h 1 for 50 min (Dose Ⅰ);1-2 weeks later,dexmedetomidine was infused in a loading dose of 1.5 μg/kg over 10 min,followed by an infusion of 0.75 μg · kg-1 · h-1 for 50 min (Dose Ⅱ).Before infusion of dexmedetomidine (T0) and at 15 and 35 min of infusion (T1.2),AVN Wenckebach point,AVN 2 ∶ 1 block point,AVN relative refractory period (AVNRRP),and AVN effective refractory period (AVNERP) were measured.Results AVN Wenckebach point and AVN 2 ∶ 1 block point were significantly decreased,and AVNRRP and AVNERP were significantly prolonged at T1,2 compared with those at T0 (P＜0.05).Compared with Dose Ⅰ,AVN Wenckebach point at T2 and AVN 2 ∶ 1 block point at T1,2 were significantly decreased,and AVNRRP and AVNERP were significantly prolonged at T1,2 in the subjects receiving Dose Ⅱ] (P＜0.05).Conclusion Dexmedetomidine can inhibit AVN conduction function in the healthy volunteers,and the inhibitory effect is enhanced with the increasing doses.
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Aim To study the protective effects of sphingosine 1-phosphate (S1P) postconditioning on rat myocardial cells injured by hypoxia/reoxygenation in reperfusion injury salvage kinase ( RISK ) signal path-way. Methods The cultured rat H9c2 cells were ran-domly divided into seven groups: ( 1 ) control group;(2) hypoxia/reoxygenation (H/R) group; (3) S1P group;(4) S1P+LY294002 group(S1P+LY); (5) LY group; ( 6 ) S1 P +PD98059 group ( S1 P +PD );(7) PD group. The viability of H9c2 cells was detec-ted using MTT method. The content of MDA in the cultured medium and the activity of T-SOD and Mn-SOD were measured with colorimetry. The concentra-tion of intracellular free calcium ion was detected by confocal microscopy. The rate of cell apoptosis was de-termined by flow cytometric analysis. Western blot was used to assess phosphorylation of Akt and ERK1/2 in H9c2 cells. Results Compared with the H/R group, S1P significantly increased vaibility of cells, lowered the rate of apoptosis, decreased the content of MDA in the culture medium, increased the activity of T-SOD and Mn-SOD, reduced concentration of intracellular calcium and increased the phosphorylation of Akt and ERK1/2 . When added LY294002 or PD98059 , the effects of S1P above were inhibited. Conclusion S1P protects H9 c2 cells against hypoxia/reoxygenation inju-ry. The protection of S1P was inhibited by LY294002, the inhibitor of PI3 K/Akt and PD98059 , the inhibitor of ERK1/2 . S1 P protects H9 c2 cells against hypoxia/reoxygenation injury via RISK pathway.
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Objective To evaluate the effect of dexmedetomidine on heart rate (HR) of rabbits through in vitro and in vivo experiments, and investigate the mechanism by which dexmedetomidine lowered HR.Methods In vitro experiment Healthy adult rabbits of both sexes, weighing 2.0-2.5 kg, aged 8-10 weeks, were studied.The 24 isolated hearts passively perfused in a Langendorff apparatus were randomly divided into 3 groups (n =8 each) using a random number table: control group (group C) , and dexmedetomidine 3 and 30 ng/ml groups (D1 and D2 groups).The isolated hearts were continuously perfused with K-H solution for 45 min in group C.After 15 min of equilibration, the isolated hearts were perfused for 30 min with K-H solution containing dexmedetomidine 3 and 30 ng/ml in D1 and D2 groups, respectively.At 15 min of equilibration, and at 15 and 30 min of perfusion with K-H solution containing dexmedetomidine, HR and left ventricular systolic pressure (LVSP) were recorded.In vivo experiment Twenty-five healthy adult rabbits of both sexes, weighing 2.0-2.5 kg, aged 8-10 weeks, were randomly divided into 5 groups (n=5 each) using a random number table: dexmedetomidine 3, 6, 9, 12, and 15 μg/kg groups (D3, D6, D9, D12, D15groups), to receive the corresponding doses of dexmedetomidine which was intravenously infused over 10 min.HR and mean arterial pressure were monitored and recorded before administration (T0) , and at 15 and 40 min after administration (T1,2).The correlation between doses of dexmedetomidine and change rate of HR was tested by Spearman correlation analysis.Results In vitro experiment Compared with group C, no significant changes were found in HR and LVSP at each time point in D1 and D2 groups (P＞0.05).In vivo experiment Compared with those at T0 , HR at T1 in D6 and D9 groups, HR at T1,2 in D12 and D15 groups, and mean arterial pressure at T1,2in D6, D9, and D12 groups were significantly decreased (P＜0.05) , and no significant change was found in HR at each time point in group D3 (P＞0.05).The correlation coefficient between doses of dexmedetomidine and change rate of HR was 0.944 (P＜0.05).Conclusion The mechanism by which dexmedetomidine lowers HR of rabbits is not related to direct inhibition of sinoatrial nodes, but associated with the balance of autonomic nervous system.
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Aim To investigate the antiarrhythmic mechanism of taurine-magnesium coordination com-pound on abnormal sodium current channel ( INa ) in-duced by hypoxia-reoxygenation in ventricular myocytes of rats. Methods Single ventricular myocytes were i-solated from each rat heart using enzymatic dissociation through Langendorff retrograde aortic perfusion. Whole-cell patch clamp was applied in voltage clamp mode to record INa both in normal ventricular myocytes and single ventricular myocytes of arrhythmia induced by hypoxia-reoxygenation. Results The peak density of INa was changed from ( 56. 89 ± 2. 07 ) pA/pF to (35. 05 ± 1. 52) pA/pF( n=6, P 0. 05), in a concentration-dependent manner, while amioda-rone restored it to (39. 44 ± 1. 24) pA/pF (n=6,P<0. 01 ) . Both high concentration of TMCC and amioda-rone could shift the I-V curve downward. In addition, TMCC and amiodarone could restore the INa inactivation curve and slow down its inactivation, whereas the acti-vation curves showed no significant differences among groups. Conclusion TMCC(200,400 μmol·L-1) could restore the H/R induced INa reduction and shift the I-V curve downward by inhibiting steady-state inac-tivation, which is suggested to be one of the mecha-nisms of the antiarrhythmic effects of TMCC in hypoxia-reoxygenation model.
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Aim To investigate the effects of TMCC on abnormal L-type calcium current (ICa,L) in rat ventric-ular cardiomyocytes during hypoxia-reoxygenation to find out the mechanism of antiarrhythmic effect. Methods Whole-cell patch clamp was used to record ICa,L in the ventricular cardiomyocytes during hypoxia-reoxygenation in rat under amiodarone and different concentrations of TMCC. Results In hypoxia-reoxy-genation model, peak ICa,L increased from ( 3. 35 ± 0. 50 ) pA/pF to ( 5. 69 ± 0. 25 ) pA/pF ( n =6 , P 0. 05),(4. 41 ± 0. 22) pA/pF, (3. 82 ± 0. 21)pA/pF(n=6, P<0. 01) by TMCC(100, 200, 400 μmol·L-1 ) and amidodarone 24. 24 μmol·L-1 restored peak ICa,L to(3. 66 ± 0. 27)pA/pF (n=6,P<0. 01 ) . Compared to control group, hypoxia-reoxy-genation turned ICa,L steady-state activation curves to left and inactivation curves to right, which quickened activation and slowed inactivation, TMCC ( 200, 400μmol · L-1 ) and amiodarone could restore the left shift activation curves and right shift inactivation curves. Conclusion TMCC can concentration-de-pendently restore the increase of calcium current due to hypoxia-reoxygenation by promoting inactivation process and inhibiting activation process, and the effect is equal to that of amiodarone. TMCC blocks ICa,L of the ventricular cardiomyocytes, which may be one of its antiarrhythmic mechanisms.
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Object To observe the effects of coumarin (CM) and Verapamil (Ver) on contractivity and its relationship with Ca 2+ in isolated ileal smooth muscle of the rabbits. Methods The effects of CM and Ver were observed in three doses by routine experimental methods in isolated rabbit ileal. Results CM and Ver inhibited the contraction of isolated ileal smooth muscle induced by acetylcholine and CaCl 2. The responses were a concentration-dependent and non-competitive manner. CM and Ver were effective against the initial and sustained peak induced by acetylcholine. Conclusion CM has a calcium-antagonistic effect which is similar to that of Ver.
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Aim To investigate the antiarrhythmic mechanism of taurine magnesium coordination compound(TMC)on the potassium current in single ventricular myocytes of guinea pig.Methods Whole-cell patch clamp was used to record IK,IK1 in single ventricular myocytes of guinea pig.Results In ventricular myocytes of guinea pig,IK was decreased from(8.67?1.04)pA/pF to(6.31?1.16)pA/pF at +70 mV.TMC had no effect on the IK1.Conclusions TMC had inhibitory effect on IK directly and this effect maybe resulted in prolonging the action potential duration(APD)and effective refractory period(ERP).It could be one of the basis of antiarrhythmic effect of TMC.
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The important progress of the relationship between genomics and cardiovascular diseases has elucidated several abnormalities of genes leading to familial cardiomyopathy and ion channel diseases.Investigations of genomics show that the difference including resistance and susceptivity to diseases among human is determined by over 3 million base pairs of all 3,000 million.Single nucleotide polymorphism plays an essential role in elucidating hereditary cardiovascular diseases.
الملخص
Aim To investigate the antiarrhythmic mechanism of taurine-magnesium coordination compound on sodium current in single rat ventricular myocytes of arrhythmia induced by aconitine.Methods Whole-cell patch clamp was used to record INa in normal cardiomyocytes and single rat ventricular cardiomyocytes of arrhythmia induced by aconitine.Results In ventricular cardiomyocytes of rat,INa was blocked by 100~400 ?mol?L-1 TMCC in a concentration-dependent manner.INa was increasd from(45.56?1.96)pA/pF to(59.19?11.49)pA/pF by 1 ?mol?L-1 aconitine,while decreased to(34.23?1.33)pA/pF by 24.24 ?mol?L-1 amiodarone.TMCC(100,200,400 ?mol?L-1)could restore INa to(51.61?5.96)pA/pF,(40.91?6.73)pA/pF,(41.50?5.50)pA/pF respectively.Amiodarone could restore INa to(40.22?1.47)pA/pF.Conclusions TMCC can restore INa,which is increased by aconitine,and the effect is equal to that of amiodarone.TMCC blocks INa of ventricular cardiomyocytes,which may be one of its antiarrhythmic mechanisms.