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Aim: To investigate the changes of endothelin( ET) receptors by isoproterenol in myocardial cells, and the invervention effects of CPU86017 and its RS isomer. Methods: Primary cultures of neonatal rat cardiomyo-cytes were prepared, and isoproterenol was added to each group for modeling, followed by drug interventions with propranolol, CPU86017 and RS chiral isomer respectively. Results: The expressions of ET_A and ET_B were increased by isoproterenol, in which the level of ET_B was higher than ET_A . This phenomenon was adjusted to different degrees by using propranolol, CPU86017 and RS chiral isomer in a dosage-relevant manner. The infervention effect of RS isomer was better than that of CPU86017 at the high dosage( 10 μmol/L). Conclusion: The cardiovascular effects of CPU86017 and RS chiral isomer could be correlative to the inhibition of the over-expressions of ET_A and ET_B.
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AIM: To investigate the CPU86017 and its enantiomers inhibit abnormal gene expression of calcineurin and NFκB in rat cardiomyopathy induced by L-thyroxin and compare the effect of CPU86017 (racemate) with its 4 enantiomers: (7S, 13R), (7S, 13S), (7R,13S), and (7R,13R)-CPU86017 in this model. METHODS: The animals were randomly divided into 7 groups. The rat hypertrophied model was produced by treatment with L-thyroxin 0.2 mg·kg-1·d-1, sc for 10 d and treated with CPU86017 or its enantiomers 4 mg·kg-1·d-1, sc from d 6 to d 10. The changes in left ventricular (LV) weight index, redox system, and the NO and iNOS activity in the myocardium were investigated. The expression of mRNA of calcineurin、NF-κB in the left ventricle was measured. RESULTS: There were significant cardiac hypertrophy and oxidative stress in rats treated by L-thyroxin. The expression of calcineurin, NFκB mRNA were upregulated (P<0.05, compared with that of control). After treatment with CPU86017 (racemate and enantiomers), LV remodeling and the redox system were improved. CPU86017 and (7S,13R)-CPU86017 showed a better improvement on LV remodeling and the redox than the other isomers and restored the normal expression of calcineurin, NF-κB (P<0.05, P<0.01), respectively. CONCLUSION: It suggested that an up-regulation of calcineurin and NFκB possibly related to the altered intracellular calcium handling system plays a role in the progression of L-thyroxin induced cardiomyopathy and CPU-86017 and its 7S,13R-CPU86017 enantiomer effectively inhibit the abnormal expression of calcineurin and NFκB genes, the NOS enzyme and oxidant stress in the cardiomyopathy.
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AIM:To investigate the bi-directional penetration of CPU-86017 across the BBB (Blood Brain Barrier) following iv and icv (intracerebroventricular) administration in mice.METHOD:The levels of CPU-86017 (p-Chlorobenzyltetrahydroberberine hydrochloride) in the brain, heart, kidney and blood of mice after acute administration of 3.0 mg/kg of CPU-86017 were measured by validated HPLC assay at several time points: 5, 10, 20, 30 and 60 minutes. RESULT:The maximum concentrations of CPU-86017 in the brain, heart, kidney and plasma achieved at 10 minutes by both routes of administration were 0.83±0.335, 25.13±4.17, 56.0±19.69, and 2.23±0.97 μg/ml in the iv group and 23.68±4.2,15.9±10.24, 7.93±4.68 and 3.32±2.3 μg/ml in the icv group, respectively. The decline in concentrations was rapid in plasma. The highest concentration of CPU-86017 was found in the kidney (56.0±19.69 μg/g) after iv administration and in the brain (23.68±4.2 μg/g) after icv injection. The difference in concentrations in the kidney and heart was not significant at 60 min after iv administration. Given by icv administration CPU-86017 reached the peripheral tissues and plasma at each of the five time points, whereas by the iv route at 20, 30 and 60 min the drug could not be detected in the brain.CONCLUSION:The permeability of CPU-86017 through the BBB was well established by two ways: blood circulation to the brain and brain to general circulation. However, a big difference exists between these ways. It is more difficult to penetrate from the blood to the brain than from brain to the peripheral.
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AIM: To investigate the effects of three extracts of Fufang Dihuang decoction on the relaxation of mesentery artery in streptozotocin(STZ)-induced diabetic rats. METHODS: Diabetic rat model was induced by i.p injection STZ at a dosage of 60 mg?kg~ -1 . 30 d later, 95% ethanol, 70% ethanol or water extract of Radix Rehmanniae was p.o administrated for 30 d at the dosage of 107.8 , 154.7 and 56.8 mg?kg~ -1 , respectively. On the 60th day, the responses of mesentery artery were determined in the absence or presence of L-argine (L-Arg), N-Nitro-L-argine (NLA) and Indomethacin (Ind). RESULTS: The relaxation of mesentery artery of diabetic rat was diminished compared with the normal control. The basal release of NO and the L-argine-induced release of NO decreased 64.6 %, 77.6 % respectively in diabetic group compared with the normal control, with the decreased proportion of NO in the endothelium dependent relaxation. 95% and 70% ethanol extract of Fufang Dihuang decoction ameliorated the impaired release of NO in rat's mesentery artery. CONCLUSION: Abnormal relaxation of mesentery artery in diabetic rat may be due to the decreased releasing of NO. The extracts of Fufang Dihuang decoction can protect the endothelium cells and improve the relaxation of mesentery artery, among them 70% ethanol extract exert the best potency, followed by 95% ethanol extract. And the water extract has a poor effect.
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AIM To study the characteristic of th e rapidly activating component (Ikr) and the slowly activating compone nt (Iks) of the delayed rectifier K+ current in guinea pig hypertrop hi ed ventricular myocytes induced by thyroxine. METHOD The whole c ell patch clamp techniques were used. RESULTS In hypertrophied ve ntricular myocytes, the magnitude of IKr and IKs were great ly augmented with more positive depolarizations, and the degree of increase of IKr tail and IKs were greater than that of IKr an d IKs tail, respectively. By measuring the amplitude of tail currents which reflected the degree of activation, the activation curve of IKs was shifted toward more negative potential, but that of IKr was marked ly unaffected in hypertrophied myocytes. CONCLUSION Hypertrophied ventricular myocytes induced by thyroxine obviously increased IKr and IKs.
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AIM The purpose is to study the influences on serum insulin and glucose by different fasting time in alloxan (ALX)-induced diabetic mice. METHODS Normal mice of serum glucose were determined at different fasting time. According to different fasting time (0 h, 6 h, 12 h, 18 h and 24 h), mice were divided into 5 diabetic experimental model (DEM) groups induced by ip ALX 200 mg/kg and 1 control group. Serum glucose (SG) and body weight were determined at experimental d0, d3, d8 and d13 and serum insulin concentration (SIC) at experimental d13. The death rate and succeeding rate were also observed during experimental time. RESULTS Along with prolonged fasting time, SG、death rate and succeeding rate were increased in DEM mice, SG of normal mice, and SIC and body weight of DEM mice were decreased. Results showed that the optimal fasting time of ALX-induced diabetic mice was 12～18 h a lower death rate and impairment to pancreatic islets. Fasting 18h diabetic mice had higher succeeding since during this time rate、lower death rate and longer hyperglycemia time. CONCLUSION This study indicated SG of mice in vivo had a protective effect against impairment action of pancreatic islets by ALX.
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AIM: To observe the alterations of matrix metalloproteinases (MMPs) and TIMPs (the inhibitor of MMPs) and to study the influence of a new endothelin receptor antagonist CPU 0213 on MMPs mRNA and TIMPs mRNA in rats with hypertrophic myocardium induced by L thyroxin (L thy). METHODS: Male Sprague Dawley rats were randomly divided into three groups and sc administrated suspension of L thy ( 0.4 mg?kg -1 ?d -1 ) for consecutive 10 d except for normal group. On the 7th day, the rats treated with L thy were given CPU 0213(ig, 100 mg ? kg -1 ?d -1 ) for 3 d . The whole collagen content in myocardium was measured. Relative LV myocardial mRNA levels of MMPs (MMP 2, MMP 9) and tissue inhibitor (TIMP 1, TIMP 2) were detected with semi quantitative RT PCR. RESUITS: The whole collagen content in myocardium induced by L thy decreased but it increased in the group CPU 0213. The expression of MMPs (MMP 2, MMP 9) mRNA was downregulated in L thy group and the expression of TIMPs mRNA was upregulated in L thy group markedly. Treated with CPU 0213, the expressions of MMP 9 and TIMP 1 mRNA were downregulated, whereas the expression of MMP 2 mRNA coming from CPU 0213 group tended to upregulate. But there was no statistical significance among these groups. CONCLUSION: CPU 0213 can inhibit the expression of MMPs and increase collagen content, which can improve heart function.
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In the article the effect of thyroid hormones was reviewed on cardiac ion channels and transports, so as to explain the changes of the action current on cardiac myocyte. Based on the molecular biology, the hormonal regulation of cardiac and transports were discussed and explained.
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Object To observe the protective effects of rehmannia root extract (Reh) on mitochondrial respiratory function in hypoxia rat. Methods Rat was killed rapidly and the body was put at room temperatare for global ischemia of 15 min. Treatment of po Reh 2 and 4 g/kg was started 2 h before hypoxia. The mitochondrial respiratory parameter of myocardium, brain and kidney was measured by oxygen electrode method. The protective effect of Reh on mitochondrion was observed in 2h po. Bepridil (Bep), an Ca 2+ channel blocker, ip 5 mg/kg 30 min prior to hypoxia served as positive control. Results In myocardium and kidney, hypoxia injury was showed similar, ST 3 and RCI value was increased as compared with the control group in a dose dependent manner, showing a selective stronger protection on renal mitochondrial than that on heart and brain. Conclusion Reh is effective in protecting metochondrial respiratory function in heart, brain and kidney from hypoxia and with the most potent effect on kidney.
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AIM To determine whether the I Kr channel protein is altered and its response to dofetilide and verapamil in cardiac remodeling by L thy roxin. METHODS Saturation binding assays in guinea pig ventricular membrane preparation with 125 I dofetilide, a radioligand for the cardiac rapidly activating delayed outward rectifier channel (I Kr ) was conducted respectively in normal, hypertrophied, Verapamil or dofetilide intervened group. RESULTS Scatchard analysis revealed two binding sites with different affinities in normal guinea pig ventricle: a high affinity site [ K d=(1 27?0 11) nmol, B max =(34 67?3 23) nmol?g -1 ] and a low affinity site [ K d=(43 48?4 83) nmol, B max =(76 41?5 37) nmol?g -1 ] ( n =5), only the high affinity site was associated with the I Kr in guinea pig ventricle. The B max of high affinity site in the hypertrophied ventricle induced by L thyroxin was down regulated to (18 13?2 27) nmol?g -1 ( n =6). Verapamil was effective to up regulate the high affinity B max to (37 26?4 32) nmol?g -1 ( n =5) but dofetilide had hardly effect on it. CONCLUSION The I Kr channel protein in guinea pig ventricular membrane was down regulated in remodeling ventricle by chronic L thyroxin treatment and improved by verapamil.
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The skeletal muscle relaxing effects of gentamicin (Gen) and amikacin (Amk) were investigated and compared with tubocu-rarine (Tub) in rat phrenic nerve-muscle preparation, conscious chicken and mouse. The potency of the neuro-muscular blocking action of Gen was two times that of Amk. The blocking effect of Gen was observed as an 'all or none' phenomenon with a bigger S value compared with Tub. The drug concentrations were decreased by pumping drug free perfusate into or-gan baths to simulate an elimination rate constant fixed at 0. 1/min. To plot effects against declined concentrations there was a clockwise hysteresis loop with Tub, but a counter-clockwise hystereksis loop presented by Gen. The mode of the skeletal muscle relaxing effect of Gen and Amk was classified as non-depolarization like Tub.
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AIM To determine the antagonistic activities of new endothelin receptor antagonist CPU0214 on the left ventricle membranes and the aorta ring contraction in normal rat and its reduction effect on the mean arterial pressure in conscious DOCA salt hypertensive rats. METHODS Left ventricle membranes of normal rat hearts achieved for competition binding assay was used to investigate the antagonistic effects of CPU0214. Aorta ring contraction induced by ET 1 in normal rat was used to investigate the antagonistic activity of CPU0214. DOCA salt hypertensive rats were induced by injection of deoxycorticosterone acetate (DOCA, sc) following with 1% NaCl as drinking for 4 wk. A multiple physiological recorder was used to record the mean arterial pressure of femoral artery. The endothelin receptor change in the left ventricle membranes of DOCA salt hypertensive rat was measured by binding assays. Intraperitoneal injection of CPU0214 was used to investigate its effect on reduction of mean arterial pressure. RESULTS In the left ventricle the IC 50 of endothelin receptor antagonist CPU0214 is 16 nmol?L -1 and CPU0214 (10 ?mol?L -1 ) inhibited the ET 1 induced isolated aorta rings contraction in normal rats. Mean arterial pressure as well as B max and K d of left ventricle were increased significantly in DOCA salt hypertensive rat. CPU0214 (60 mg?kg -1 ip) significantly reduced the mean arterial pressure of conscious DOCA salt hypertensive rats especially during 60～90 min after administration. CONCLUSIONS CPU0214 has significantly antagonistic effects on the left ventricle membrane and the isolated aorta ring contraction in normal rat, which is verified by CPU0214 as a strong endothelin receptor antagonist. Furthermore its effect on the mean blood pressure reduction in conscious DOCA salt hypertensive rats, which is manifested as an abnormal endothelin system, shows its prosperity of drug development value as a new endothelin receptor antagonist.
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AIM To investigate the cardiovascular activity of new compound V03(CPU228) derived from dofetilide. METHODS Arrhythmias was induced by the occlusion and reperfusion of left anterior descending coronary artery. The effects of CPU228 and dofetilide on QT interval and inducing Tdp were compared in anesthetized rabbits during stimulation with methoxamine. The contractions of thoracic aortic rings induced by KCl (rat) and Phe (guinea pig) in Ca 2+-free and calcium recovered K-H solution was studied to determinate the activity of CPU228 on intracellular calcium mobilization and calcium entry. RESULTS ① CPU228 suppressed the maximal arrhythmia scores, decreased the AUC of arrhythmia score( reduced the duration of VF and VT significantly). PU228 is more potent than dofetilide.②The potency of CPU228 of inducing Tdp is significantly weaker than that of dofetilide.③There were significantly inhibitions of CPU228 on the contractions of aortic rings induced by KCl and Phe in Ca 2+-free solution and dofetilide only had a inhibition on the former. CPU228 inhibited contractions of aortic ring by adding calcium which influx via L-type calcium channel while dofetilide had no effects on these. CONCLUSION CPU228 has stronger inhibition on coronary occlusion and reperfusion arrhythmia and lower potency of inducing Tdp than dofetilide. All the results suggest that CPU228 is a nonselective I Kr-blocker combined with a blockade on the L-type Ca 2+ channel and?adrenergic receptor.
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The maximum specific binding(Bmax)and the dissociation constants(K D) of 8H -dihydroalprenolol in rat myocardial membrane are 104.1 +4. 7 fmol/mg protein and 10.1+2.7nM, respectively, and the Hill coeffici-ent(nn) is equal to 1.007+0.002. The half inhibition concentration concentration ( IC50) of bunitrolol and propranolol on 3H - dihydroal- prcnolol binding to myocardial B-adrenergic receptors are 3.30+ 0. 74 x 10- 8M ,and 3. 87+0.66 x 10-7M , the apparant dissociation constants (Kl) are 2.2+0.48x10-8M and 2.58+0.44x10-7M, respectively. The affinity of bunitrolol to myocardial B-adrener-gic receptors is 11.7 times as potent as propra'nolol.
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Analgesia caused by ip baclofen 6. 4 a.nd 12. 8 mg/kg was examined by the hot plate method, showing no accompanied significant changes in 5-HT and 5-HIAA in mouse brains. After loading of L-tfyptophan, the analgesic effect of baclofen was markedly enhanced in both potency and duration, a.nd was related to increases in 5-HT and 5-HIAA in the brain0 Baclofen analgesia was still seen 3d after p-chloro-pheny 1-alanine treatment which rendered 5-HIAA level down to 39% of control. The enhanced functon of 5-HT system in the brain exerted significant synergic effect' on analgesic effect which, however, may be elicited by activating the GABA receptor.
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The urinary noradrenaline (NA) and adrenaline (A) were determined by means of fluorometric assay with double wavelength technique in 12 volunteers who were asked to run over a distance of 800 m with moderate speed. The ereatinine concentration in urine was also monitored and taken to estimate the excreting function of kidney during exercise. The heart rate (HR) and blood pressure(BP) were simultaneously measured. During the period of running 1) The ratio of urinary NA to creatinine and that of A to creatinine (NA or A ng/creatinine mg) increased significantly by 215% and 97%, respectively. The HR and BP elevated by 92% and 20%, respectively. The urinary NA was still markedly high in the recovery period. 2) While the urinary level of A had come back to normal range. The change in HR was directly related to the urinary NA but not to A level. The excreting function of kidney was markedly reduced by exercise. 3) The data of urinary NA and A expressed as the ratio (NA or A ng/creatinine rag) were recommended. The estimation of urinary NA is the most sensitive approach to measure the extent of regulatory mechanism in the response to physical training.