去甲乌药碱对实验性心力衰竭的治疗作用

去甲乌药碱(DMC)是中药附子的有效成分之一。静脉滴注DMC2μg/kg/min共5min,使豚鼠正常心脏的收缩力明显加强,LVSP和LV dP/dt_max分别增加58±7和25±7%;心衰后,LVSP和LV dP/dt_max分别下降到心衰前的40±5和30.5±2.8%。DMC可使之恢复到79±14和75±9.9%,DMC也能加强离体豚鼠衰竭心脏的收缩力。DMC的强心作用与ISO相似,但前者作用较弱,作用维持时间较长,这可能与他们的作用机制不同有关。     

环维黄杨星D对大鼠心脏功能及血压的作用

目的观察环维黄杨星D(CVB-D)对正常大鼠在体心脏功能和血压的调节作用。方法雄性SD大鼠灌胃给予CVB-D 3.35 mg·kg~(-1)·d~(-1),分别于给药2,4和6周后,用血流动力学方法观察大鼠的收缩压、舒张压、左室收缩压(LVSP)、左室舒张末压(LVEDP)、左室压力最大变化速率(±dp/dt_(max))以及心率。结果与对照组相比,灌胃给予CVB-D 6周后,大鼠LVSP增高,收缩压降低。而各时间点给药组LVEDP、±dp/dt_(max)、舒张压及心率均未发生明显改变。结论CVB-D对在体大鼠有一定的增强心脏功能和降低主动脉压力效应,同时不会引起心动过速。     

KP-102 (growth hormone-releasing peptide-2) attenuates ischemia/reperfusion injury in isolated rat hearts

KP-102, a synthetic growth hormone (GH)-releasing peptide, exerts a variety of effects on cardiac function. In the present study, we investigated the direct cardiac effects of KP-102 with regard to ischemia/reperfusion injury by using isolated rat hearts. Isolated Wistar rat hearts were mounted on a Langendorff apparatus and subjected to 30 min of ischemia followed by 40 min of reperfusion. The rat hearts were treated with 0.1–10 nmol/l KP-102 beginning from 15 min before ischemia until the end of the experiment, with the exception of the ischemia period. Cardiac parameters such as the left ventricular end-diastolic pressure (LVEDP), left ventricular developed pressure (LVDP), maximum dP/dt (+dP/dt_max), minimum dP/dt (−dP/dt_max), and heart rate (HR) were measured. The following ischemia/reperfusion-induced cardiac dysfunctions were observed: increased LVEDP and decreased LVDP, +dP/dt_max, and −dP/dt_max. KP-102 at a dose of 0.1 nmol/l or more induced lower LVEDP and higher LVDP and gave higher +dP/dt_max and −dP/dt_max values during the reperfusion as compared with the control groups. In particular, KP-102 at 10 nmol/l clearly suppressed the increase in the LVEDP after reperfusion; eventually, the LVEDP was restored to the preischemia level. At 40 min of reperfusion, 10 nmol/l KP-102 noticeably increased the LVDP, +dP/dt_max, and −dP/dt_max, as compared with the control. KP-102 had no effect on the HR throughout the experiment. In conclusion, KP-102 improved cardiac function in rat isolated hearts subjected to ischemia/reperfusion injury, which is independent of GH secretion.     

Cardioprotective effect of matrine on isoproterenol‐induced cardiotoxicity in rats

Objectives This study was designed to explore the effect and mechanism of matrine, an active component of Chinese traditional medicine, on isoproterenol‐induced acute cardiotoxicity in rats. Methods Acute myocardial injury was induced in rats by daily subcutaneous injection of isoproterenol (85 mg/kg) for two days. Haemodynamic and biochemical parameters were measured and histopathological examination was performed. Key findings Chronic oral administration of matrine (50, 100 or 200 mg/kg per day for 10 days) significantly reduced the release of lactic dehydrogenase, glutamic oxaloacetic transaminase and creatine kinase after isoproterenol‐induced myocardial ischaemic injury, improved the left ventricular (LV) dysfunction, including increased LV systolic pressure (LVSP), maximum rate of developed LV pressure (LV dP/dt_max) and minimum rate of developed LV pressure (LV dP/dt_min), increased the activity of superoxide dismutase, catalase and glutathione peroxidase, and also decreased the content of the lipid peroxidation product malondialdehyde in plasma and myocardial tissues in rats. Acute oral administration of matrine at a dose of 100 or 200 mg/kg for two days also had a cardioprotective effect on this rat model. The protective role of matrine on isoproterenol‐induced myocardial damage was further confirmed by histopathological examination. There were no significant changes in heart rate and blood pressure in all experimental groups. Conclusions Our results suggest that matrine has a significant cardioprotection against isoproterenol‐induced cardiotoxicity through its antioxidant property.     

粉防己碱对DOCA盐性高血压心肌肥厚大鼠心脏血流动力学的影响

粉防己碱可显著降低DOCA盐性高血压心肌肥厚大鼠的血压,左室湿重;在工作心脏研究中发现其改善肥厚心室的收缩(AP,LVSP,+dp/dt_max)舒张(一dp/dt_max,LVEDP,T值)性能,尤以舒张性能改善明显,并恢复泵功能(CO)和冠脉流量(CF);在左室压力容积关系法研究显示有改善肥厚心室左室顺应性和左室僵硬度的作用。提示:Tet有逆转心肌肥厚和改善肥厚心肌舒张收缩功能,左室顺应性和心肌劲度的作用。     

制备大鼠离体心脏损伤模型的最佳缺血再灌注时间

目的 探索离体心脏最佳缺血再灌注(I/R)时间,增加制备可用于心肌保护药物的方法筛选的离体心脏I/R模型的成功率。方法 采用Langendorff离体心脏恒压灌流模式,缺血31 min后,分别于再灌5, 10, 20和30 min时测定心电图、左心室压力(LVP)、冠脉流量(CF)、左心室舒张末期压(LVEDP)和收缩末期压(LVESP);观察心律失常发生率,计算左心室发展压(LVDP)、收缩期舒张期左心室内最大上升/下降速率(±dp/dt_max)和心率(HR)。结果 离体心脏再灌后HR和CF低于停灌前,差异显著(P<0.05);停灌期间,LVEDP升高,心肌挛缩。再灌时90%心脏可成功自主复跳,100%复跳心脏出现心律失常(室速或室颤),持续约5~10 min。再灌后LVDP下降、左心室最大舒缩速度下降。结论 停灌31 min,再灌30 min可成功制备出用于药物筛选的离体心脏I/R损伤模型。     

Assessment of QT-prolonging drugs in the isolated normal and failing rabbit hearts

Lengthening of QTc is the usual signal to indicate torsadogenic potential of a therapeutic agent. The ICH S7B guideline recommends that new chemical entities should be assessed for potential of delayed ventricular repolarization in animal models. The aim of this study was to determine a feasibility of using isolated failing heart rabbit to assess the QT-lengthening drugs in comparison with their effects on isolated normal heart rabbits. Heart failure was induced by ligation of the left anterior descending and descending branch of left circumflex coronary arteries. One month after ligation, all rabbits were anesthetized and the hearts were removed quickly, and they were perfused with the oxygenated Krebs-Henseleit solution to which escalating concentrations of QT-lengthening compounds were added. RR, QT, and QTc(F) were not significantly different, at rest, between failing and normal hearts. During baseline, dP/dtmax was lower and dP/dtmin was higher for failing hearts than for normals. In responses to all three QT-lengthening compounds, RR, QT and QTc(F) lengthened similarly in a dose-response manner in both the failing and normal hearts. Neither the failing nor the normal hearts developed fatal arrhythmias, torsades de pointes. Langendorff preparations of failing hearts are as good as normal isolated hearts and can be use to assess the potential of delayed ventricular repolarization of test articles.     

Influence of intravenous infusion of ethanol on regional blood flow in conscious rats

Abstract— The effects of intravenous infusions of ethanol and saline (0·9% NaCl) on mean arterial pressure (MAP), heart rate (HR), total peripheral resistance (TPR), cardiac contractility (dP/dt_max) and systemic haemodynamics were studied in conscious, unrestrained rats by the radioactive microsphere technique. Saline (0·03 and 0·06 mL min^?1 kg^?1 for 12 min each dose) in the time-control group did not affect MAP, HR, TPR, dP/dt_max or vascular conductances in any organs or beds. While the low dose ethanol (2·4 mg min^?1 kg^?1) did not alter MAP, HR, TPR, systemic haemodynamics or dP/dt_max, the high dose (4·8 mg min^?1 kg^?1) slightly reduced MAP and TPR but did not affect HR, cardiac output or dP/dt_max. Both doses of ethanol vasodilated the intestine and spleen, but vasoconstricted the skin. The high dose caused additional vasodilatation in the heart and testes and the low dose also constricted the skeletal muscle bed. Our results show that ethanol, at non-hypotensive or slightly hypotensive doses, has marked vasodilator effects in the heart, intestine, spleen and testes.     

A translational assessment of preclinical versus clinical tools for the measurement of cardiac contractility: Comparison of LV dP/dtmax with echocardiography in telemetry implanted beagle dogs

IntroductionRegarding evaluation of drug-induced changes in left ventricular contractility in safety pharmacology there is still a gap in knowledge between preclinically and clinically used measurements.MethodsAs a step towards translation of preclinical to clinical outcomes, this study in telemetered dogs was initiated to compare indexes of contractility, such as LV dP/dt_max (contractility measured as the maximum raise of pressure in the left ventricle) and LV dP/dt_max/P (contractility measured as the maximum raise of pressure in the left ventricle, corrected for pressure) (telemetry; both commonly preclinically used) and EF (ejection fraction) and FS (fractional shortening) (echocardiography; both commonly clinically used). Different inotropic states were induced by minoxidil, milrinone, isoprenaline, clonidine, atenolol and verapamil.ResultsBoth techniques demonstrated reproducible changes in contractility which showed a clear linear association. A change in LV dP/dt_max of 1000 mm Hg/s (in the range of 2500 to 7500 mm Hg/s; in healthy dogs) corresponded with a change in ejection fraction of approximately 7% and a fractional shortening of approximately 6%. A change of 10/s LV dP/dt_max/P (in the range of 35 to 85/s; in healthy dogs) corresponded with a change in ejection fraction of approximately 7% and a fractional shortening of 7%.DiscussionThe correlation found in this study could potentially enable a better – translational – assessment of the clinical relevance of changes in contractility indices measured with telemetry devices in preclinical safety studies.     

(–)-Epigallocatechin-3-<Emphasis Type="Italic">O</Emphasis>-gallate (EGCG) attenuates the hemodynamics stimulated by caffeine through decrease of catecholamines release

A human study of the effects on hemodynamics of caffeine and epigallocatechin-3-O-gallate (EGCG) was performed. Caffeine tablets (200 mg) were orally administered to healthy males aged between 25 and 35 years 30 min after oral administration of EGCG tablets (100 and 200 mg). The increase in BP induced by caffeine was inhibited when co-administrated with EGCG. We found that caffeine slightly decreased heart rate (HR) in the volunteers. Although EGCG enhanced HR reduction, the effect was not significant. In addition, caffeine increased blood catecholamine levels, but EGCG inhibited the increase in noradrenaline, adrenaline and dopamine levels induced by caffeine. Whether EGCG decreases the elevated HR and systolic perfusion pressure, and ventricular contractility induced by adrenergic agonists in the isolated rat heart was investigated. The modified Krebs–Henseleit solution was perfused through a Langendorff apparatus to the isolated hearts of rats. HR, systolic perfusion pressure, and developed maximal rates of contraction (+dP/dt_max) and relaxation (?dP/dt_max) were increased by epinephrine (EP) and isoproterenol (IP). In contrast, EGCG decreased the elevated HR, systolic perfusion pressure, and left ventricular ±dp/dt_max induced by EP and/or IP. In conclusion, EGCG could attenuate the hemodynamics stimulated by caffeine through decreasing catecholamine release.     

蟾酥对豚鼠心脏电生理的影响

目的探讨蟾酥对豚鼠心脏的急性毒性。方法豚鼠一次性ig给予蟾酥125和250 mg·kg-1,记录心电图并监测左心室内压力上升最大速率(dp/dtmax),最大收缩压(Pmax),心率血压乘积(RPP)和心室最小舒张压(Pmin)。结果蟾酥使豚鼠心电图发生显著改变;与正常对照组P-R间期(27.8±5.1)ms相比,蟾酥125和250 mg·kg-1组显著延长,分别为44.5±7.2和(57.1±8.9)ms(P<0.01);蟾酥也引起心电图QRS时程增宽和心率加快;dp/dtmax,Pmax和RPP显著下降以及Pmin显著升高(P<0.05)。与阳性对照地高辛300mg·kg-1相比,蟾酥组P-R间期,QRS时程,dp/dtmax,Pmax,RPP和Pmin无显著性差异,但心率显著增快(P<0.01)。结论蟾酥导致豚鼠心律失常和心功能下降。     

Plasma Concentrations and Haemodynamic Effects of d-Sotalol after β-Blockade in Dogs

This study was designed to investigate the haemodynamic effects of d-sotalol at plasma concentrations producing class III antiarrhythmic effects. d-Sotalol 1, 4 and 10 mg/kg intravenously was given after β-blockade (propranolol 0.25 mg/kg intravenously) to seven pentobarbital anaesthetized dogs. Left ventricular (LV) systolic and end-diastolic pressures, LV dP/dt_max, mean aortic pressure, stroke volume, cardiac output and total peripheral resistance were not significantly changed by d-sotalol. There was a linear correlation between the dose of d-sotalol infused and the plasma concentration of d-sotalol obtained. Heart rate decreased and QT-time increased with increasing plasma concentrations of d-sotalol, whereas the QRS-width did not change. There was a linear correlation between the decrease in heart rate and the increase in QT-time, and between the plasma concentration of d-sotalol and increase in QT-time. In conclusion, the study indicates that after β-blockade, d-sotalol has no cardiodepressive effects at concentrations that prolong repolarization.     

益心舒胶囊联合比索洛尔对舒张性心衰大鼠的治疗作用

目的 探讨益心舒胶囊联合比索洛尔治疗舒张性心力衰竭心脏血流动力学的影响。方法 采用高盐喂养建立舒张功能不全性高血压大鼠模型,将24只舒张性心力衰竭大鼠随机分为3组,分别给予蒸馏水、比索洛尔水溶液、比索洛尔-益心舒胶囊水溶液治疗,共6周,观察左心室压力、左心室充盈时间、左心室舒张末期压力、等容收缩期左心室内压力上升的最大速率。结果 益心舒联合比索洛尔组大鼠的左心室舒张末期压显著低于对照组和比索洛尔组,但对左心室血压的影响无统计学差异。益心舒联合比索洛尔组等容收缩期左心室内压力上升的最大速率显著高于对照组(P<0.05),而等容舒张期左心室压力下降的最大速率和左心室充盈时间(t-dp/dt_max)在3组间未见统计学差异。结论 益心舒胶囊联合比索洛尔可有效改善舒张性心力衰竭大鼠的左心室舒张功能,而不影响左心室血压。     

Cardiovascular effects of the calcium sensitizer, levosimendan, in heart failure induced by rapid pacing in the presence of aortic constriction.

1. The haemodynamic effects of a novel cardiotonic drug, levosimendan, which has both calcium-sensitizing and phosphodiesterase III (PDE III) inhibitory properties, were studied in conscious dogs in which heart failure had been induced by prolonged cardiac pacing in the presence of aortic constriction. These effects were compared with those in sham-operated dogs with essentially normal cardiac function. 2. Eighteen mongrel dogs were instrumented for the measurement of left ventricular pressure (LVSP, LVEDP) and contractile function (dP/dt; dP/dt/P). In twelve dogs a balloon catheter, positioned in the thoracic aorta, was inflated producing an approximate 60% reduction in effective aortic diameter. Twenty min later rapid ventricular pacing (240 beats mean-1) was commenced and maintained for 48 h by means of a bipolar pacing electrode introduced into the right ventricle. This electrode served also for recording changes in the endocardial electrogram in the absence of pacing. Six of these dogs were used to evaluate the haemodynamic changes of pacing-induced heart failure; a further six of these dogs the haemodynamic changes elicited by levosimendan under these conditions. Six sham-operated dogs (group 2) served as controls. 3. In six dogs (group 1) the haemodynamic alterations were assessed after the development of heart failure. In the presence of aortic constriction, 48 h continuous rapid cardiac pacing resulted in a marked deterioration in left ventricular function which remained stable for at least 48 h after cessation of pacing. Thus, there was a marked reduction in LVSP (15%), +dP/dtmax (35%), -dP/dtmax (36%) and also in dP/dt/P (29%), whereas LVEDP was increased considerably (from 6.4 +/- 1.4 to 20.0 +/- 2.2 mmHg).(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute effects of acebutolol on cardiovascular function in man.

1 The acute cardiovascular effects of acebutolol were measured at constant paced heart rate in thirteen patients investigated for possible coronary artery disease, six of whom showed significant coronary stenosis with regional myocardial dysfunction, seven of whom proved normal. Acebutolol 0.75 mg/kg i.v. was given to three patients with coronary artery disease and three normals, and 1 mg/kg i.v. to the other patients.2 Measurements were made of cardiac output, left ventricular and arterial pressures, and left ventricular angiography. Isovolumic and ejection phase parameters of left ventricular function, and systemic vascular resistance were derived. Plasma levels of acebutolol were measured. 3 The acute effects of acebutolol were a slight fall in cardiac output, LV dp/dt and dP/dt/P. There was no change in LV or arterial pressures, no consistent change in LVEDP or EDV, and no consistent change in ejection fraction or mean VCF. These changes imply a small negative inotropic effect, more marked at the higher dose. 4 The effects of acebutolol differed in patients with ischaemic heart disease compared with normals in that LVEDP and EDV increased, mean VCF decreased and cardiac output was lowered more. 5 These data are consistent with myocardial and vascular effects of beta-adrenoceptor blockade more marked at the higher dose and more marked in patients with ischaemic heart disease.     

Effect of neuromuscular blocking agents pancuronium bromide and its monoquaternary analogue Org NC 45 on regional blood flow and cardiac metabolism in pigs

The effects of pancuronium bromide (60, 120, 300, and 600 μg.kg^?1, i.v.) and its monoquaternary analogue Org NC 45 (300,750, and 1500 μg.kg^?1, i.v.) on the systemic and regional hemodynamic variables were studied in the anesthetized pig. Pancuronium exhibited a dose-dependent positive chronotropic and inotropic activity. The enhanced oxygen requirement of the myocardium was successfully met by a combination of higher blood supply to, and oxygen extraction by, the tissue. No changes were noticed in cerebral, renal or hepatic arterial blood flow. On the other hand, Org NC 45, which unlike pancuronium lacks vagolytic and sympathomimetic actions, did not cause an increase in heart rate or left ventricular dP/dt_max (LV dp/dt_max). Instead, in the two highest doses (750 and 1500 μg.kg^?1) Org NC 45 decreased arterial blood pressure, LV dP/dt_max and the blood supply to the brain, kidneys, and liver. Neither compounds showed any effect on cardiac metabolism of glucose, lactate, or free fatty acids (FFA), although arterial blood glucose concentration did decrease following the two highest doses of each compound. Since Org NC 45, in a dose of 300 μg/kg^?1, which is seven to ten times the ED₉₀ for neuromuscular paralysis in man, is completely devoid of systemic and regional hemodynamic effects, and pancuronium in similar dose ratio is not, Org NC 45 might be preferred for use in cardiac anesthesia.     

Class III antiarrhythmic action and inotropy: effects of dofetilide in acute ischemic heart failure in dogs.

We studied the hemodynamic and metabolic effects of the novel class III antiarrhythmic agent dofetilide (UK-68,798) in acute ischemic heart failure. In pentobarbital-anesthetized dogs, heart failure was induced by microembolization of the area supplied by the main left coronary artery until a stable left ventricular (LV) end-diastolic pressure of 27 +/- 2 mm Hg was achieved. Embolization depressed LV systolic pressure, LV dP/dtmax, LV dP/dtmin, and cardiac output. None of these parameters were changed following i.v. infusion of dofetilide 5, 10, or 25 micrograms/kg, during spontaneous and paced cycle length of 300 ms (n = 9). Heart rate decreased by 12 +/- 8, 19 +/- 7, and 21 +/- 7 beats/min (p less than 0.05), while QT time increased by 23 +/- 7, 33 +/- 9, and 40 +/- 10 ms (p less than 0.05) after 5, 10, and 25 micrograms/kg, respectively. Ventricular effective refractory period increased from 128 +/- 10 to 153 +/- 11 ms after 25 micrograms/kg (n = 4). Arterial concentration and net myocardial uptake of glucose, lactate, and free fatty acids were not significantly influenced by dofetilide. In conclusion, dofetilide, at doses that prolonged repolarization, was devoid of cardiodepressive effects in acute ischemic heart failure.     

淫羊藿总黄酮对异丙基肾上腺素诱导心力衰竭大鼠去甲肾上腺素血管紧张素Ⅱ的影响

目的探讨淫羊藿总黄酮对充血性心力衰竭大鼠血浆去甲肾上腺素(NE)、血管紧张素(Ang)Ⅱ的影响。方法实验选用清洁级雄性SD大鼠60只,随机分为正常对照组(n=10),模型组50只皮下注射异丙基肾上腺素2次(170mg/kg),6周后应用超声心动图检测,以左室射血分数≤45%确定造模成功,将心力衰竭大鼠模型随机分为对照组、美托洛尔治疗组和淫羊藿总黄酮治疗组,18周使用左心导管进行血流动力学检查,利用酶联免疫吸附试验(ELISA)检测NE和放射免疫法检测血浆AngⅡ,并取心肌观察病理形态学特征。结果与正常对照组比较,模型组血浆NE、ANGⅡ显著升高,心功能指标明显恶化,心室质量指数显著升高,心室重构明显;与模型组比较,使用淫羊藿总黄酮及美托洛尔均能显著降低血浆NE、AngⅡ水平,心功能指标明显好转,心室质量指数明显降低,心室重构好转。结论淫羊藿总黄酮能通过降低心力衰竭大鼠血浆NE、AngⅡ的浓度,显著改善心功能,逆转心室重构。     

Korean Red Ginseng Induced Cardioprotection against Myocardial Ischemia in Guinea Pig

This study was designed to evaluate the protective effect of Korean red ginseng (KRG) against ischemia/reperfusion (I/R) injury in isolated guinea pig heart. KRG has been shown to possess various ginsenosides, which are the major components of Panax ginseng. These components are known naturally occurring compounds with beneficial effects and free radical scavenging activity. The heart was induced to ischemia for 60 min, followed by 120 min reperfusion. The hearts were randomly allocated into five groups (n=8 for each group): normal control (N/C), KRG control, I/R control, 250 mg/kg KRG group and 500 mg/kg KRG group. KRG significantly increased hemodynamics parameters such as aortic flow, coronary flow and cardiac output. Moreover, KRG significantly increased left ventricular systolic pressure (LVSP), the maximal rate of contraction (+dP/dt_max) and maximal rate of relaxation (-dP/dt_max). Also, treatment of KRG ameliorated electrocardiographic index such as the QRS, QT and RR intervals. Moreover, KRG significantly suppressed the lactate dehydrogenase, creatine kinase-MB fraction and cardiac troponin I and ameliorated the oxidative stress markers such as malondialdehyde and glutathione. KRG was standardized through ultra performance liquid chromatograph analysis for its major ginsenosides. Taken together, KRG has been shown to prevent cardiac injury by normalizing the biochemical and oxidative stress.     

Changes in haemodynamics and left ventricular function during intravenous nifedipine infusion with and without additional propranolol in patients with coronary artery disease. A randomized,placebo controlled trial

Summary The haemodynamic effects of a combined intravenous treatment of nifedipine and propranolol in ten patients with coronary artery disease compared to a single treatment with nifedipine or placebo were investigated.Nifedipine infusion resulted in a reduction of left ventricular (LV) afterload and LV volumes with an increase in heart rate and EF and no change of the double product, coronary sinus flow, LV diastolic parameters and dp/dt_max. Addition of propranolol lowers myocardial oxygen demand by reducing heart rate and dp/dt_max together with a sustained afterload reduction with no change in LV volumes and EF.The vasodilatatory action of nifedipine pretreatment balanced the negative effects of acute beta-receptor blockade on LV function and allows the reduction of myocardial oxygen demand without a deterioration of LV function.