热休克蛋白70对兔未成熟心肌和心肌间质的影响

目的: 探讨热休克蛋白70(HSP70)对未成熟心肌和心肌间质的影响. 方法:健康新生长耳大白兔12只随机分为2组. 对照组(C组):ip生理盐水0.4 mL,24 h后取离体心脏,常规建立Langendorff离体心脏灌注模型,灌注15 min转为工作心15 min后停灌45 min,恢复灌注15 min改为工作心30 min;实验组(E组):ip去甲肾上腺素, 24 h后取离体心脏,方法同对照组. 测定心肌细胞中HSP70含量、血流动力学指标、心肌含水量(MWC)、心肌肌酸激酶(CK)和乳酸脱氢酶(LDH)漏出率、三磷酸腺苷(ATP)含量、超氧化物歧化酶(SOD)和丙二醛(MDA)含量、心肌组织羟脯氨酸(HP)含量、内皮素(ET) 含量、心肌细胞内Ca2 含量、心肌线粒体Ca2 -ATPase活性及其Ca2 含量、心肌线粒体合成ATP能力[ATP]m,心肌超微结构. 结果:E组HSP70含量明显高于C组(P<0.01);MWC低于C组(P<0.05);ATP含量、SOD活性、心肌线粒体Ca2 -ATPase活性、[ATP]m, HP含量优于C组(P<0.01),MDA含量、CK, LDH漏出率、心肌细胞内Ca2 含量、心肌线粒体Ca2 含量、ET含量低于C组(P<0.01),心肌超微结构损伤较C组明显减轻. 结论:HSP70对缺血再灌注未成熟心肌和心肌间质具有明显的保护作用.     

Deleterious effect of exogenous angiotensin-I on the extent of regional ischaemia and its inhibition by captopril

The endogenous activity of the local renin-angiotensin system(RAS) and the anti-ischaemic properties of captopril were investigatedin electrically driven rabbit Langendorff hearts (constant pressure:70 cmH₂O, Tyrode solution, Ca²⁺ 1.8 mmol.l^–1). Cumulativeconcentration-response curves showed no significant difference(P>0.05) between the reduction of the global coronary flow(CF) by exogenous angiotensin-I or angiotensin-II (EC₅₀ = 10^–10mol.l^–1). It is concluded that the local RAS in isolatedrabbit hearts is highly sensitive, whereas its endogenous activityis very low due to very low endogenous angiotensin-I content.Myocardial ischaemia (MI) was induced by the occlusion of aleft coronary artery branch and MI was quantified from NADHsurface fluorescence photography. MI was significantly enlarged(+35%) (P <0.05) by exogenous angiotensin-I (6x10^–9mol.l^–1). The reduction in CF and the increment in MIby angiotensin-I could be completely prevented by adding captoprilat a low concentration (10^–6 mol.l^–1) to the perfusionbuffer. In the absence of exogenous angiotensin-I, captoprilalone (10^–6 mol.l^–1) neither significantly enhancedCF (P >0.05), nor diminished MI (P >0.05), supportingthe finding of very low endogenous activity of tile local RASin this model. We, moreover, conclude that at a low concentration(10^–6 mol.l^–1) captopril does not possess directcardioprotective properties independent of its ACE inhibitingaction.     

Early cardiotoxicity of the CHOP regimen in aggressive non-Hodgkin's lymphoma.

BACKGROUND: To determine the incidence of early cardiotoxicity induced by the CHOP regimen in patients with aggressive non-Hodgkin's lymphoma (NHL) and to identify associated risk factors. PATIENTS AND METHODS: A retrospective analysis included 135 consecutive patients who had been treated with the CHOP (cyclophosphamide, doxorubicin, vincristin, prednisone) regimen as first-line therapy between 1994 and 2000. The cardiac evaluation was based on a determination of the resting left ventricular ejection function (LVEF) by gated blood-pool imaging. Cardiotoxicity was defined as a significant decrease in LVEF or clinical evidence of congestive heart failure (CHF). RESULTS: Twenty-seven (20%) patients developed a cardiac event within 1 year of treatment. Among these, 14 patients had clinical signs of CHF. Three patients died suddenly from presumed cardiac causes. In multivariate analysis, a cumulative dose of doxorubicin >200 mg/m(2) [odds ratio (OR) = 4.2, P = 0.005)] and age over 50 years (OR = 2.9, P = 0.03) appeared to be significant risk factors. CONCLUSION: Early clinical and subclinical cardiotoxicity was frequent in patients receiving the CHOP regimen. The threshold of the cumulative dose of doxorubicin appeared to be low: at doses >200 mg/m(2), 27% of patients had cardiac events. Elderly patients appeared to be at higher risk. The development of cardioprotective strategies or alternative treatments are mandatory for aggressive NHL patients.     

Therapeutic potential of A1 adenosine receptor ligands: a survey of recent patent literature

Background: In recent years, a number of companies, universities and other institutions have invested in research on new molecules acting as agonists, antagonists and enhancers on A₁ adenosine receptors (ARs) and in the evaluation of their new therapeutic applications. Objective: To review recent patenting activity on this topic. Methods: The first part of this article describes the compounds patented, subdivided by functional activity, and the second part the most relevant therapeutic applications or new uses for A₁ AR ligands, with a focus on compounds in or soon to be in clinical trials. Conclusion: Although a number of potential therapeutic applications are proposed in the recent literature, at present, in the authors' opinion, very few A₁ ligands are close to coming on the market, probably due to limited selectivity towards the target tissue or organ.     

The role of nicorandil in the treatment of myocardial ischaemia

Nicorandil is an anti-anginal agent that has been used in the United Kingdom for over 6 years and is becoming increasingly popular. It induces coronary and peripheral vasodilatation via a dualistic mode of action, mediated by the opening of potassium-ATP channels (K_ATP) and its nitrate effect by stimulation of adenyl cyclase, with an increase in cGMP levels. Comparison to nitrates and other anti-anginal agents have shown it to be of equal efficacy in relieving ischaemic symptoms. Recent evidence suggests a role for nicorandil as a myocardial preconditioning agent but this may be limited by systemic vasodilatation. There is ongoing research into its role in improving the long-term outcome of patients with ischaemic heart disease (IHD). It has been shown to be of proven efficacy in the treatment of IHD and further research will clarify other uses of this agent.     

Quantity and Quality Relationships in Cardiovascular Medicine

Hospital volume and often also operator volume have documented impacts on the quality of care for aortic and aortocoronary bypass surgery, for percutaneous angioplasty and for radiofrequency ablation for arrhythmias, whereas data are less consistent for treatment of acute myocardial infarction. A review of this research is given. In the Nordic countries hospitals are small, and often the plateau of the learning curve cannot be reached. To discourage low-volume centers from embarking upon too complicated interventional or surgical procedures, the author suggests that a minimal number should be set for certain major procedures, both for hospitals and for physicians.     

Melatonin receptor‐mediated protection against myocardial ischemia/reperfusion injury: role of SIRT1

Melatonin confers cardioprotective effect against myocardial ischemia/reperfusion (MI/R) injury by reducing oxidative stress. Activation of silent information regulator 1 (SIRT1) signaling also reduces MI/R injury. We hypothesize that melatonin may protect against MI/R injury by activating SIRT1 signaling. This study investigated the protective effect of melatonin treatment on MI/R heart and elucidated its potential mechanisms. Rats were exposed to melatonin treatment in the presence or the absence of the melatonin receptor antagonist luzindole or SIRT1 inhibitor EX527 and then subjected to MI/R operation. Melatonin conferred a cardioprotective effect by improving postischemic cardiac function, decreasing infarct size, reducing apoptotic index, diminishing serum creatine kinase and lactate dehydrogenase release, upregulating SIRT1, Bcl‐2 expression and downregulating Bax, caspase‐3 and cleaved caspase‐3 expression. Melatonin treatment also resulted in reduced myocardium superoxide generation, gp91^phox expression, malondialdehyde level, and increased myocardium superoxide dismutase (SOD) level, which indicate that the MI/R‐induced oxidative stress was significantly attenuated. However, these protective effects were blocked by EX527 or luzindole, indicating that SIRT1 signaling and melatonin receptor may be specifically involved in these effects. In summary, our results demonstrate that melatonin treatment attenuates MI/R injury by reducing oxidative stress damage via activation of SIRT1 signaling in a receptor‐dependent manner.     

Cardioprotective Efficacy of Verapamil and Mibefradil in Young UM-X7.1 Cardiomyopathic Hamsters

Summary. Since calcium overload and increased in T-type calcium channel activity have been observed in the cardiomyopathic (CM) hamster, we hypothesized that mibefradil (Ro 40-5967), a new T- and L-type calcium channel blocker, may exert significant cardioprotection in the early phase of the disease. Young (30-day-old) CM hamsters of the UM-X7.1 subline were treated with mibefradil or verapamil for 4 to 6 weeks. Mibefradil doses were in the range of 0.5 to 8 mg/kg/day while verapamil was given at a dose of 5–10 mg/kg/day, both drugs being injected twice daily (sc and ip alternatively). At the end of the treatment period, myocardial and skeletal muscle (tongue) were harvested and processed for assessment of necrotic changes and calcification. In hearts from control CM hamsters, numerous necrotic and calcified foci were observed. These myocardial necrosis markers were not attenuated by mibefradil in the dose range studied whereas verapamil significantly reduced their severity. The dystrophic process in skeletal muscle (tongue) was not inhibited by mibefradil or verapamil. These results suggest that mechanisms other than inhibition of T- and L-type calcium channels are related to the cardioprotection observed in the presence of verapamil. A specific action on the sarcoplasmic reticulum (ryanodine-sensitive calcium channel) or the mitochondria may explain the efficacy of phenylalkylamines (verapamil) in this condition.     

Cardioprotection Afforded by Norepinephrine-mediated Postconditioning in Isolated Rat Hearts

Objectives Previous studies have demonstrated that endogenous norepinephrine （NE） plays an important role in the mediation of ischemic preconditioning. The present study is designed to determine whether NE is also involved in mediation of the protective effects of postconditioning. Methods The rat hearts were rapidly excised under anesthesia and attached to a Langendorff apparatus via the aorta for retrograde perfusion with Krebs-Henseleit buffer solution. All hearts were subjected to 30 min of left coronary artery occlusion followed by 60 min of reperfusion, except the control group. Animals were randomly divided into 5 groups as follows： （1） control group, the hearts were underwent same procedures without ischemic insult ; （2） ischemia reperfusion group, the left coronary artery was occluded for 30 rain and followed by 60 min of reperfusion ; （3） ischemic postconditioning （IPost） group, immediately at the onset of reperfusion, the heart was initiated with 1 min of full coronary flow, followed by 1 min of re-occlusion, repeated for a total of three cycles; （4） IPost plus prazosin group, the heart was perfused with prazosin for 10 min before ischemia; （5） IPost plus reserpine group, a single dose of reserpine was administered by i.m. injection, 24 hours before the experiment. Coronary flow was measured by timed collection of coronary effluent and sample of coronary effluent at 5 min of reperfusion were collected for the measurement of creatine kinase （CK）. Infarct size and risk area were determined at the end of experiments. Results 30 min of ischemia and followed by 60 rain of reperfusion caused a significant decrease in cardiac function and a significant increase in CK release and infarct size. Postconditioning with three cycles of 1-min ischemia and 1-min reperfusion markedly improved cardiac function and reduced CK release and infarct size. However, the cardioprotection afforded by postconditioning was abolished by prazosin （10^-6M） , a selective α adrenergic receptor an     

Cardiac uses of phosphodiesterase-5 inhibitors

Phosphodiesterase-5 inhibitors (PDE5Is) improve erectile function by enhancing nitric oxide availability in the penis and its supplying vasculature, resulting in vasodilation and increased blood flow. PDE5Is might benefit cardiovascular diseases because phosphodiesterase-5 is also located elsewhere in the body, including the pulmonary and systemic vasculature and in hypertrophied myocardium. PDE5Is are approved for pulmonary arterial hypertension, given that they improved several hemodynamic and clinical parameters in large randomized trials. Initial evidence suggests that PDE5Is benefit patients with congestive heart failure and secondary pulmonary hypertension. PDE5Is seem to improve hemodynamic and clinical parameters in patients with high-altitude pulmonary edema (HAPE) and high-altitude pulmonary hypertension. In climbers with prior episodes of HAPE, PDE5Is prevented HAPE in 2 small randomized trials. In small randomized trials of PDE5Is, patients with Raynaud's phenomenon demonstrated improved blood flow, fewer symptoms and frequency of attacks, and resolution of digital ulcers. In addition to enhancing vasodilation, PDE5Is seem to protect the myocardium through complex pathways that involve nitric oxide, cyclic guanosine monophosphate, protein kinase G, extracellular-signal-regulated kinase, B-cell lymphoma protein-2, and Rho kinase inhibition. In animal models of acute myocardial infarction, PDE5Is consistently reduced infarct size indicating cardioprotection and PDE5Is also promote reverse remodeling and reduce myocardial apoptosis, fibrosis, and hypertrophy. PDE5Is might also benefit patients with treatment-resistant hypertension, preeclampsia, or peripheral arterial disease. This review presents the pathophysiology and trial data with regard to the use of PDE5Is for cardiac diseases.