Intravenous administration of vascular endothelial growth factor improves cardiac performance and inhibits cardiomyocyte apoptosis

This study investigated the effects of vascular endothelial growth factor (VEGF) intravenous administration on cardiac performance and cardiomyocyte apoptosis in a rat model of acute myocardial infarction. Left coronary artery ligation produced extensive myocardial infarction in 48 rats and sham operated in 24 animals. Twenty-four hours after surgery, the rats were randomized to receive VEGF165-heparin (treated group) or heparin-saline (control group) treatment. The sham-operated animals were also to receive VEGF165-heparin (sham group) treatment. VEGF165 (2 microg/ml) with heparin (50 U) or heparin-saline (50 U/ml) was administered daily via the tail vein for 7 and 14 days. Fifty-eight rats survived and included in the study. There were not significant effects of VEGF on hemodynamic parameters in sham animals. As compared with control animals at 9 days after ligation (with 10 rats for each group), rats treated with VEGF had significantly higher maximum rate of left ventricular pressure rise (+ dP/dtmax) or fall ( - dP/dtmax) and microvessel counts, and significantly lower left ventricular end-diastolic pressure (LVEDP) and infarct size. At 16 days after surgery (12, 7 and 9 rats in sham, control and treated groups; respectively), VEGF treatment significantly increased mean arterial pressure (MAP), left ventricular systolic pressure (LVSP), +/- dP/dtmax and microvessel counts, and significantly decreased LVEDP and infarct size. VEGF treatment significantly inhibited cardiomyocyte apoptosis and the expression of p53, Fas and Bax protein, and increased the expression of Bcl-2 protein in myocardium at 9 days after myocardial infarction.     

Role of aspirin in modulating myocardial ischemic reperfusion injury

The role of low-dose aspirin (3 mg/kg, i.v.) in attenuating ischemic reperfusion injury was studied in a canine model. Regional ischemia for 40 min was produced by temporary occlusion of the left anterior descending coronary artery and thereafter reperfusion instituted for 3 h. Mean arterial pressure (MAP), heart rate (HR), left ventricular end diastolic pressure (LVEDP), positive (+) LV dP/dt _max and negative (–) LV dP/dt _max were monitored alongwith myocardial adenosine triphosphate (ATP), creatine phosphate (CP), glycogen and lactate. Following reperfusion, there was a significant fall in (i) MAP, (ii) (+) LV dP/dt _max and (iii) (–) LV dP/dt _max. LVEDP was corrected after about 2h of reperfusion. Replenishment of only myocardial CP occurred, without any change in ATP and glycogen, although lactate accumulation was corrected.Aspirin administered 15 min before reperfusion (posttreatment) caused normalisation of LVEDP within 15 min and prevented any deterioration in (–) LV dP/dt _max, although it had no effect on MAP and (+) LV dP/dt _max. After 3h of reperfusion (post-treatment), myocardial ATP, CP, glycogen and lactate contents became normal. The number of premature ventricular complexes was significantly reduced after aspirin treatment. The present study indicates that low-dose aspirin post-treatment can ameliorate at least some of the deleterious consequences of reperfusion injury of the myocardium.     

缓激肽在依那普利对心肌梗死大鼠心肌肥厚及心功能影响中的作用

目的:探讨依那普利(enalapril)对大鼠心肌梗塞(M1)后心肌肥厚及心功能的影响是否与其抑制缓激肽(BK)降解的途径有关。方法:将大鼠随机分为:①假手术对照组(sham-operated control),②心肌梗死组(MI),③依那普利干预组(MI+enalapril),④依那普利和BKB₂受体阻断剂Hoe-140共同干预组(MI+enalapril+Hoe-140),⑤血管紧张素ⅡⅠ型受体阻断剂losartan干预组(Ml+losartan)。3个药物干预组从MI术后第3d开始给药,持续4周,然后测定左心室舒张末压(LVEDP)、+dp/dt_max及左心室重/体重(LVW/BW)、左心室非梗死区组织的平均(每核)心肌细胞体积,并进行组间比较。结果:3个药物干预组的LVEDP、LVW/BW及V(m)n均低于MI组(均Pp/dt_max和MI组相比无显著差别。3个药物干预组之间平均动脉压(MAP)无明显差异,但Ml+enalapril+Hoe-140组的LVW/BW及V(m)n的值却高于MI+enalapril组。结论:Enalapril可阻抑大鼠MI后的心肌肥厚并改善左心室功能,这种作用的部分机制是由于其促使了心肌组织BK的积累,即BK参与了enalapril阻抑心肌肥厚及改善心功能的作用,且这些作用不依赖于血压的影响。     

The T-type calcium channel blocker mibefradil reduced interstitial and perivascular fibrosis and improved hemodynamic parameters in myocardial infarction-induced cardiac failure in rats

Fibrillar collagen accumulates within the interstitium and around coronary arteries following cardiac failure and is responsible for abnormal myocardial stiffness and reduced coronary performance associated with impaired cardiac function. The aim of the study was to determine the effects of long-term treatment with the T-type calcium channel antagonist mibefradil on myocardial remodeling and cardiac function after chronic myocardial infarction (MI). MI was induced by permanent ligation of the left coronary artery in male Wistar rats. Animals were assigned to sham-operated, placebo-treated or mibefradil-treated (10 mg/kg per day p.o.) MI groups. Treatment with mibefradil was started either 7 days before, 24 h after, or 7 days after ligation and continued for 6 weeks after MI. At this time point, mean arterial blood pressure (MAP), heart rate (HR), left ventricular end-diastolic pressure (LVEDP) and cardiac contractility (dP/dt_max) were measured in conscious rats. Morphometric parameters were determined in picrosirius red-stained hearts: total heart weight (THW), interstitial and perivascular collagen volume fraction (ICVF, PCVF), myocardial infarct size (IS), vascular perimeter (VP), inner vascular diameter (IVD) and media thickness (MT). Six weeks after MI, MAP and dP/dt_max were decreased, and LVEDP was increased in placebo-treated animals. In mibefradil-treated animals whose treatment started 7 days before or 24 h after MI, MAP and dP/dt_max were higher, and LVEDP was lower than in placebo-treated controls. THW, ICVF, PCVF and MT were higher in placebo-treated animals. Mibefradil treatment resulted in higher ICVF and IS, higher VP and IVD (when started 7 days before MI) and lower PCVF and MT (when started 7 days before or 24 h after MI) than were observed in placebo-treated controls. Chronic treatment with mibefradil reduced interstitial and perivascular fibrosis and improved cardiac function in MI-induced heart failure in rats. Cardiac remodeling was best prevented when treatment was begun before the ischemic event. Received: 16 March 1999 / Accepted: 23 August 1999     

非兴奋性电刺激对正常及心肌梗死兔心功能的影响及其作用的局部性

目的:观察于绝对不应期发放电刺激对正常和心肌梗死(MI)兔在体心脏心功能的影响及其对心肌作用的局部性。方法:64只家兔随机分为正常组和MI组两大组,每组又分为前壁和后壁两组。复制MI模型,4周后每组开胸,窦性心律下,分别于前壁组和后壁组的左心室前壁和后壁,发放绝对不应期方波电刺激(CCM)。观察左心室收缩压(LVSP)左心室舒张末压(LVEDP)及其微分(±dp/dt_max)的变化。结果:正常组前壁和后壁CCM刺激时LVSP及+dp/dt_max均显著大于刺激前(P<0.05),LVEDP低于、-dp/dt_max负值大于刺激前(P<0.05),且不同部位的CCM刺激对心功能的影响不同,左心室前壁的上述作用大于后壁(P<0.05);MI组前壁和后壁CCM刺激时LVSP及+dp/dt_max亦大于刺激前(P<0.05),LVEDP低于、-dp/dt_max负值亦大于刺激前(P<0.05),但前后壁两组之间无显著差别(P＞0.05)。结论:于绝对不应期发放电刺激能明显增强正常和MI后心肌的收缩和舒张功能,CCM刺激对心肌的作用是局部性的。     

Balance of pro‐ versus anti‐angiogenic splice isoforms of vascular endothelial growth factor as a regulator of neuroblastoma growth

Neuroblastoma (NB) is the second most common extracranial tumour of childhood. Angiogenesis plays a crucial role in the growth and development of NB and vascular endothelial growth factor (VEGF), one of the most potent stimuli of angiogenesis, has been studied extensively in vitro. VEGF₁₆₅ has been shown to be the predominant angiogenic isoform expressed in NB cell lines and tumours. In this study, we investigated the anti‐angiogenic isoform of VEGF‐A, generated from distal splice site selection in the terminal exon of VEGF (VEGF₁₆₅b) and shown to be down‐regulated in epithelial malignancies. The expression of both the pro‐ (VEGF_xxx) and the anti‐angiogenic (VEGF_xxxb) isoforms was compared in a range of NB and ganglioneuroma (GN) tumours. Whereas VEGF_xxxb and VEGF_xxx were both expressed in GN, specific up‐regulation of the VEGF_xxx isoforms was seen in NB at RNA and protein levels. Highly tumourigenic NB cell lines also showed up‐regulation of the angiogenic isoforms relative to VEGF_xxxb compared to less tumourigenic cell lines, and the isoforms were differentially secreted. These results indicate that VEGF₁₆₅ is up‐regulated in NB and that there is a difference in the balance of isoform expression from anti‐angiogenic VEGF₁₆₅b to angiogenic VEGF₁₆₅. Treatment with recombinant human VEGF₁₆₅b significantly reduced the growth rate of established xenografts of SK‐N‐BE(2)‐C cells (4.24 ± 1.01 fold increase in volume) compared with those treated with saline (9.76 ± 3.58, p < 0.01). Microvascular density (MVD) was significantly decreased in rhVEGF₁₆₅b‐treated tumours (19.4 ± 1.9 vessels/mm³) in contrast to the saline‐treated tumours (45.5 ± 8.6 vessels/mm³). VEGF₁₆₅b had no significant effect on the proliferative or apoptotic activity, viability or cytotoxicity of SK‐N‐BE(2)‐C cells after 48 h. In conclusion, VEGF₁₆₅b is an effective inhibitor of NB growth. These findings provide the rationale for further investigation of VEGF₁₆₅b in NB and other paediatric malignancies. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

MuRF-1在大鼠心肌梗死后慢性心衰心脏中的表达变化及其分子机制的探讨

目的：研究肌肉环指蛋白1（MuRF-1）在心肌梗（MI）死后慢性心衰大鼠心脏中的表达变化及其分子机制,对心功能及心肌肌钙蛋白I（cTnI）的影响及其与cTnI的关系。方法：将48只制作成功的心肌梗死大鼠及假手术大鼠纳入研究,分为sham 组、MI组、MG-132组及TNF-α组,检测各样本血流动力学指标及血清N末端原脑钠肽水平（NT-proBNP）,观察心肌组织学变化;原位杂交及real-time PCR法半定量测定心肌组织MuRF-1 及cTnI mRNA表达,Western blotting法确定心肌MuRF-1及cTnI蛋白质水平,并对MuRF-1及cTnI的相关性进行分析。结果：与MI及TNF-α组相比,MG-132能够显著降低NT-proBNP（P<0.05）,使心衰的发生率及死亡率有下降趋势,心肌组织损伤减轻,并使大鼠左心室收缩压（LVSP）升高（P<0.01）,左心室等容收缩期室内压最大上升速率（+dp/dt_max）增加（P<0.01）,左心室舒张末压（LVEDP）明显降低（P<0.01）。与sham组相比,MI组MuRF-1的mRNA及蛋白质表达均显著升高（P<0.05）,cTnI水平降低（P<0.05）;MG-132能够明显降低心肌梗死后MuRF-1表达（P<0.05）,升高cTnI水平（P<0.01）;TNF-α则起相反作用。相关性分析显示,MuRF-1与cTnI呈显著负相关（P<0.01）。结论：MuRF-1在慢性心衰中表达显著升高,使心功能损害加重,其作用通过抑制cTnI表达而实现;抑制蛋白酶体活性能够通过抑制MuRF-1表达而升高cTnI水平,改善心功能。MuRF-1的激活可能是慢性心力衰竭的机制之一。     

Postnatal development in intermittent hypoxia enhances resistance to myocardial ischemia/reperfusion in male rats

To assess the tolerance of rats that developed from birth in intermittent hypoxia (IH) to myocardial ischemia and reperfusion, we set up a reproducible model in our laboratory. IH rats were raised 60 days from birth in a hypobaric chamber at 5000 m for 6 h daily, while controls were in continuous normoxic conditions. At 60 days after birth, the antioxidant capacity of the heart was determined; arterial and venous partial pressures of oxygen were measured at sea level and 5000 m altitude. In addition, isolated hearts of each group were perfused in Langendorff mode and submitted to 30 min global ischemia followed by 30 min reperfusion to compare functional recovery and lactate dehydrogenase release. For the IH rats, recovery of left ventricular developed pressure (DP), the maximum of the positive or negative first derivative of left ventricular pressure with respect to time (±LV dP/dt), end-diastolic pressure (EDP), and pressure-rate product (PRP) were all superior (P<0.05) to those of control rats. The myocardial antioxidant capacity was also significantly increased in the left ventricle of IH rats. Further, at 5000 m altitude the arterio-venous oxygen gradient (Pa–vO₂) was significantly (P<0.01) higher in the IH rats than in the controls. These data indicate that IH from birth enhances the tolerance of the heart to ischemia/reperfusion, elevates the myocardial antioxidant capacity, and increases oxygen extraction.     

Effects of cold‐water immersion on VEGF mRNA and protein expression in heart and skeletal muscles of rats

Aim: The effects of cold exposure on gene and protein expression of vascular endothelial growth factor (VEGF), in heart and skeletal muscles, were studied in male adult Wistar rats. Methods: Cold immersion was accomplished by submerging the rats in shoulder‐deep water maintained at ～18 °C, either acutely (1 h) or chronically (1 h day^?1, 5 days week^?1 for 20 weeks). The expressions of VEGF mRNA and protein in heart, gastrocnemius, and soleus muscles were examined by Northern and Western blotting and competitive‐polymerase chain reaction techniques. Results: The expressions of VEGF mRNA and protein were markedly increased in cardiac muscle of the cold‐immersed group, particularly in the 1‐hour exposure group, whereas VEGF mRNA and protein in gastrocnemius were decreased significantly after an acute exposure. Although the protein level in gastrocnemius remained low in the chronically exposed group, the expression of mRNA of VEGF₁₆₅ with chronic exposure in this group returned to the control level and that of VEGF₂₀₆ was 15% greater than that in controls. The expression of mRNA for VEGF₁₆₅ in soleus was also lowered by acute cold exposure, although that for VEGF₂₀₆ was stable. However, VEGF protein was increased by 50%. After 20 weeks, all of these parameters were increased over the levels found in the controls. Conclusion: These results suggest that the VEGF gene may be a major regulatory factor in cardiac and skeletal muscle adaptation to the cold environment stimulating angiogenesis and thermogenesis.     

The effect of sarcoplasmic reticulum blockade on the force/frequency relationship and systolic contraction patterns in the newborn pig heart

 We investigated the relationship between heart rate and contractility in seven anaesthetized young piglets by measuring contractility at different atrial pacing rates. To study the origin of this relationship we repeated the measurements after blocking the sarcoplasmic reticulum calcium release channel with ryanodine. We assessed contractility using indices derived from instantaneous left ventricular pressure and volume measured by micromanometric and conductance catheters during rapid inferior vena cava occlusion, thus generating the end-systolic pressure-volume relationship, which was characterized by its slope E _es, and the maximum rate of change of ventricular pressure (dP/dt _max)/end-diastolic volume relationship, also charaterized by its slope. All animals showed an increase in contractility with increasing heart rate (intact force/frequency relationship) which was abolished after ryanodine. The most striking effect of ryanodine on baseline haemodynamics was the dramatic decrease of dP/dt _max to about 50% of its original value, while peak developed pressure and E _es did not change. We conclude that the young piglet, despite its immaturity, has a functional sarcoplasmic reticulum, illustrated by an intact force/frequency relationship. In addition, blockade of the sarcoplasmic reticulum in vivo has profoundly different effects during early and late systole, indicating that indices of contractility derived during different parts of the cardiac cycle represent different aspects of systole. Received: 22 August 1996 / Received after revision and accepted: 18 August 1997     

The inotropic effect of atrial natriuretic factor in the anesthetized rabbit

This study was designed to investigate whether atrial natriuretic factor (ANF) administered over the physiological, pathological and pharmacological range has a negative inotropic action on the heart. Anesthetized rabbits were infused with increasing doses of ANF (0.05, 0.25 and 0.5g kg^–1min^–1), while measuring hemodynamic variables including the maximum rate of change of left ventricular pressure (dP/dt _max) as an index of inotropic state. Plasma levels of immunoreactive ANF (iANF) were measured to relate the hemodynamic changes to actual plasma levels of the peptide. Administration of ANF was associated with decreases in blood pressure, left ventricular pressure and dP/dt _max so that after 0.5 g kg^–1 min^–1 infusion, these variables had decreased by 21±2 mmHg, 21±5.3 mmHg and 925±175 mmHg/s, respectively (P<0.01). There were no significant changes in right atrial pressure, left ventricular end-diastolic pressure or heart rate. Since dP/dt _max can be influenced by changing hemodynamic variables and baroreflex changes, a second group of rabbits was studied in which afterload and heart rate were held artificially constant. Again, in this group of rabbits, infusions of ANF led to decreasing inotropic state, so that at the highest infusion rate, a 14% decrease in dP/dt _max was observed (P<0.05). By comparison, hydralazine, a drug which causes active vasodilatation but no direct inotropic action, significantly (P<0.01) decreased blood pressure, left ventricular pressure and dP/dt _max when infused at a rate of 10 g kg^–1 min^–1. However, in animals in which afterload was controlled, hydralazine did not affect any of the variables measured. The results indicate that ANF does have a negative inotropic action in the anesthetized rabbit.     

曲古抑菌素A对心衰大鼠心脏促炎细胞因子及心功能的影响

目的: 观察组蛋白脱乙酰化酶抑制剂曲古抑菌素A(TSA)对心肌梗死后心衰(HF)大鼠心脏肿瘤坏死因子(TNF-α)、白细胞介素-1β(IL-1β)和诱导型一氧化氮合酶(iNOS)及心功能的影响。方法: 采用冠状动脉左前降支结扎术致心肌梗死制备大鼠HF模型和假手术模型(sham),给予TSA或vehicle处理。给药4周后,测定血流动力学参数,应用免疫组织化学和ELISA检测左室心肌TNF-α、IL-1β和iNOS的水平,并测定右室/体重(RV/BW)、肺重/体重(LW/BW)。结果: 与HF+vehide组相比,给予TSA后可使HF大鼠心肌组织内增高的TNF-α、IL-1β和iNOS含量明显降低(P<0.05),左室舒张末压(LVEDP)和LW/BW降低(P<0.05);降低的左室内压最大上升速率(+dp/dt_max)和左室内压最大下降速率(-dp/dt_max)明显升高(P<0.05)。结论: 组蛋白脱乙酰化酶抑制剂TSA抑制心肌梗死后HF大鼠心肌组织TNF-α、IL-1β及iNOS的产生,并且可能通过该抑制作用改善HF大鼠的心功能,减轻肺淤血。     

心肌梗塞大鼠心肌间质胶原重构与血流动力学改变的相关研究

目的：研究心肌梗塞后细胞外间质重构和心功能改变之间的关系。方法：在结扎左冠状动脉的大鼠心肌梗塞模型上动态观察梗塞区（IZ）和非梗塞区（NIZ）胶原含量及胶原I/III比值的变化及其与左室收缩和舒张功能参数的相关性。结果：心梗3 d以后IZ和NIZ胶原含量均明显大于假手术组相应时间的测值（P<0.05,P<0.01）。IZ胶原I/III比值3 d时低,7 d以后明显高（P<0.01）。NIZ在14d时I/III比值明显高。将心梗后42 d时IZ和NIZ胶原含量和Ⅰ/Ⅲ比值与+P'_max和-P'_max进行相关分析表明,NIZ胶原含量与+P'_max和-P'_max均呈负相关,r=-0.589,P>0.05和r=-0.788,P<0.01;NIZ胶原I/III比值与+P'_max和-P'_max亦呈负相关（r=-0.504,r=-0.545,P>0.05）。IZ胶原含量与+P'max呈正相关,r=0.70,P<0.05与-P'_max无相关性（r=-0.29）。IZ 胶原I/III比值与+P'_max和-P'_max均无相关性。结论：心梗后梗塞区胶原沉积有助于改善收缩功能,而非梗塞区的胶原增生则损害收缩和舒张功能.     

An improved isolated, left ventricular ejecting, murine heart model

 An improved, isolated, left ventricular-ejecting, murine heart model is described and evaluated. Special attention was paid to the design and impedance characteristics of the artificial aortic outflow tract and perfusate composition, which contained glucose (10 mM plus insulin) and pyruvate (1.5 mM) as substrates. Temperature of the isolated perfused hearts was maintained at 38.5 °C. During antegrade perfusion (preload 10 mm Hg, afterload 50 mm Hg, 2.5 mM Ca²⁺) proper design of the aortic outflow tract provided baseline values for cardiac output (CO), left ventricular developed pressure (LVDP) and the maximum first derivative of left ventricular pressure (LV dP/dt _max) of 11.1±1.7 ml min^–1, 83±5 mm Hg and 6283±552 mm Hg s^–1, respectively, resembling findings in the intact mouse. During 100 min normoxic antegrade perfusion CO declined non-significantly by less than 10%. Varying pre- and afterloads resulted in typical Frank-Starling relationships with maximal CO values of 18.6±1.8 ml min^–1 at pre- and afterload pressures of 25 and 50 mm Hg, respectively. Left ventricular function curves were constructed at free [Ca²⁺] of 1.5 and 2.5 mM in the perfusion medium. Significantly higher values for CO, LVDP and LV dP/dt _max and LV dP/dt _min were obtained at 2.5 mM Ca²⁺ at all loading conditions investigated. Phosphocreatine and creatine levels remained stable throughout the perfusion period. Despite a small but significant decline in tissue ATP content, the sum of adenine nucleotides did not change during the normoxic perfusion period. The tissue content of glycogen increased significantly. Received: 28 April 1998 / Received after revision and accepted: 10 September 1998     

Repeated normoxic hyperbaric exposures induce haemodynamic and myocardial changes in rats

Summary The effect of repeated exposure to ambient pressures of 5 bar (500 kPa), in atmospheres comprising normal partial pressures of oxygen [0.2 bar (20 kPa)] and nitrogen [0.8 bar (80 kPa)] and 4 bar (400 kPa) helium, on cardiac function and morphology was assessed in conscious rats. Ten test rats underwent chamber dives daily for 40 consecutive days, and ten control rats were exposed in the same chamber for an equal period of time, but in air at 1 bar (100 kPa). Cardiac output (Q_c) and myocardial blood flow (Q_myocardial) were determined by the microsphere method. After 40 days, the body mass was 7% greater in the control than in the test rats (P<0.05), although they were given exactly the same amount of standard food. The test rats had a significantly higher (7% absolute, 12% ventricular mass to body mass, P<0.05) heart mass (left ventricular myocardium, including the ventricular septum) than the control rats. The percentage tissue dry mass of the right and left ventricles was equal in the two groups. Microscopic examination revealed a number of small focal necroses in the left ventricle of the test rats but none in the control rats. The left ventricular pressure (LVP) and the maximum velocity of LVP increase (contractility) and decrease were significantly increased (25%–96%, P<0.001) in the pre-exposed compared to the control rats at 1 bar (100 kPa). The systolic arterial pressure, heart rate and respiratory frequency were similar in the two groups at 1 bar (100 kPa). The LVP and + dP/dt increased linearly and in parallel in both groups during compression, although at 5 bar (500 kPa) the test rats had reached a significantly higher LVP and + dP/dt level. However, the heart rate was unchanged in both groups. The pre-exposed rats had a higher left Q_myocardial [1 bar (100 kPa)=33%, P<0.05; and 5 bar (500 kPa)=maximum 40%, P<0.05] than the control rats. The systolic arterial blood pressure also increased during compression to its maximum after 20 min at 5 bar (500 kPa) in both groups. The mean arterial pressure, respiratory frequency, end-diastolic pressure and Q_c were unchanged throughout the experiments. A pressure drop of 42 mmHg (5.6 kPa) between the left ventricle and the arteries would suggest stenosis in the aortic valve region in the test rats. In conclusion, the cardiac function as well as myocardial mass and morphology were changed after 40 consecutive exposures to 5 bar (500 kPa) in conscious rats.     

Organ blood flow and cardiac contractility in anaesthetized cats at 5 bar (500 kPa) ambient pressure

Summary Previous in vivo and in vitro experiments have demonstrated increased cardiac contractility and increased total myocardial blood flow ( ) when rats were exposed to normoxic 5-bar (500 kPa) ambient pressure. In the present study, regional blood flow was measured using the microsphere method on nine anaesthetized cats at surface and normoxic 5-bar (500 kPa) ambient pressure. Left ventricular pressure (LVP) and cadiac contractility, measured as peak left ventricular +dP/dt and –dP/dt were measured in six of the cats. Arterial pressure, heart rate and cardiac output remained unchanged after compression, but total increased by 29% (P<0.01) and cerebral blood flow increased by 66% (P<0.05). At the same time +dP/dt and –dP/dt was increased by 83% and 102%, respectively (P<0.01), while LVP was enhanced by 14% (P<0.05). Except for a moderate decrease in partial pressure of oxygen, acid base status in arterial blood remained unchanged. The results indicate that the effects of increased ambient pressure on the heart are general physiological phenomena, which are not only limited to the laboratory rat.     

bFGF通过促进心脏血管新生改善心肌梗死后小鼠心脏重构

目的:探讨碱性成纤维细胞生长因子(basic fibroblast growth factor,b FGF)对心肌梗死小鼠心脏的保护作用及机制。方法:采用异氟烷麻醉C57/B6小鼠(8~12周龄)后,侧开胸结扎冠状动脉左前降支,建立小鼠心肌梗死模型;设立假手术组为对照,心肌梗死模型小鼠随机分为心梗组和bFGF给药组,其中bFGF组小鼠心梗7d后给予5μg b FGF隔天腹腔注射给药;在小鼠心梗第28天时采用心脏多普勒超声检测心功能,以左室舒张末期内径、左室收缩末期内径、左心室射血分数和左心室短轴缩短分数评价心脏功能改变;28 d后处死小鼠,行病理切片观察心肌纤维化程度和心肌梗死区内血管新生的情况;Western blot检测血管新生指标。结果:bFGF给药组小鼠心肌纤维化程度较心梗模型组明显减少;第28天行超声心动图检查结果示,心梗组小鼠心功能较假手术组差,而bFGF给药组小鼠心功能与心梗组比较有明显的改善;小鼠心肌病理切片免疫荧光观察结果发现,bFGF给药组心肌梗死区的新生血管比心梗组明显增多;Western blot实验表明,bFGF能够激活AKT/HIF-1α/VEGF通路。结论:隔天腹腔注射bFGF能够减少心肌梗死小鼠心肌纤维化,改善心功能。bFGF可能通过AKT/HIF-1α/VEGF信号通路促进血管新生,从而保护心脏。     

Left ventricular pressure–volume relationships during normal growth and development in the adult rat – studies in 8‐ and 50‐week‐old male Wistar rats

Aims: Left ventricular (LV) pressure–volume relations provide relatively load‐independent indexes of systolic and diastolic LV function, but few data are available on pressure–volume relations during growth and development in the normal adult heart. Furthermore, to quantify intrinsic ventricular function the indexes should be normalized for heart weight. However, in many studies the indexes are reported in absolute terms, or body weight‐correction is used as a surrogate for heart weight‐correction. Methods: We determined pressure–volume relations in young (8‐week‐old, n = 13) and middle‐aged (50‐week‐old, n = 19) male Wistar rats in relation to their heart and body weights. The animals were anaesthetized and a 2F pressure‐conductance catheter was introduced into the LV to measure pressure–volume relations. Results: Heart and body weights were significantly higher in the 50‐week‐old rats, whereas the heart‐to‐body weight ratio was significantly lower (2.74 ± 0.32 vs. 4.41 ± 0.37 mg g^?1, P < 0.001). Intrinsic systolic function, quantified by the slopes of the end‐systolic pressure–volume relation (E_ES), the dP/dt_MAX vs. end‐diastolic volume relation (S‐dP), and the preload recruitable stroke work relation (PRSW), normalized for heart weight, was slightly decreased in the 50‐week‐old rats (S‐dP: ?6%, P < 0.004; PRSW: ?3%, P < 0.06). Heart weight‐corrected diastolic indexes were not significant different. The absolute indexes qualitatively showed the same results, but body‐weight corrected pressure–volume indexes showed improved systolic function and significantly depressed diastolic function. Conclusions: Intrinsic systolic function slightly decreases from the juvenile to the middle‐aged period in normal male Wistar rats. Furthermore, correction of pressure–volume indexes for body weight is not an adequate surrogate for heart weight‐correction in these animals.     

Glutathione deficiency intensifies ischaemia‐reperfusion induced cardiac dysfunction and oxidative stress

The efficacy of glutathione (GSH) in protecting ischaemia‐reperfusion (I‐R) induced cardiac dysfunction and myocardial oxidative stress was studied in open‐chest, stunned rat heart model. Female Sprague–Dawley rats were randomly divided into three experimental groups: (1) GSH‐depletion, by injection of buthionine sulphoxamine (BSO, 4 mmol kg^–1, i.p.) 24 h prior to I‐R, (2) BSO injection (4 mmol kg^–1, i.p.) in conjunction with acivicin (AT125, 0.05 mmol kg^–1, i.v.) infusion 1 h prior to I‐R, and (3) control (C), receiving saline treatment. Each group was further divided into I‐R, with surgical occlusion of the main left coronary artery (LCA) for 30 min followed by 20 min reperfusion, and sham. Myocardial GSH content and GSH : glutathione disulphide (GSSG) ratio were decreased by ?50% (P < 0.01) in both BSO and BSO + AT125 vs. C. Ischaemia‐reperfusion suppressed GSH in both left and right ventricles of C (P < 0.01) and left ventricles of BSO and BSO + AT125 (P < 0.05). Contractility (+dP/dt and –dP/dt) in C heart decreased 55% (P < 0.01) after I and recovered 90% after I‐R, whereas ±dP/dt in BSO decreased 57% (P < 0.01) with ischaemia and recovered 76 and 84% (P < 0.05), respectively, after I‐R. For BSO + AT125, ±dP/dt were 64 and 76% (P < 0.01) lower after ischaemia, and recovered only 67 and 61% (P < 0.01) after I‐R. Left ventricular systolic pressure in C, BSO and BSO + AT125 reached 95 (P > 0.05) 87 and 82% (P < 0.05) of their respective sham values after I‐R. Rate‐pressure double product was 11% (P > 0.05) and 25% (P < 0.05) lower in BSO and BSO + AT125, compared with Saline, respectively. BSO and BSO + AT125 rats demonstrated significantly lower liver GSH and heart Mn superoxide dismutase activity than C rats after I‐R. These data indicate that GSH depletion by inhibition of its synthesis and transport can exacerbate cardiac dysfunction inflicted by in vivo I‐R. Part of the aetiology may involve impaired myocardial antioxidant defenses and whole‐body GSH homeostasis.