Cardiac function in open-chest dogs after left to right ventricular shunting and right coronary artery occlusion

Patients with acquired ventricular septal defect (VSD) after myocardial infarction have a particularly bad prognosis if right ventricular function is severely impaired. The significance of an ischaemic right ventricular free wall on cardiac function during interventricular shunting was examined in open-chest dogs. An external interventricular shunt could be opened and closed at will, and by occlusion of the right coronary artery (RCA), a part of the right ventricular free wall was rendered ischaemic. Aortic flow decreased by 8 +/- 2% when the shunt was opened in the presence of a normal right ventricle, and by 16 +/- 2% (difference: P less than 0.05) in the presence of right ventricular ischaemia. Aortic flow fell by 19 +/- 3% when the RCA was occluded. Right ventricular dyskinesia was demonstrated after occlusion of RCA, by recording segment lengths in the right ventricular free wall. The dyskinesia was aggravated when the shunt was opened. The left ventricle exerted a 'negative' work on the ischaemic right ventricular free wall. Retention of blood in the right ventricle, with a subsequent decline in left ventricular filling and an almost unchanged interventricular shunting of blood, explain why aortic flow fell more when the shunt was opened in the presence of right ventricular ischaemia.     

Nicardipine augments local myocardial perfusion after coronary artery reperfusion in dogs

Nicardipine is a potent coronary and systemic vasodilator without depression of ventricular function. We investigated the changes in local myocardial perfusion (LMP) according to the nicardipine administration after coronary reperfusion in a beating canine model. A Doppler probe was placed around the left anterior descending coronary artery (LAD) and thermal diffusion microprobe was implanted in the myocardium perfused by the exposed LAD. To define the nicardipine effects, we compared the two groups (control group, n=7 vs nicardipine group, n=7). In nicardipine group, 5 microgram/kg/min nicardipine was infused continuously. After the release of the LAD occlusion, LAD blood flow were increased compared to the baseline of both groups. However, there was no difference between groups in the LAD blood flow. The LMP after LAD reperfusion did not recover to the baseline level until 30 min after LAD reperfusion in control group (74%, 52% and 70% at 10, 20 and 30 min after LAD reperfusion, respectively). In nicardipine group, however, the LMP recovered to the baseline level at 20 min (99%), and increased more than the baseline level at 30 min (141%) after LAD reperfusion. Our findings suggest that the nicardipine augments the LMP following the release of a coronary occlusion.     

大鼠在体心肌缺血再灌注损伤细胞膜钙转运通道蛋白mRNA的表达变化

目的 探讨大鼠心肌在体缺血再灌注(IR)损伤后细胞膜钙转运通道蛋白的mRNA变化对钙超载的作用。方法 12只SD大鼠按随机数字法分为IR组和对照组。IR组通过结扎（缺血20 min）后松解(再灌注60 min)前降支造成心肌IR,对照组则免除结扎松解前降支。应用生理记录仪连续监测两组大鼠缺血开始前及再灌注60 min后心率、平均动脉压等血流动力学指标。全自动生化仪检测缺血前及再灌注60 min后两组大鼠血钙及肌钙蛋白T(cTnT)的水平。荧光定量PCR检测再灌注60 min后两组大鼠左心室缺血区和右心室心肌细胞膜钙转运通道蛋白即心肌细胞膜钠钙交换器1(NCX1),L型钙通道(LVDCC)α-1C和胞膜钙转运ATP酶1(PMCA1 )mRNA的表达。结果两组大鼠缺血前的心率、平均动脉压均高于再灌注60 min后,而两组间缺血前和再灌注60 min后的心率、平均动脉压差异则无统计学意义。两组血浆Ca2+浓度在缺血前与再灌注60 min后差异无统计学意义,同时间点两组之间的差异也没有统计学意义。缺血前IR组与对照组血浆cTnT浓度水平相近,缺血60 min后IR组血浆cTnT浓度较对照组升高[(4.29±2.22) μg/L比(1.62±0.60)μg/L,P=0.031];两组血浆cTnT浓度在缺血前与再灌注60 min后差异也有统计学意义（均P＜0.05）。NCX1,LVDCCα-1C和PMCA1的mRNA表达在再灌注60 min后同心室两组间和同组内左右心室之间的差异均无统计学意义（NCX1：对照组左心室为50±4,右心室为47±9;IR组左心室为55±6,右心室为53±11;LVDCCα-1C:对照组左心室为33±7,右心室为30±7;IR组左心室为28±3,右心室为37±5;PMCA1,对照组左心室为70±10,右心室为53±11;IR组左心室为66±12,右心室为78±8;均P＞0.05）。结论 大鼠在体心肌缺血20 min再灌注60 min后,NCX1、LVDCCα-1C和PMCA1的mRNA表达水平均无显著改变,提示钙超载并非由细胞膜钙转运通道蛋白数量改变引起。     

Ischaemic contracture and myocardial perfusion in isolated rat heart

Summary The development of left ventricular contracture and myocardial perfusion defect was studied in isolated rat hearts during global ischaemia of 90 min duration. The left ventricular pressure was measured by a balloon catheter inserted into the ventricle and filled with water. The pressure reached the maximum at 16 min of ischaemia. The left ventricular volume and compliance (passive distensibility) were measured by the same balloon, the former by connecting the balloon to an open catheter and the latter by applying a constant additional volume (0.020 ml) into the balloon. The left ventricular volume and compliance both decreased progressively for 20 min of ischaemia after which they remained low for the rest of the observation period (90 min). The myocardial perfusability was tested by infusing 0.1 per cent sodium fluorescein in isotonic saline into the cannulated aortic root of the isolated heart preparation. The percentage perfused with the fluorescent tracer in horizontal frozen myocardial sections was estimated by point counting from colour photographs taken under ultraviolet light. The proportion of the perfused area decreased gradually from 100% at 0 min of ischaemia to 93, 67, 43 and 37% at 15, 30, 60 and 90 min of ischaemia, respectively. It was concluded that ischaemic contracture of the left ventricle is followed by the development of a myocardial perfusion defect in isolated ischaemic rat heart.     

Cyclic fluctuations in the cardiac performance of the isolated Langendorff-perfused mouse heart: pyruvate abolishes the fluctuations and has an anti-ischaemic effect

During the development of a Langendorff preparation of isolated mouse hearts, hitherto undescribed cyclic fluctuations in left ventricular pressure and coronary flow were independently observed in three laboratories. Isolated mouse hearts were perfused with crystalloid glucose-containing Krebs-Hensleit buffer in a constant pressure model, and left ventricular pressures were measured via an intraventricular balloon catheter. After acquiring technical skill in preparing the mouse hearts, the perfusionists observed that fluctuations in cardiac performance with a cycle period lasting 5-10 min occurred shortly after initiation of perfusion. Each fluctuation cycle consisted of a phase of increase and a phase of decrease. Synchronized with the fluctuations in left ventricular pressure, increases and decreases in dP/dt max took place. Analogous fluctuations in coronary flow occurred, with onset 1-2 min later than changes in left ventricular systolic pressure. In some preparations a gradual ST-segment elevation was seen on the electrocardiogram during the systolic pressure increase phase. The amplitude of the fluctuations could be augmented by increasing the perfusion pressure, and reduced, but not abolished, by lowering the pressure. Changes in buffer calcium, magnesium, or sodium concentration did not alter the fluctuations, nor did any change of anaesthetics, mouse strain, or left ventricular drainage. Altering the perfusion mode from constant pressure to constant flow did not prevent the occurrence of the cyclic fluctuations. The hearts became stable and the fluctuations disappeared when the buffer was supplemented with 2 mm pyruvate. In the present study, pyruvate given throughout stabilization and reperfusion also markedly attenuated the ischaemic insult, as evidenced by the delayed ischaemic contracture and a reduced magnitude of ischaemic contracture. A cardioprotective effect was only visible at early reperfusion, did not affect the final functional recovery. In conclusion, a phenomenon of cyclic fluctuations in left ventricular pressure followed by fluctuations in coronary flow was observed in isolated mouse hearts. These could be abolished by adding 2 mm pyruvate to the perfusion buffer. Pyruvate in the buffer also markedly attenuated the post-ischaemic deterioration of cardiac performance seen in this mouse model.     

Cyclic fluctuations in the cardiac performance of the isolated Langendorff‐perfused mouse heart: pyruvate abolishes the fluctuations and has an anti‐ischaemic effect

During the development of a Langendorff preparation of isolated mouse hearts, hitherto undescribed cyclic fluctuations in left ventricular pressure and coronary flow were independently observed in three laboratories. Isolated mouse hearts were perfused with crystalloid glucose‐containing Krebs–Hensleit buffer in a constant pressure model, and left ventricular pressures were measured via an intraventricular balloon catheter. After acquiring technical skill in preparing the mouse hearts, the perfusionists observed that fluctuations in cardiac performance with a cycle period lasting 5–10 min occurred shortly after initiation of perfusion. Each fluctuation cycle consisted of a phase of increase and a phase of decrease. Synchronized with the fluctuations in left ventricular pressure, increases and decreases in dP/dt max took place. Analogous fluctuations in coronary flow occurred, with onset 1–2 min later than changes in left ventricular systolic pressure. In some preparations a gradual ST‐segment elevation was seen on the electrocardiogram during the systolic pressure increase phase. The amplitude of the fluctuations could be augmented by increasing the perfusion pressure, and reduced, but not abolished, by lowering the pressure. Changes in buffer calcium, magnesium, or sodium concentration did not alter the fluctuations, nor did any change of anaesthetics, mouse strain, or left ventricular drainage. Altering the perfusion mode from constant pressure to constant flow did not prevent the occurrence of the cyclic fluctuations. The hearts became stable and the fluctuations disappeared when the buffer was supplemented with 2 mm pyruvate. In the present study, pyruvate given throughout stabilization and reperfusion also markedly attenuated the ischaemic insult, as evidenced by the delayed ischaemic contracture and a reduced magnitude of ischaemic contracture. A cardioprotective effect was only visible at early reperfusion, did not affect the final functional recovery. In conclusion, a phenomenon of cyclic fluctuations in left ventricular pressure followed by fluctuations in coronary flow was observed in isolated mouse hearts. These could be abolished by adding 2 mm pyruvate to the perfusion buffer. Pyruvate in the buffer also markedly attenuated the post‐ischaemic deterioration of cardiac performance seen in this mouse model.     

Preconditioning does not attenuate cardiac dysfunction after global ischaemia in the guinea-pig

Ischaemic preconditioning reduces infarct size, but the effects on cardiac function after global ischaemia are more controversial. Additionally, species differences may exist. The present study investigates the effects of preconditioning on cardiac performance in the globally ischaemic, Langendorff-perfused guinea-pig heart. Hearts were stabilized for 25 min, and divided into the following groups: (1) (n = 8) control perfusion for 16 min before 30-min global ischaemia and 30-min reperfusion, (2) (n = 7) two episodes of 3-min ischaemia and 5-min reperfusion before global ischaemia, (3) (n = 7) 5-min ischaemia and 10-min reperfusion before ischaemia, (4) (n = 8) control perfusion before 40-min ischaemia and 30-min reperfusion, (5) (n = 8) Preconditioning as group 2 before ischaemia as group 4, (6) (n = 9) Control perfusion before 50-min ischaemia and 30-min reperfusion, (7) (n = 10) Preconditioning as group 2 before ischaemia as group 6. A dose-dependent reduction of left ventricular systolic pressure, and increase of end-diastolic pressure was observed during reperfusion after 30-, 40- and 50-min ischaemia. Preconditioning did not influence these changes, nor did it attenuate the incidence of severe reperfusion arrhythmias or reduction of coronary flow. In conclusion, ischaemic preconditioning does not improve cardiac function during reperfusion of the globally ischaemic, isolated guinea-pig heart.     

Effects on infarct size and on arrhythmias by controlling reflow after myocardial ischaemia in pigs

Part of the myocardial damage after an ischaemic period might be related to the reperfusion conditions. Many abrupt changes occurring in the heart during reperfusion may add to the damage during the preceding ischaemic period, and increase in infarct size. In this study we tested the hypothesis that infarct size and occurrence of ventricular arrhythmias might be reduced by restricting reflow after an ischaemic period. Seventeen pigs underwent 45 min of total occlusion of the left anterior descending coronary artery with an hydraulic occluder. In the intervention group reperfusion was restricted to 50% of baseline during the first minute, to 100% during the next minute, kept constant for 1 min, and thereafter allowed to increase by 50% of baseline flow every minute until free reflow. In the control group reflow was not restricted. Arrhythmias were recorded. After 2.5 h of reperfusion the heart was excised. Infarct size was measured by using triphenyltetrazolium chloride (delineation of necrosis), fluorescent microspheres (delineation of area at risk) and planimetry. No reduction in infarct size (% of area at risk) was found between the intervention group and the control group (75.9 +/- 5.3% vs. 72.4 +/- 4.3%). The incidence of ventricular arrhythmias and ventricular fibrillation were not found to be different between the groups during reperfusion. Hemodynamic parameters were not significantly different between the two groups. Our data indicate that no substantial protection against myocardial infarct or ventricular arrhythmias could be achieved by controlling reflow using the present protocol after a period of myocardial ischaemia in pigs. Accordingly, our data do not support the notion that control of reflow may be beneficial when treating coronary artery occlusion with percutaneous coronary angioplasty (PCA).     

脂质胞壁酸延迟预适应对大鼠供心停搏/复灌性损伤的影响

目的：探讨脂质胞壁酸（LTA）诱导的延迟预适应对大鼠供体心脏停搏/复灌性损伤的影响。 方法： 采用心脏Langendorff灌流模型，腹腔注射LTA后24 h，观察心脏停搏保存4 h后再灌注30 min及60 min时心脏功能及再灌注末灌流液中心肌型肌酸激酶同功酶（CK-MB）、乳酸脱氢酶（LDH）及一氧化氮（NO）含量，并用dUTP缺口末端标记（TUNEL）法检测左室心肌细胞凋亡。 结果： LTA预适应组再灌注30 min和60 min时心脏的冠脉流量，左室发展压及压力最大上升和下降速率等参数值显著大于对照组（均P<0.01）。LTA预适应组灌流液中NO含量明显大于对照组（P<0.01），而CK-MB和LDH的水平和心肌凋亡指数小于对照组（均P<0.01）。一氧化氮合酶抑制剂L-NG-硝基精氨酸甲酯（L-NAME）能取消LTA预适应的保护效应。 结论： LTA预适应能显著改善供体心脏停搏/再灌注后的心功能，减少心肌坏死和细胞凋亡，内源性NO在介导LTA预适应中发挥关键作用。     

Various inotropic effects of angiotensin II in post‐ischaemic rat hearts depending on ischaemic time with possible involvement of protein kinase C

Aims: The present study investigated if the inotropic effect of angiotensin II (AngII) is altered during post‐ischaemic reperfusion in hearts subjected to mild and severe ischaemia. The possible involvement of protein kinase C (PKC) in the change in the inotropic effect was also investigated. Methods: Isolated Langendorff‐perfused rat hearts were perfused under constant flow with oxygenated Krebs–Henseleit buffer and paced at 360 beats min^?1. A saline‐filled balloon catheter inserted into the left ventricle was used for measurement of contractile force. In the first series of experiments, hearts were subjected to continuous perfusion, 15‐ or 25‐min global ischaemia followed by 45‐min reperfusion. At the end of reperfusion, 0.1 μmol L^?1 AngII was infused for 5 min. In a second series of experiments, AngII was infused in hearts subjected to 25‐min ischaemia followed by 45‐min reperfusion in the absence or presence of the PKC inhibitor chelerythrine chloride (5 μmol L^?1). Results: The current study demonstrates that AngII exerts a positive inotropic effect in normoxic hearts with an increase of left ventricular developed pressure (LVDP) by 11% (P < 0.05 vs. prior to AngII infusion). In post‐ischaemic hearts subjected to 15‐min ischaemia no effect of AngII was observed. In hearts subjected to 25 min of ischaemia, however, AngII evoked a negative inotropic response with a decrease of LVDP by 18% (P < 0.05 vs. prior to AngII infusion). The negative inotropic effect of AngII was inhibited by the PKC inhibitor chelerythrine chloride. Conclusions: AngII exerts negative inotropic effect in severely injured post‐ischaemic heart, possibly through the PKC pathway.     

Ischaemic episodes of less than 5 minutes produce preconditioning but not stunning in the isolated rat heart

The aim of the present study was to examine whether ischaemic episodes of less than 5 min could induce preconditioning or stunning in the isolated rat heart. Hearts were subjected to total global ischaemia of 1, 2 and 4 min followed by 10 min of reperfusion before an 18-min main ischaemic period and 30 min of reperfusion. The effects on physiology, purine metabolism and anaerobic glycolysis were compared with a control group subjected to the main ischaemia only. The brief ischaemic episodes did not produce stunning based on the recovery of left ventricular developed pressure (LVDP) and heart rate (HR) product during the first reperfusion. Preconditioning of 11–14% increased recovery of LVDP x HR during the second reperfusion was observed in the 1- and 4-min group. In the 2-min group a low repayment of flow debt during the first reperfusion was associated with a slightly reduced recovery of LVDP x HR compared to the other preconditioned groups during the second reperfusion. Only in the 4-min group was preconditioning associated with fewer breakdown products of the purine nucleotide pool (adenosine) and anaerobic glycolysis (lactate) in both tissue and effluate after the main ischaemia. Preconditioning (reflected in recovery of function) could be produced with ischaemic episodes of less than 5 min that did not produce stunning. Thus, stunning is probably not the primary cause of preconditioning.     

Attenuation of oxidant damage in the postconditioned heart involves non-enzymatic response and partial catalytic protection

Oxidant stress, among other effectors, is implicated in the sequel of myocardial reperfusion injury. It is generally accepted that maintaining the balance between oxidant and antioxidant signalling within the cell provides protection against reperfusion damage. The cardioprotective strategy of postconditioning (PC) reduces reperfusion injury through complex mechanisms; however, the contribution of the antioxidant system has not been fully investigated. In this study, isolated rat hearts were subjected to PC after 30 min global ischaemia, and then to 5 min (IR5) or 60 min of reperfusion (IR60). Postconditioning significantly increased the left ventricular developed pressure and the double product (heart rate × left ventricular developed pressure) for both early (PC5) and prolonged reperfusion (PC60, PC before 60 min of reperfusion). Necrotic tissue diminished to 10.8% in PC60 hearts, compared with 49% of infarct size measured in IR60 hearts (P < 0.05 versus IR60). Also, protein carbonylation and malondialdehyde levels decreased and were correlated with a significant augmentation in CuZn superoxide dismutase activity (P < 0.05, PC60 versus IR60) and increased glutathione redox state (GSH:GSSG ratio; P < 0.05, PC60 versus IR60). Diethylthiocarbamate, a non-selective superoxide dismutase inhibitor, significantly diminished the protection afforded by PC when administered throughout the protocol. However, administration of this inhibitor only during reperfusion had no effect on PC-induced cardioprotection. These results indicate that non-enzymatic antioxidants account for the protective effect of PC, modifying the oxidant stress caused by ischaemic reperfusion in rats. The contribution of CuZn superoxide dismutase activity in the observed cardioprotective effect is less clear, and could be relevant if acting in concert with other PC-activated mechanisms.     

压力超负荷对大鼠左室心肌肌型LIM蛋白mRNA和蛋白表达的影响

目的:了解压力超负荷大鼠左室肥厚心肌肌型LIM蛋白(MLP)mRNA和蛋白水平的变化, 探讨病理性左室肥厚心肌是否存在细胞骨架蛋白的缺失。方法:观察大鼠腹主动脉缩窄术后1、4、8、16周各组血流动力学参数、心室肥厚指数、MLPmRNA表达和蛋白水平的变化。结果:腹主动脉缩窄术后4周左室肥厚指数较术后1周组明显增加(P＜0.05), 术后8周组左室心肌MLPmRNA的表达较术后1、4周组明显下降(P＜0.05), 但各组左室心肌MLP蛋白水平差异无显著(P＞0.05)。结论:在病理性左室肥厚心肌出现明显心力衰竭前, MLP转录水平下调, 而MLP蛋白水平无明显改变。提示MLP作为心肌细胞骨架的基础, 对维持肥厚左室心肌的收缩功能起重要作用。     

High afterload during 10 min of regional ischaemia affects diastolic creep but not systolic function in reperfused (stunned) myocardium

The effect of afterload during regional ischaemia on myocardial stunning was studied in 15 pentobarbital anaesthetized cats. 10 min occlusion of the left anterior descending artery (LAD) was followed by 60 min of reperfusion. Afterload was decreased by intravenous infusion of nitroglycerine 3–8 μg kg^-1 min^-1 in group I (n=8); left ventricular peak systolic pressure (LVSP) 84±4 mmHg (mean±SEM) during coronary artery occlusion. In group II (n=7) LVSP was increased to 188±10 mmHg by inflating an intraaortic balloon during coronary artery occlusion. Regional function in the LAD perfused region was evaluated by cross-oriented sonomicrometry. Myocardial tissue blood flow was evaluated by radio-labelled microspheres. Afterload alterations did not affect regional systolic shortening (10.8±2.0% vs. 11.0±1.5% in group I and II, respectively, after 60 min of reperfusion). However, increased end-diastolic dimensions (diastolic creep) in both the circumferential and longitudinal segments were markedly more pronounced in the high afterload group (group II). Also important, the markedly increased myocardial tissue blood flow during reperfusion in group II as compared with group I (2.30±0.18 vs.  1.34±0.08 mL min^-1 g^-1 and 2.58±0.23 vs. 1.49±0.07 mL min^-1 g^-1 in subepicardial and subendocardial layers in the LAD perfused region) suggests that increased diastolic creep increased metabolic demands. This study indicates that passive stretching of the ischaemic area during coronary artery occlusion is an important mechanism behind diastolic creep.     

Regional contractile blockade at the onset of reperfusion reduces infarct size in the dog heart

An important mechanism of lethal myocardial reperfusion injury is the development of cellular hypercontracture at the onset of reperfusion. Hypercontracture can lead to cytolysis by mutual mechanical disruption of myocardial cells. 2,3-Butanedione monoxime (BDM) inhibits myofibrillar cross-bridge cycling and may therefore reduce infarct size in ischaemic reperfused myocardium. This study investigated whether a temporary presence of BDM protects against myocardial reperfusion injury in an intact-animal preparation. Anaesthetized open-chest dogs (n=10) underwent 1 h of left anterior descendent artery (LAD) occlusion and received intracoronary BDM (25 mM, n=5) or vehicle (n=5) for 65 min starting with an anoxic local infusion 5 min before reperfusion. Infarct size was assessed by triphenyltetrazolium staining after 6 h reperfusion. The infusion of BDM was accompanied by a transient reduction of left ventricular systolic pressure from 84.3±11.2 mm Hg during occlusion to 66.4±9.9 mm Hg at 30 min reperfusion (mean±SD, P<0.01 vs. control). LAD-flow and regional wall motion in the area at risk showed no difference between groups. Infarct size (% of area at risk) was reduced from 24.4±8.7 (control) to 6.6±2.0% (BDM) (P<0.01). The results demonstrate that development of necrosis in reperfused myocardium can be greatly reduced by temporary presence of the contractile inhibitor BDM at the onset of reperfusion.     

Lentivirus-mediated overexpression of angiotensin-(1-7) attenuated ischaemia-induced cardiac pathophysiology

Myocardial infarction (MI) results in cell death, development of interstitial fibrosis, ventricular wall thinning and ultimately, heart failure. Angiotensin-(1-7) [Ang-(1-7)] has been shown to provide cardioprotective effects. We hypothesize that lentivirus-mediated overexpression of Ang-(1-7) would protect the myocardium from ischaemic injury. A single bolus of 3.5 × 10(8) transducing units of lenti-Ang-(1-7) was injected into the left ventricle of 5-day-old male Sprague-Dawley rats. At 6 weeks of age, MI was induced by ligation of the left anterior descending coronary artery. Four weeks after the MI, echocardiography and haemodynamic parameters were measured to assess cardiac function. Postmyocardial infarction, rats showed significant decreases in fractional shortening and dP/dt (rate of rise of left ventricular pressure), increases in left ventricular end-diastolic pressure, and ventricular hypertrophy. Also, considerable upregulation of cardiac angiotensin-converting enzyme (ACE) mRNA was observed in these rats. Lentivirus-mediated cardiac overexpression of Ang-(1-7) not only prevented all these MI-induced impairments but also resulted in decreased myocardial wall thinning and an increased cardiac gene expression of ACE2 and bradykinin B2 receptor (BKR2). Furthermore, in vitro experiments using rat neonatal cardiac myocytes demonstrated protective effects of Ang-(1-7) against hypoxia-induced cell death. This beneficial effect was associated with decreased expression of inflammatory cytokines (tumour necrosis factor-α and interleukin-6) and increased gene expression of ACE2, BKR2 and interleukin-10. Our findings indicate that overexpression of Ang-(1-7) improves cardiac function and attenuates left ventricular remodelling post-MI. The protective effects of Ang-(1-7) appear to be mediated, at least in part, through modulation of the cardiac renin-angiotensin system and cytokine production.     

Heart-rate-proportional oxygen consumption for constant cardiac work in dog heart

We studied whether there is an optimal heart rate (HR) that would minimize myocardial oxygen consumption (MVO2) per min for a constant minute cardiac work. We measured minute MVO2 (ml O2/min) of the left ventricle paced at increasing rates (100-200 beats/min) in 10 right-heart-bypassed dogs. In each experiment, cardiac output was kept constant with a constant-flow bypass pump, and mean aortic pressure was also kept constant by inflation or deflation of an intra-aortic balloon. Minute cardiac work was thus kept constant. Minute MVO2 was obtained as the product of mean coronary arteriovenous O2 difference and mean coronary blood flow drained from the collapsed right ventricle. Both left ventricular Emax (contractility index defined as the slope of the left ventricular end-systolic pressure-volume relation) and PVA (pressure-volume area as a measure of total mechanical energy of contraction) were obtained by an abrupt aortic occlusion method. The obtained-minute MVO2-HR relationship showed a good linear positive correlation (r = 0.824-0.995) in every heart. We accounted for this relationship by the changes in PVA and Emax that we had proposed as primary determinants of MVO2. We conclude that minute MVO2 for a constant minute cardiac work increased monotonically with increases in HR from 100 to 200 beats/min, being minimum at the lowest HR, and that this relation was ascribable to the HR-proportional increase in the MVO2 component for the excitation-contraction coupling.     

Histamine release and its effects in ischaemia-reperfusion injury of the isolated rat heart

Histamine is released from the heart during ischaemia-reperfusion injury. As histamine has cardiac effects, we investigated the role of histamine in ischaemia-reperfusion injury of isolated rat hearts. A Langendorff-model with 30 min global (37 ^oC) ischaemia followed by 60 min reperfusion was employed. The effects of ischaemia alone (n= 10, group 1.1+n = 10, group 2.1, 2 different series), and ischaemia with H₁- and H₂-receptor blockade with cimetidine (10 μM, n= 10), chlorpheniramine (10 μm, n= 8), terfenadine (10 μM, n= 8), and promethazin (10 μM, n= 9), or both cimetidine and chlorpheniramine (n = 8), were studied. Histamine was measured in the coronary effluent and cardiac tissue of group 1.1. Release of histamine increased from 6.5 ± 1 pmol min^-1 before ischaemia to 19 ± 3 pmol min^-1 at the start of reperfusion. Ischaemia decreased left ventricular developed pressure to 18 ± 11 % (1.1) and 50 ± 11 % (2.1) of initial value (mean ± SEM) at the start of reperfusion. Left ventricular end-diastolic pressure increased from 0 to 79 ± 8 mmHg (1.1) and 39 ± 9 (2.1) mmHg, while left ventricular systolic pressure was unchanged (101 ± 12% in 1.1 and 101 ± 10% in 2.1). Severe arrhythmias were induced in 90 (1.1) and 30 (2.1)% of the hearts, while coronary flow decreased during reperfusion. H₂-blockade did not modify the changes in left ventricular pressures, coronary flow, or heart rate induced by ischaemia. Three different Hj-blockers increased left ventricular systolic pressure, inhibited the decrease of developed pressure, attenuated the increase of end-diastolic pressure, and totally inhibited reperfusion arrhythmias. The effect of both blockers together was similar to that of H₁-blockers alone. Coronary flow was increased during reperfusion in two of the groups with Hj-blocker compared with ischaemic controls. Increased release of histamine from ischaemic-reperfused rat hearts concurred with depression of left ventricular function and arrhythmias during early reperfusion. Cardiac dysfunction during reperfusion was attenuated by three different Hj-receptor blockers.     

Functional properties and responses to ischaemia-reperfusion in Langendorff perfused mouse heart

Despite minimal model characterisation Langendorff perfused murine hearts are increasingly employed in cardiovascular research, and particularly in studies of myocardial ischaemia and reperfusion. Reported contractility remains poor and ischaemic recoveries variable. We characterised function in C57/BL6 mouse hearts using a ventricular balloon or apicobasal displacement and assessed responses to 10-30 min global ischaemia. We examined the functional effects of pacing, ventricular balloon design, perfusate filtration, [Ca(2+)] and temperature. Contractility was high in isovolumically functioning mouse hearts (measured as the change in pressure with time (+dP/dt), 6000-7000 mmHg s(-1)) and was optimal at a heart rate of approximately 420 beats min(-1), with the vasculature sub-maximally dilated, and the cellular energy state high. Post-ischaemic recovery (after 40 min reperfusion) was related to the ischaemic duration: developed pressure recovered by 82 +/- 5 %, 73 +/- 4 %, 68 +/- 3 %, 57 +/- 2 % and 41 +/- 5 % after 10, 15, 20, 25 and 30 min ischaemia, respectively. Ventricular compliance and elastance were both reduced post-ischaemia. Post-ischaemic recoveries were lower in the apicobasal model (80 +/- 4 %, 58 +/- 7 %, 40 +/- 3 %, 32 +/- 7 % and 25 +/- 5 %) despite greater reflow and lower metabolic rate (pre-ischaemic myocardial O(2) consumption (V(O2,myo)) 127 +/- 15 vs. 198 +/- 17 microl O(2) min(-1) g(-1)), contracture, enzyme and purine efflux. Electrical pacing slowed recovery in both models, small ventricular balloons (unpressurised volumes < 50-60 microl) artificially depressed ventricular function and recovery from ischaemia, and failure to filter the perfusion fluid to < 0.45 microm depressed pre- and post-ischaemic function. With attention to these various experimental factors, the buffer perfused isovolumically contracting mouse heart is shown to be stable and highly energized, and to possess a high level of contractility. The isovolumic model is more reliable in assessing ischaemic responses than the commonly employed apicobasal model.     

No dependency of a new index for oxygen cost of left ventricular contractility on heart rates in the blood-perfused excised rat heart

We have reported the linear relation of myocardial oxygen consumption per beat (VO(2)) and systolic pressure-volume area (PVA) in the left ventricle of the cross-circulated rat heart. The VO(2) intercept (PVA-independent VO(2)) is primarily composed of VO(2) for Ca(2+) handling in excitation-contraction coupling and basal metabolism. Recently, we proposed a new index for oxygen cost of contractility obtainable as a slope of a linear relation between PVA-independent VO(2) and left ventricular contractility. This index indicates the Ca(2+) handling VO(2) per unit contractility change. However, a dependency of this index on heart rate has not yet been investigated. The aim of the present study was to investigate the dependency of oxygen cost of contractility on heart rate. This is a critical point to compare this cost under different heart rates. At first we found no differences of VO(2)-PVA relations at 240 and 300 beats/min (bpm). Therefore, after control VO(2)-PVA relation at 300 bpm, we gradually enhanced left ventricular contractility by Ca(2+) at a midrange left ventricular volume and obtained the gradually increased PVA-independent VO(2). At each contractility level, the pacing rate was alternately changed at 240 and 300 bpm. We obtained the two composite VO(2)-PVA relation lines and found no significant differences between the slopes of PVA-independent VO(2) and left ventricular contractility relations at 240 and 300 bpm. The present results indicated no dependency of oxygen cost of left ventricular contractility on heart rates within 240--300 bpm. Based on this fact, we concluded that even under the different pacing rates within 240--300 bpm, this oxygen cost is valid for assessing cardiac mechanoenergetics, especially the economy of total Ca(2+) handling in E-C coupling.