Delayed cardioprotection afforded by nitroglycerin is mediated by alpha-CGRP via activation of inducible nitric oxide synthase

Previous investigations have demonstrated that delayed preconditioning induced by nitroglycerin is mediated by endogenous calcitonin gene-related peptide (CGRP). In the present study, we examined whether CGRP-mediated delayed preconditioning induced by nitroglycerin is involved in activation of inducible nitric oxide synthase (iNOS). Male Wistar rats were pretreated with nitroglycerin 24 h before the experiment, and then the left main coronary artery of rat heart was subjected to 60-min occlusion followed by 3 h reperfusion. Infarct size, the plasma level of cGMP and CGRP, and expression of CGRP isoforms (alpha-CGRP and beta-CGRP) mRNA in lumbar dorsal root ganglia were measured. Pretreatment with nitroglycerin (120 microg/kg, i.v.) markedly reduced infarct size. Nitroglycerin caused a significant increase in the expression of alpha-CGRP mRNA, but not beta-CGRP mRNA, concomitant with an increase in plasma concentrations of cGMP and CGRP. These effects of nitroglycerin were completely abolished by pretreatment with aminoguanidine (300 mg/kg, i.p.), a selective inhibitor of iNOS activity, or dexamethasone (5 mg/kg, i.p.), the iNOS expression inhibitor. The present results suggest that delayed cardioprotection afforded by nitroglycerin is mediated by the alpha-CGRP isoform via generation of NO derived from iNOS.     

3,4,5,6-Tetrahydroxyxanthone Protects Against Myocardial Ischemia-Reperfusion Injury in Rats

In the present study, we tested the protective effect of 3,4,5,6-tetrahydroxyxanthone, a synthetic xanthone derivative, on myocardial ischemia-reperfusion injury in rats. Ischemia-reperfusion injury was induced by 30 min of global ischemia and 30 min of reperfusion in isolated rat hearts or 30 min coronary artery occlusion and 120 min reperfusion in vivo, respectively. Heart rate, coronary flow (CF), left ventricular pressure (LVP), and its first derivative (+/- dp/dt (max)) were recorded, and the activity of creatine kinase in coronary effluent and tumor necrosis factor-alpha (TNF-alpha) content in myocardial tissues were measured in vitro. The activity of serum creatine kinase, the level of TNF-alpha and interleukin-6 (IL-6), and myocardial infarct size were measured in vivo. 3,4,5,6-tetrahydroxyxanthone (30, 100 or 300 microM) caused a significant improvement of cardiac function (LVP and +/- dp/dt (max)) and a decrease in the release of creatine kinase in coronary effluent as well as the level of TNF-alpha in myocardial tissues in vitro. 3,4,5,6-tetrahydroxyxanthone (0.5 or 1.0 mg/kg, i.v.) also markedly decreased infarct size and the release of creatine kinase and TNF-alpha, and increased serum IL-6 level in vivo. These results suggest that 3,4,5,6-tetrahydroxyxanthone possesses a protective effect on myocardial ischemia-reperfusion injury, and that the protective effects of 3,4,5,6-tetrahydroxyxanthone may be related to inhibition of TNF-alpha production and stimulation of IL-6 generation by inhibition of ROS production.     

High-density lipoproteins protect isolated rat hearts from ischemia-reperfusion injury by reducing cardiac tumor necrosis factor-alpha content and enhancing prostaglandin release

The incidence and severity of primary cardiac events are inversely related to the plasma concentration of high-density lipoproteins (HDLs). We investigated whether HDLs may exert a direct cardioprotection in buffer-perfused isolated rat hearts, which underwent a 20-minute low-flow ischemia followed by a 30-minute reperfusion. The administration of HDLs at physiological concentrations (0.5 and 1.0 mg/mL) during the 10 minutes immediately before ischemia rapidly and remarkably improved postischemic functional recovery and decreased creatine kinase release in the coronary effluent. Reconstituted HDLs containing apolipoprotein A-I (apoA-I) and phosphatidylcholine, but not lipid-free apoA-I or phosphatidylcholine liposomes, were also effective in protecting the heart from ischemia-reperfusion injury. HDLs at reperfusion were less effective than when given before ischemia. HDLs caused a dose-dependent reduction of ischemia-induced cardiac tumor necrosis factor-alpha (TNF-alpha) expression and content, which correlated with the improved functional recovery. A parallel increase of TNF-alpha release in the coronary effluent was observed, due to a direct binding of cardiac TNF-alpha to HDLs. Taken together, these findings argue for a cause-effect relationship between the HDL-mediated removal of TNF-alpha from the ischemic myocardium and the HDL-induced cardioprotection. Indeed, etanercept, a recombinant TNF-alpha-blocking protein, caused a dose-dependent improvement of postischemic functional recovery. HDLs also enhanced ischemia-induced prostaglandin release, which may contribute to the cardioprotective effect. A low plasma HDL level may expose the heart to excessive ischemia-reperfusion damage, and HDL-targeted therapies may be helpful to induce immediate or delayed myocardial protection from ischemia-reperfusion injury.     

缺血预处理减轻肥厚心肌缺血再灌注损伤及其信号途径

目的探讨缺血预处理(IPC)对肥厚心肌体外缺血再灌注(IR)损伤的影响及其信号机制。方法48只心肌肥厚大鼠随机分为4组:IR对照组I、PC组I、PC加磷脂酰肌醇-3激酶(PI3K)抑制剂Wortmannin处理组、Wortmannin处理对照组,观察IPC对心肌肥厚大鼠体外IR心脏左心室收缩压、冠状动脉流量、肌酸磷酸激酶(CPK)和乳酸脱氢酶(LDH)释放、心肌梗死范围以及心肌蛋白激酶B(Akt)、糖原合成酶激酶-3β(GSK-3β)磷酸化的影响。结果与IR对照组比较,IPC组心脏左心室收缩压、冠状动脉流量显著提高,CPK、LDH释放减少,心肌梗死范围减小,心肌Akt、GSK-3β磷酸化水平增高,Wortmannin能够抑制IPC所致的Akt、GSK-3β磷酸化,但只能部分消除IPC的心脏保护效应。结论IPC能够减轻心肌肥厚大鼠体外心脏IR损伤,PI3K、Akt、GSK-3β信号途径参与介导IPC对体外IR肥厚心肌的保护作用。     

Effect of tumor necrosis factor-alpha on endothelial and inducible nitric oxide synthase messenger ribonucleic acid expression and nitric oxide synthesis in ischemic and nonischemic isolated rat heart

OBJECTIVES: The present study aimed to investigate the influence of endogenous tumor necrosis factor-alpha (TNF-alpha) that was synthesized during ischemia and exogenous TNF-alpha on endothelial and inducible nitric oxide synthase (eNOS and iNOS) messenger ribonucleic acid (mRNA) expression and nitric oxide (NO) production in the isolated rat heart. BACKGROUND: Tumor necrosis factor-alpha is recognized as being a proinflammatory cytokine with a significant cardiodepressant effect. One of the proposed mechanisms for TNF-alpha-induced cardiac contractile dysfunction is increased NO production via iNOS mRNA upregulation, but the role of NO in TNF-alpha-induced myocardial dysfunction is highly controversial. METHODS: Isolated rat hearts studied by a modified Langendorff model were randomly divided into subgroups to investigate the effect of 1-h global cardioplegic ischemia or the effect of 1-h perfusion with exogenous TNF-alpha on the expression of eNOS mRNA and iNOS mRNA and on NO production. RESULTS: After 1 h of ischemia, there were significant increases in TNF levels in the effluent (from hearts), and eNOS mRNA expression had declined (from 0.91 +/- 0.08 to 0.68 +/- 0.19, p < 0.001); but there were no changes in iNOS mRNA expression, and NO was below detectable levels. Perfusion of isolated hearts with TNF-alpha had a cardiodepressant effect and decreased eNOS mRNA expression to 0.67 +/- 0.04 (p < 0.002). Inducible nitric oxide synthase mRNA was unchanged, and NO was below detectable levels. CONCLUSIONS: We believe this is the first study to directly show that TNF-alpha does not increase NO synthesis and release but does downregulate eNOS mRNA in the ischemic and nonischemic isolated rat heart.     

A randomized comparison of crystalloid and blood-containing cardioplegic solutions in 60 patients

To determine whether adding blood to a cardioplegic solution affects myocardial preservation, a randomized prospective study was carried out in 60 patients undergoing coronary revascularization to compare the effects of crystalloid potassium cardioplegics (group C) and potassium cardioplegic solutions to which blood has been added (group B) on markers of myocardial metabolism (lactate, inorganic phosphate, base deficit release, glucose and lactate uptake, oxygen extraction), myocardial damage (creatine kinase [CK]-MB levels), and cardiac performance (cardiac index and left atrial pressure). The solution with added blood had a significantly (p less than .05) greater oxygen content, a lower pH, and higher concentrations of potassium, calcium, sodium, and glucose. In group B patients there was a suggestion (p less than .06) of greater uptake of oxygen during the beginning of the initial cardioplegic infusion. During reperfusion there was no evidence of differential release of the metabolites of anaerobiosis and myocardial oxygen extraction and glucose and lactate uptake were similarly depressed in both groups. Likewise, CK-MB release after bypass was the same in both groups. Prompt, adequate functional recovery of cardiac index and left atrial pressure was observed in both groups. It was concluded that although there may be more oxygen available from the blood-containing solution during early infusion, there is no evidence that under the conditions of this investigation adding blood to cardioplegic solution improves myocardial preservation.     

Beneficial effect of the addition of nitroglycerin to the cardioplegic solution on lipid peroxidation during coronary artery bypass surgery

The effects of the addition of a nitric oxide (NO) donor to the cardioplegic solution on reperfusion injury and lipid peroxidation (LPO) in coronary artery bypass grafting (CABG) are not known. Therefore, this work was conducted to determine the possible effects of nitroglycerin on LPO and reperfusion injury as a result of CABG. A prospective double-blind, placebo-controlled study was conducted in 30 consecutive patients with coronary artery disease who underwent CABG with cardiopulmonary bypass. The patients were randomly assigned to receive 3 microg/kg of nitroglycerin added to the cardioplegic solution (NTG group) or 3 microg/kg of placebo added to the cardioplegic solution (placebo group). MDA increased significantly in the placebo group compared to the NTG group during the ischemic (P < 0.01) and reperfusion periods (P < 0.01). The level of troponin I decreased significantly in the NTG group compared to the placebo group during the ischemic and reperfusion periods (P < 0.001). The level of NO increased significantly in the NTG group compared to the placebo group during the ischemic and reperfusion periods (P < 0.01). LPO was increased in response to CPB during CABG, together with simultaneous decreases in serum nitric oxide levels, whereas LPO was significantly decreased in response to CPB with nitroglycerin, together with simultaneous increases in the levels of serum nitric oxide.     

Relation between functional response to nitroglycerin and extent of myocardial necrosis in dogs: mapping of the left ventricle by 2-dimensional echocardiography

The relation between functional response to brief nitroglycerin infusions and extent of myocardial damage was studied sequentially in closed-chest dogs with acute occlusion of the left anterior descending coronary artery. Two-dimensional echocardiography was used to derive segmental left ventricular (LV) function (systolic fractional area change and systolic wall thickening), and this function was compared with the extent of necrosis measured 5 hours after occlusion in equivalent segments of corresponding pathologic slabs. Two-dimensional echocardiographic study before the dogs were killed indicated that remote nonnecrotic segments always responded to nitroglycerin by significant augmentation of segmental LV function. Segments in which necrosis was less than 40% showed a significant nitroglycerin-induced potentiation in segmental LV function. In contrast, segments in which necrosis was greater than 60% had no potentiation with nitroglycerin. In those segments in which eventual necrosis was 60 to 80%, significant nitroglycerin-induced augmentation in segmental LV function was observed only before and 30 minutes after the coronary occlusion. When the degree of necrosis was greater than 80%, no significant potentiation of segmental LV function was observed even as early as 30 minutes after occlusion. Thus, the degree of nitroglycerin-induced potentiation of segmental cardiac function is closely associated with the extent of myocardial necrosis in the particular ventricular segment. Two-dimensional echocardiography coupled with a nitroglycerin potentiation test might be useful for assessment of the viability of ischemic myocardium.     

Aspartic Acid and mannitol enhance protective efficiency of asanquineous cardioplegic solution

The aim of this work was to assess effects of a novel asanquineous cardioplegic solution (CP-5), buffered with trisamine (pH 7.6+/-0.1 at 22 degrees C) and containing 21.5 mM aspartic acid and 20.0 mM mannitol, on postischemic functional and metabolic recovery of isolated rat heart. A modified Ringer solution with 25 mM KCl (pH 7.6+/-0.1 at 22 degrees C) and the St. Thomas' cardioplegic solution (pH 7.8+/-0.1 at 22 degrees C) were used as controls. Osmolarity of all cardioplegic solutions were 340+/-5. After 20-min initial perfusion according to Neely (steady state) the hearts were subjected to 40-min normothermal total ischemia followed by 30-min antegrade reperfusion. Cardioplegic solutions were infused prior to ischemia at rate of the initial coronary flow for 5 min at room temperature. During reperfusion the hearts of CP-5 group completely recovered coronary flow and significantly enhanced restoration of the majority functional indices compared to the hearts in both control groups. This effect was combined with less lactate accumulation and preservation of higher ATP and phosphocreatine (PCr) levels in the heart tissue by the end of ischemia and, probably was induced by inclusion of aspartic acid into composition of CP-5. By the end of reperfusion the hearts treated with CP-5 completely recovered PCr content and restored ATP level up to 65.2+/-4.6% of initial one. A better energy state of reperfused hearts in CP-5 group was accompanied by reduction of myocardial lactate tissue to the preischemic value. Restoration of ATP, PCr and lactate content was significantly poor in both control groups during reperfusion. The least formation of a spin adduct of the short life oxygen radicals was found in the myocardial effluent of the hearts of CP-5 group at the early reperfusion using EPR technique. These data suggest a reduced release of oxygen radical generating systems from postischemic myocardium into perfusate due to antioxidant effect of mannitol. The obtained results substantiate addition of aspartic acid and mannitol to the asanquineous cardioplegic solution, buffered with trisamine, to enhance efficacy of myocardial protection against ischemia and reperfusion injury.     

Taurine prevents myocardial ischemia/reperfusion-induced oxidative stress and apoptosis in prolonged hypothermic rat heart preservation

Taurine (2-aminoethanesulfonic acid) is a potent antioxidant and inhibits cell apoptosis in ischemic reperfusion injury. In this study we evaluated whether addition of taurine to St. Thomas' cardioplegic solution enhances its myocardial protective effects in prolonged hypothermic heart preservation in rats. Hearts isolated from male Sprague–Dawley rats were mounted on a Langendorff apparatus to estimate baseline cardiac function, then arrested and stored in St. Thomas' cardioplegic solution, with taurine (10 mM; taurine group, n = 8) or without taurine (control group, n = 8), for 6 h at 4°C. After storage, the hearts were reperfused and heart rate (HR), coronary flow (CF), left ventricular developed pressure (LVP), and positive maximum left ventricular developing pressure (max LV dp/dt) were measured. The LV tissue was examined immunohistochemically for determining DNA oxidative stress and cell apoptosis. Compared with control groups, recovery of LVP (P < 0.001), max LV dp/dt (P < 0.001), and coronary flow (P < 0.001) were significantly enhanced, whereas glutamic oxaloacetic transaminase (P < 0.01), lactate dehydrogenase (P < 0.05), creatine phosphate kinase (P < 0.01), 8-hydroxy-2′-deoxyguanosine index (P < 0.01), caspase-3 mRNA expression (P < 0.05), and percentage of TUNEL-positive cardiomyocytes (P < 0.05) were reduced in the taurine group. Addition of taurine to St. Thomas' cardioplegic solution improved cardiac function recovery for prolonged hypothermic rat heart preservation by suppressing DNA oxidative stress and cell apoptosis.     

Adenosine Transport Blockade Restores Attenuated Cardioprotective Effects of Adenosine Preconditioning in the Isolated Diabetic Rat Heart: Potential Crosstalk with Opioid Receptors

Considering the reduced ability of cardiac fibroblasts to release adenosine and increased ability of interstitial adenosine uptake during diabetes mellitus, the present study investigated the effect of adenosine preconditioning and the existence of cross-talk with opioid receptor activation in the diabetic rat heart subjected to ischemia–reperfusion (I/R). Langendorff-perfused normal and streptozotocin (65 mg/kg, i.p., once)-administered diabetic (after 8-weeks) rat hearts were subjected to 30-min global ischemia and 120-min reperfusion. Myocardial infarct size using triphenyltetrazolium chloride staining, markers of cardiac injury such as lactate dehydrogenase (LDH) and creatine kinase (CK-MB) release, coronary flow rate (CFR) and myocardial oxidative stress were assessed. The diabetic rat heart showed high degree of I/R injury with increased LDH and CK-MB release, high oxidative stress and reduced CFR as compared to the normal rat heart. The adenosine preconditioning (10 μM) afforded cardioprotection against I/R injury in the normal rat heart that was prevented by naloxone (100 μM) pre-treatment. Conversely, adenosine preconditioning-induced cardioprotection was abolished in the diabetic rat heart. However, co-administration of dipyridamole (100 μM), adenosine reuptake inhibitor, markedly restored the cardioprotective effect of adenosine preconditioning in the diabetic rat heart, and this effect was also abolished by naloxone pre-treatment. The reduced myocardial availability of extracellular adenosine might explain the inability of adenosine preconditioning to protect the diabetic myocardium. The pharmacological elevation of extracellular adenosine restores adenosine preconditioning-mediated cardioprotection in the diabetic myocardium by possibly involving opioid receptor activation.     

Staphylococcal alpha-toxin provokes coronary vasoconstriction and loss in myocardial contractility in perfused rat hearts: role of thromboxane generation

BACKGROUND: Cardiac performance is severely depressed in septic shock. Endotoxin has been implicated as the causative agent in Gram-negative sepsis, but similar abnormalities are encountered in Gram-positive sepsis. We investigated the influence of the major exotoxin of Staphylococcus aureus, staphylococcal alpha-toxin, in isolated perfused rat hearts. METHODS AND RESULTS: Alpha-toxin 0.25 to 1 microg/mL caused a dose-dependent increase in coronary perfusion pressure that more than doubled. In parallel, we noted a decrease in left ventricular developed pressure and the maximum rate of left ventricular pressure rise (dP/dt(max)), dropping to a minimum of <60% of control. These changes were accompanied by a liberation of thromboxane A(2) and prostacyclin into the coronary effluent. The release of creatine kinase, lactate dehydrogenase, potassium, and lactate did not surpass control heart values, and leukotrienes were also not detected. Indomethacin, acetylsalicylic acid, and the thromboxane receptor antagonist daltroban fully blocked the alpha-toxin-induced coronary vasoconstrictor response and the decrease in left ventricular developed pressure and dP/dt(max), whereas the lipoxygenase inhibitor nordihydroguaiaretic acid, the platelet activating factor antagonist WEB 2086, and the alpha-adrenergic antagonist phentolamine were entirely ineffective. Inhibition of nitric oxide synthase even enhanced the alpha-toxin-induced increase in coronary perfusion pressure and the loss in myocardial performance. CONCLUSIONS: Purified staphylococcal alpha-toxin provokes coronary vasoconstriction and loss in myocardial contractility. The responses appear to be largely attributable to the generation of thromboxane and are even enhanced when the endogenous nitric oxide synthesis is blocked. Bacterial exotoxins, such as staphylococcal alpha-toxin, may thus be implicated in the loss of cardiac performance encountered in Gram-positive septic shock.     

Ischemic preconditioning and nicorandil pretreatment improve donor heart preservation.

The present study investigated the effects of ischemic preconditioning (IPC) and nicorandil pretreatment on myocardial storage in a donor heart preservation model. Isolated rat hearts were separated into groups: group 1, non-preconditioned control group; group 2, 2.5 min of normothermic ischemia followed by 15 min of normothermic Langendorff perfusion (one IPC cycle); and group 3, 2 cycles of IPC. All hearts were subsequently stored in University of Wisconsin solution at 4 degrees C for 2, 4 and 6h, and the concentrations of high-energy phosphate metabolites were measured for each time point. Heart function parameters (aortic flow, coronary flow and cardiac output) were measured when the heart was reperfused following the 2, 4 or 6 h of preservation. The effects of nicorandil, an ATP-sensitive potassium channel opener, on heart function following preservation were also evaluated. Nicorandil was injected intravenously before heart harvesting. The results showed that the energy status was well preserved in the IPC groups. The 2-cycle IPC group showed better recovery of heart function following preservation. Pretreatment with nicorandil also improved functional recovery of the heart following preservation. The present study showed that IPC of the rat heart resulted in improved myocardial energy metabolism and functional recovery after hypothermic preservation, and that nicorandil has potential for pharmacological preconditioning in heart preservation for transplantation.     

Energy Metabolism After Ischemic Preconditioning in Streptozotocin-Induced Diabetic Rat Hearts

Objectives. The aim of this study was to compare the cardioprotective effects of preconditioning in hearts from streptozotocin-induced diabetic rats with its effects in normal rat hearts.Background. The protective effect of ischemic preconditioning against myocardial ischemia may come from improved energy balance. However, it is not known whether preconditioning can also afford protection to diabetic hearts.Methods. Isolated perfused rat hearts were either subjected (preconditioned group) or not subjected (control group) to preconditioning before 30 min of sustained ischemia and 30 min of reperfusion. Preconditioning was achieved with two cycles of 5 min of ischemia followed by 5 min of reperfusion.Results. In the preconditioned groups of both normal and diabetic rats, left ventricular developed pressure, high energy phosphates, mitochondrial adenosine triphosphatase and adenine nucleotide translocase activities were significantly preserved after ischemia-reperfusion; cumulative creatine kinase release was smaller during reperfusion; and myocardial lactate content was significantly lower after sustained ischemia. However, cumulative creatine kinase release was less in the preconditioned group of diabetic rats than in the preconditioned group of normal rats. Under ischemic conditions, more glycolytic metabolites were produced in the diabetic rats (control group) than in the normal rats, and preconditioning inhibited these metabolic changes to a similar extent in both groups.Conclusions. The present study demonstrates that in both normal and diabetic rats, preservation of mitochondrial oxidative phosphorylation and inhibition of glycolysis during ischemia can contribute to preconditioning-induced cardioprotection. Furthermore, our data suggest that diabetic myocardium may benefit more from preconditioning than normal myocardium, possibly as a result of the reduced production of glycolytic metabolites during sustained ischemia and the concomitant attenuation of intracellular acidosis.     

内源性降钙素基因相关肽在整体大鼠心肌缺血预适应中的作用

为确定预适应缺血时释放的内源性降钙素基因相关肽是否在整体大鼠心肌缺血预适应中起重要作用,分别用放射免疫法测定缺血预适应、降钙素基因相关肽多克隆抗体及对照组的血浆降钙素基因相关肽浓度。并用硝基四唑氮兰染色判定梗死区面积,以坏死区占危险区的百分数表示。结果表明,缺血预适应组第一次和第三次缺血末的血浆降钙素基因相关肽浓度均较对照组显著增高（Ｐ〈０．０１）,以后者增加更为明显。缺血预适应能明显抑制缺血／现     

Intravenous nitroglycerin unloading in acute myocardial infarction.

Low-dose intravenous nitroglycerin infusion can be safely administered during acute myocardial infarction to unload the left ventricle and salvage ischemic myocardium and left ventricular geometry and function. In an experimental conscious dog model, low-dose infusion titrated to decrease mean blood pressure by 10% over the first 6 hours after coronary artery ligation resulted in 51% decrease in infarct size, 54% decrease in preload, and more than 50% increase in collateral blood flow. The same benefits were seen when methoxamine was given to counteract that 10% decrease in blood pressure. Similar short-term nitroglycerin infusion also limited remodeling in the dog model. More important, no myocardial salvage was seen with excessive nitroglycerin-induced hypotension to levels less than 80 mm Hg. Clinically, prolonged low-dose nitroglycerin infusion was evaluated in a prospective, randomized, single-blinded, placebo-controlled study of 310 patients with acute infarction: 154 received nitroglycerin and 156 received placebo. Nitroglycerin was titrated to reduce mean blood pressure by 10% in normotensive patients and up to 30% in hypertensive (blood pressure greater than 140/90 mm Hg) patients, but not to less than 80 mm Hg. Nitroglycerin produced several benefits compared with placebo: (1) smaller creatine kinase infarct size; (2) less regional left ventricular dysfunction, better global ejection fraction, and less infarct expansion and thinning; (3) better clinical functional status and hemodynamics; (4) fewer inhospital complications such as acute left ventricular failure and dilation due to marked infarct expansion, left ventricular thrombus, cardiogenic shock, and infarct extension; and (5) fewer deaths up to 1 year in patients with anterior Q-wave infarction.     

Phenotypic adaptation of the late preconditioned heart: myocardial oxygen consumption is reduced

OBJECTIVES: Although the signalling pathways of late preconditioning have been extensively investigated, its consequence for myocardial metabolism remains unknown. Thus, myocardial oxygen consumption (MVO2) was evaluated before and under late preconditioning. METHODS: In 7 chronically instrumented dogs, we measured MVO2 in vivo at baseline and during inotropic stimulation with dobutamine (10 and 20 microg/kg/min, i.v.) before (Day 0) and 24 h after (Day 1) a 10-min circumflex coronary artery occlusion. RESULTS: At Day 0, dobutamine dose-dependently increased the triple product (heart ratexleft ventricular systolic pressurexleft ventricular maximum dP/dt), MVO2, coronary blood flow, and coronary sinus pO2. At Day 1, the triple product was similar at baseline and at each dose of dobutamine but MVO2 was significantly blunted as compared to Day 0 (-15+/-4%, -22+/-3% and -19+/-4% at baseline, dobutamine 10 and 20 microg/kg/min, respectively). Importantly, the relationship between MVO2 and triple product was significantly rightward shifted with late preconditioning, i.e., MVO2 was reduced for any level of triple product. At Day 1, the relationship between coronary blood flow and MVO2 was not altered as compared to Day 0 but coronary sinus pO2 was significantly increased vs. Day 0 for any level of coronary blood flow, suggesting that late preconditioning exerted no vasomotor effect but rather changed myocardial oxygen handling. These effects were abolished by administration of S-methyl-isothiourea (1.5 mg/kg, i.v.), a iNOS inhibitor. CONCLUSION: This study demonstrates that ischemic late preconditioning is characterized by a major reduction in MVO2, both at baseline and under inotropic stimulation. NO from iNOS contributes to this modification of metabolic phenotype.     

Studies on cumene hydroperoxide-induced lipid peroxidation in the isolated perfused rat heart

In the isolated, perfused rat heart, lipid peroxidation, induced by cumene hydroperoxide (Cum OOH), is accompanied by the release of malondialdehyde (MDA). Using a modified perfusion technique resulting in the separate collection of coronary and interstitial effluent, it can be shown that upon Cum OOH (0.5 mM) perfusion there is an immediate release of MDA in the coronary effluent and a delayed release in the interstitial fluid, indicating the susceptibility and coronary vascular tissue towards free radical-induced lipid peroxidation. Perfusion with Cum OOH leads to an initial increase of the coronary flow and a depressed contractility followed by a cardiac arrest concomitantly with the onset of MDA release in the interstitial fluid. Finally, during prolonged perfusion the coronary flow diminishes and contracture of the heart muscle ('stone heart') develops. These phenomena resemble those occurring during the 'calcium paradox'. Although the contractility diminishes immediately after the perfusion with Cum OOH the tissue ATP level and energy charge (formula; see text) remain constant. From the moment of cardiac arrest the ATP and creatine phosphate levels gradually decrease and the energy charge drops simultaneously with the appearance of MDA in the interstitial fluid. In contrast to the calcium paradox there is no simultaneous increase in the myocardial AMP level. Various mitochondrial enzymes (cytochrome c oxidase, monoamine oxidase, carnitinepalmitoyltransferase I and palmitoyl CoA synthetase) were tested and not affected by Cum OOH perfusion. During the development of contracture after 20 min of Cum OOH perfusion massive contraction band necrosis of cardiac tissue occurs. However, overall protein release is lower when compared with the protein release during the calcium paradox.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nitroglycerin-induced coronary vasodilatory responses in patients during isometric handgrip exercise

Intracoronary nitroglycerin is frequently administered during invasive procedures such as coronary angioplasty or thrombolysis which may be associated with pain and sympathetic neural stimulation. Whether sympathetic-mediated reflex vasoconstriction interferes with nitroglycerin-induced augmentation of coronary blood flow is unknown. Therefore, coronary and systemic hemodynamics were measured in 19 patients during isometric handgrip exercise (3 min x 25% maximal effort), during intracoronary nitroglycerin, and during handgrip plus intracoronary nitroglycerin. Nine patients had no significant left anterior descending coronary artery stenosis (group 1) and ten patients had greater than 70% left anterior descending coronary artery stenosis (group 2). Handgrip exercise increased heart rate, mean arterial pressure, and coronary sinus and great vein flow 15% while increasing coronary resistance 10%. Intracoronary nitroglycerin (200 micrograms) reduced mean arterial pressure -4 +/- 6% and increased great cardiac vein flow 35-72%. Anterior left ventricular regional coronary flow responses to intracoronary nitroglycerin were unaffected by sympathetic stimulation for group 1. Group 2 had a greater increase in great vein flow with intracoronary nitroglycerin plus handgrip compared to nitroglycerin alone due to increased mean arterial pressure with no change in the great vein resistance. These data indicate that sympathetic stimulation does not alter the nitroglycerin-induced augmentation of coronary sinus and great vein blood flow in patients with and without significant left anterior descending coronary artery stenosis. In patients undergoing invasive interventions who may have increased circulating catecholamines, mild sympathetic (isometric) stimulation does not appear to interfere with the coronary vasodilatory responses to intracoronary nitroglycerin.