Reduced release of vasoconstrictors from the porcine heart after repeated periods of ischemia

Objective To examine if the decline in post-ischemic hyperemic flow after repeated brief periods of myocardial ischemia is accompanied by augmented cardiac release of the vasoconstrictors endothelin-1 (ET-1) and norepinephrine (NE).

Design Mid-LAD (left anterior descending coronary artery) was occluded for 10 min with 30 min intervals a total of four times in six anesthetized pigs. Blood from the anterior interventricular coronary vein was drained through a shunt to the right atrium to facilitate blood sampling. Plasma concentrations of ET-1 and NE were repeatedly measured in arterial and coronary venous blood to estimate cardiac vasoconstrictor release.

Results Plasma concentrations of ET-1 and NE remained unaltered, but cardiac release of both vasoconstrictors rose briefly during reperfusion due to the hyperemia. However, release declined progressively after repeated periods of ischemia and reperfusion and amounted to 53% (NE) and 17% (ET-1) of initial release after the fourth period of ischemia.

Conclusion The decline in post-ischemic hyperemia after repeated brief periods of myocardial ischemia is not accompanied by a progressive accentuation of cardiac ET-1 and NE release.     

肝素对顿抑心肌功能影响的实验研究

目的：探讨肝素化剂量肝素对在体家兔短暂缺血－再灌注顿抑心肌的功能的影响。方法：23只雄性家兔，分为实验（A）组和对照（B）组，建立在体心肌短暂缺血（15min）－再灌主（60min）损伤模型。A组于前降支阻断前20min给予肝素（700U／kg）。分别于给药前、缺血前、再灌注期间，检测2组NO、ET－1、MDA、SOD水平，测定血流动力学指标变化，对心肌超微结构做定性观察。结果：A组在给药后20min，NO含量即较给药前明显升高（P＜0．05），且在整个再灌注期较B组有显著性差别（P＜0．05），心功能、超微结构明显改善。结论：肝素参与短暂缺血－再灌注顿抑心肌功能的保护，机制可能是通过药物性预适应，增强内皮源性NO的产生，从而减轻心肌缺血－再灌注损伤。     

Experimental study of pegylated liposomal hemoglobin on norepinephrine release and reperfusion arrhythmias in isolated guinea pig hearts.

PURPOSE: Under myocardial reperfusion conditions, hemoglobin (Hb)-based artificial blood showed effectiveness for post-ischemic dysfunction. However, there are no studies about the effects of this product on reperfusion arrhythmias (ventricular fibrillation, VF) associated with norepinephrine (NE) release. This study was to evaluate the effects of the timing of the administration of pegylated liposomal Hb (LHb, P(50)=40-45 mmHg, 1 mg/mL) on NE release and VF. MATERIALS AND METHODS: Isolated guinea pig hearts (n=6 in each group) were randomly divided into four groups in Krebs-Henseleit solution being supplemented or not with LHb as follows: pre-ischemia (PRE), reperfusion (REP), or PRE+REP groups. The hearts were perfused for 30 min (preischemic period) and then subjected to 30 min of global ischemia, followed by 30 min of reperfusion with a normothermic Langendorff apparatus at 30 mm Hg aortic pressure in a constant pressure model. RESULTS: No differences were documented among the four groups in heart rate, left ventricular-developed pressure, or coronary flow rate. However, the REP group significantly decreased the duration of VF and NE release, but it did not inhibit the incidence of VF. CONCLUSION: These results suggest that the administration of LHb, especially with the timing of reperfusion, might prevent reperfusion arrhythmias linked to the inhibition of NE release.     

Triiodothyronine in the recovery of stunned myocardium in dogs

Two groups of dogs were subjected to a 15-minute period of regional myocardial ischemia by snaring the left anterior descending coronary artery proximal to its first diagonal branch. After release of the snare, the dogs were given either placebo (group 1: n = 7) or triiodothyronine (T3) therapy (group 2: n = 6). The dose of T3 given was 0.2 microgram/kg at 30-minute intervals to a total of six doses. Plasma free T3 level fell significantly during the ischemic period in both groups and continued to fall after reperfusion in group 1. In both groups, cardiac function deteriorated significantly during the period of ischemia and rapidly returned to control level after reperfusion. After 90 minutes of reperfusion, however, deterioration of left ventricular function was observed in group 1 and was significantly worse than in group 2, in which hemodynamic function was maintained and, in fact, improved to levels superior to control. It is suggested that T3 therapy may be worthy of trial in patients in whom reperfusion of the myocardium takes place after a relatively short ischemic period (the "stunned myocardium").     

Calcitonin gene-related peptide enhances the recovery of contractile function in stunned myocardium

INTRODUCTION: Calcitonin gene-related peptide, a potent vasodilating inotropic agent, increases coronary artery perfusion when administered exogenously and reduces ischemic injury in nonmyocardial tissue. However, it is unclear whether this agent improves recovery of myocardial performance after reversible myocardial ischemia. METHODS: Nine dogs underwent complete occlusion of the left anterior descending coronary artery for 15 minutes and were monitored during 24 hours of reperfusion. Calcitonin gene-related peptide (0.07 microgram. kg(-1). min(-1)), nitroglycerin (65 microgram. kg(-1). min(-1)), or saline solution placebo was infused intravenously during initial reperfusion. Ischemia/reperfusion was repeated in concurrent 24-hour periods until all animals received infusions in random order. Micromanometry and sonomicrometry determined left ventricular pressure and myocardial segment length. Myocardial performance, based on the linear relationship between stroke work and end-diastolic segment length, was estimated with the preload recruitable work area.Results were analyzed as percent control and compared statistically with the use of repeated measures analysis of variance. RESULTS: Recovery of myocardial performance was augmented during reperfusion with calcitonin gene-related peptide infusion relative to placebo     

Adrenomedullary epinephrine excretion and myocardial norepinephrine release during cardiopulmonary bypass

It has long been known that shock or surgical stress promotes an epinephrine (E) excretion from the adrenomedullary glands. In fourteen adult cardiac patients, plasma E values in both superior vena cava (SVC) cannula and inferior vena cava (IVC) cannula during total cardiopulmonary bypass (CPB) are studied at three stages, before aortic cross clamp (pre AXC), after release of aortic cross clamp (post AXC) and at 34 degrees C rectal temperature in rewarming (34 degrees C RT). Although E values in both SVC and IVC are slightly higher values than normal in pre AXC, they increase sharply to peaked values at post AXC and decline uniformly close to normal at 34 degrees C RT. IVC-E is constantly significantly higher (statistically) than SVC-E at each of all three stages. It is strongly suggested that E response to CPB is mainly originated from the adrenomedullary glands, and cardiac reflex which has sympathetic efferent limbs triggered by myocardial ischemia can indicate the increase in E during AXC. Myocardial norepinephrine (NE) release in heart ischemia such as acute myocardial infarction has been generally accepted. To examine whether myocardial NE release occurs during AXC, if there is the association of NE release with any clinical parameters, the second investigation is done in twenty-six adult cardiac patients. Plasma NE values in both the radial artery (A) and the coronary sinus (CS) are measured at six stages, pre AXC (stage 1), post AXC (stage 2), post CPB (stage 3), three hours after off CPB (stage 4), six hours off CPB (stage 5) and twelve hours off CPB (stage 6).(ABSTRACT TRUNCATED AT 250 WORDS)     

Wall motion and metabolic changes after coronary occlusion and reperfusion

Experiments were conducted in open-chest pigs in which experimental myocardial ischemia was produced. Two groups of animals were evaluated: (1) those with short episodes of coronary occlusion and reperfusion, and (2) those with an initially longer period of occlusion (equal to the sum of the short multiple occlusions) and reperfusion. Indices of myocardial wall motion as determined by echocardiogram, of energy production as measured by mitochondrial oxidative phosphorylation, and of cellular membrane integrity as measured by calcium uptake by sarcoplasmic reticulum vesicles and calcium content of tissue and mitochondria were obtained. Our observation revealed better myocardial preservation in the group with brief periods of occlusion and reperfusion than those with a sustained period of ischemia followed by reperfusion. The concept that myocardium is less well preserved due to reperfusion damage by intermittent aortic cross-clamping or intermittent coronary perfusion during open heart surgery compared to uninterrupted cardiac arrest needs to be reexamined in light of the data presented and investigated in the hypothermic, cardioplegia model.     

Isoflurane attenuates myoglobin release during ischemic and/or reperfusion periods

Background: Recently, we have developed cardiac microdialysis for detection of protein leakage from the injured myocardium. We examined whether the exposures to isoflurane would exert a beneficial effect on myocardial injury caused by ischemia or reperfusion.
Methods: A dialysis probe was implanted into the left ventricle free wall in the rabbits. The dialysate myoglobin level served as an index of myocardial interstitial myoglobin levels. Rabbits were randomly assigned to one of three groups: (1) without exposure to isoflurane (vehicle, n =6), (2) inhale 1 MAC isoflurane once for 30 min (ISO30-1, n =6), and (3) twice for 30 min (ISO30-2, n =6). All rabbits underwent 30 min of coronary occlusion and 60 min of reperfusion. To determine whether the isoflurane induced myocardial protection against chemical hypoxia, sodium cyanide (30 mM) was administered and dialysate myoglobin levels were measured with ( n =6) and without pre-exposure to isoflurane twice for 30 min ( n =6).
Results: In all three groups dialysate myoglobin levels were increased by coronary occlusion and furthermore augmented by reperfusion. In comparison with the vehicle group, the ISO30-1 group suppressed only the increase in the dialysate myoglobin level during reperfusion. The ISO30-2 group suppressed during both the ischemic and reperfusion periods. Cyanide induced increases in dialysate myoglobin levels. These increments in dialysate myoglobin levels were suppressed by repeated exposure to isoflurane.
Conclusion: Repeated exposure to isoflurane suppressed myocardial myoglobin release caused by both ischemia and reperfusion injury. Isoflurane may provide protection against myocardial ischemia/reperfusion and hypoxic injuries.     

Impact of endothelin-1 on microcirculatory disturbance after partial hepatectomy under ischemia/reperfusion in thioacetamide-induced cirrhotic rats

BACKGROUND: Endothelin (ET)-1 contributes to hepatic ischemia and reperfusion (HIR) injury in normal liver. This study was conducted to clarify the role of ET-1 in HIR injury in cirrhotic state. MATERIALS AND METHODS: Using thioacetamide-induced cirrhotic rats with spontaneous portosystemic shunt, we determined the changes in plasma aspartate aminotransferase (AST) levels, plasma and hepatic ET-1 values, 7-day survival rates, and hepatic oxygen saturation (SO(2)) by time-resolved spectroscopy as an indicator of hepatic microcirculation under intermittent or continuous total hepatic ischemia with subsequent partial hepatectomy. RESULTS: Hepatic ET-1 levels in cirrhotic rats were significantly higher than those in noncirrhotic rats. Plasma and hepatic ET-1 levels at 1, 3 and 6 h of reperfusion after intermittent hepatic ischemia were significantly lower than those after continuous hepatic ischemia. In cirrhotic animals subjected to intermittent hepatic ischemia, the elevation of plasma AST levels at 1, 3 and 6 h of reperfusion and the decline in hepatic SO(2) at the end of 60-min hepatic ischemia and after reperfusion were significantly suppressed when compared with those subjected to continuous hepatic ischemia. Pretreatment with a nonselective endothelin receptor antagonist in continuous hepatic ischemia significantly ameliorated plasma AST levels and hepatic SO(2) values with less hepatic sinusoidal congestion, resulting in an improvement in the 7-day survival rate. CONCLUSIONS: Continuous hepatic ischemia in the cirrhotic liver has disadvantages relating to microcirculatory derangement with more ET-1 production in partial hepatectomy. In liver surgery, pharmacological regulation of ET-1 production may lead to attenuation of reperfusion injuries for ischemically damaged cirrhotic liver.     

Pretreatment of donors with endothelin receptor antagonist TAK-044 improves cardiac functional recovery following preservation with University of Wisconsin solution

OBJECTIVE: Previous studies suggest that endothelin-1 (ET-1) plays a role in myocardial ischemia/reperfusion injury. Although administration of an endothelin receptor antagonist to the recipient has been shown to improve myocardial function after ischemia/reperfusion in a rat heart transplantation model, the effect of administering an endothelin receptor antagonist to the donor has not yet been examined. This study was designed to investigate the effects of pretreating donors with an ET(A)/ET(B) endothelin receptor antagonist (TAK-044) on myocardial function after cold preservation of a rat heart. DESIGN: Male rats were pretreated with normal saline (control group, n = 8), TAK-044 (TAK group, n = 8, 1 mg/kg). Following cardiac arrest using cardioplegia, we washed out the coronary vascular beds with cold University of Wisconsin solution followed by 6-h preservation. After preservation, the hearts were mounted on a Langendorff apparatus to estimate aortic flow (AF), coronary flow (CF), cardiac output (CO), systolic pressure (SP), heart rate (HR), and rate-pressure product (RPP: HR x SP). The concentration of lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) within the coronary perfusate during reperfusion was measured. RESULTS: AF, SP, and CO were significantly greater in the TAK group than in the control group (p = 0.0045, 0.004, and 0.0295, respectively). CONCLUSION: Pretreatment of donors with a nonselective endothelin receptor antagonist (TAK-044) improved cardiac functional recovery following preservation and may be beneficial for prolonged myocardial preservation.     

Pretreatment of Donors with Endothelin Receptor Antagonist TAK-044 Improves Cardiac Functional Recovery Following Preservation with University of Wisconsin Solution

Objective : Previous studies suggest that endothelin-1 (ET-1) plays a role in myocardial ischemia/reperfusion injury. Although administration of an endothelin receptor antagonist to the recipient has been shown to improve myocardial function after ischemia/reperfusion in a rat heart transplantation model, the effect of administering an endothelin receptor antagonist to the donor has not yet been examined. This study was designed to investigate the effects of pretreating donors with an ET A /ET B endothelin receptor antagonist (TAK-044) on myocardial function after cold preservation of a rat heart. Design : Male rats were pretreated with normal saline (control group, n = 8), TAK-044 (TAK group, n = 8, 1 mg/kg). Following cardiac arrest using cardioplegia, we washed out the coronary vascular beds with cold University of Wisconsin solution followed by 6-h preservation. After preservation, the hearts were mounted on a Langendorff apparatus to estimate aortic flow (AF), coronary flow (CF), cardiac output (CO), systolic pressure (SP), heart rate (HR), and rate-pressure product (RPP: HR &#50 SP). The concentration of lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) within the coronary perfusate during reperfusion was measured. Results : AF, SP, and CO were significantly greater in the TAK group than in the control group ( p = 0.0045, 0.004, and 0.0295, respectively). Conclusion : Pretreatment of donors with a nonselective endothelin receptor antagonist (TAK-044) improved cardiac functional recovery following preservation and may be beneficial for prolonged myocardial preservation.     

Endothelial cell dysfunction after ischemic arrest and reperfusion: a possible mechanism of myocardial injury during reflow

To determine the mechanism(s) responsible for decreased coronary flow after global cardiac ischemia and reperfusion, we studied 40 isolated rabbit hearts before and after 30 minutes of normothermic ischemic arrest and reperfusion. In the control group (n = 10) we evaluated the time course of recovery of coronary flow, vascular reactivity, and myocardial function. In experimental groups A (n = 10) and B (n = 10), metabolic control of autoregulation was assessed by plots of myocardial oxygen consumption versus coronary flow generated by incremental increases in heart rate. The slope and intercept of these plots suggested that autoregulation of coronary flow was maintained after ischemia. In group B hearts (n = 10) hyperosmolar reperfusion with mannitol decreased myocardial water by 2% (p less than 0.01) but did not increase coronary flow. Endothelium-dependent function was assessed in group C (n = 10) by the administration of an endothelium-dependent vasodilator (serotonin) and a smooth muscle vasodilator (adenosine). Coronary artery smooth muscle function was comparable in hearts before and after ischemia. However, endothelium-dependent increases in coronary flow to serotonin were significantly impaired after ischemia (p less than 0.01), and this was accompanied by a significant decrease in prostacyclin synthesis by the endothelium (p less than 0.001). Global cardiac ischemia and reperfusion damages coronary artery endothelium, causing increased coronary vasomotor tone; this may be an important mechanism of decreased coronary perfusion and subsequent myocardial injury during reflow.     

Mechanism of Myocardial Protection by Isoflurane: Role of Adenosine Triphosphate-regulated Potassium (K sub ATP) Channels

Background: The mechanism of the protective actions of volatile anesthetics in ischemic myocardium has not been clearly elucidated. The role of myocardial adenosine triphosphate-regulated potassium (KATP) channels in isoflurane-induced enhancement of recovery of regional contractile function after multiple brief occlusions and reperfusion of the left anterior descending coronary artery (LAD) was studied in dogs anesthetized with barbiturates.

Methods: Dogs (n = 32) were instrumented to measure left ventricular and aortic blood pressure, cardiac output, LAD coronary blood flow velocity, and subendocardial segment length. Regional myocardial perfusion was measured using radioactive microspheres. Hemodynamics and percentage segment shortening (%SS) in the LAD perfusion territory were evaluated after instrumentation was complete; after pretreatment with the KATP channel antagonist, glyburide (0.05 mg/kg sup -1) or drug vehicle (polyethylene glycol in ethyl alcohol; control experiments); and in the presence or absence of 1 MAC isoflurane administered for 30 min before and during five 5-min occlusions and reperfusion of the LAD in four experimental groups. Isoflurane was discontinued at the onset of the final reperfusion period. Measurements of hemodynamics, %SS, and myocardial perfusion were repeated at several intervals during 180 min after reperfusion of the LAD.

Results: Left anterior descending coronary artery occlusion caused regional dyskinesia during each 5-min occlusion in each dog. Control and glyburide-pretreated dogs demonstrated poor recovery of %SS by 180 min after reperfusion (2 +/- 10 and 7 +/- 6% of baseline, respectively). In contrast, dogs anesthetized with isoflurane exhibited complete recovery of function (%SS) by 180 min after reperfusion (82 +/- 8% of baseline). Enhanced recovery of regional contractile function by isoflurane was abolished by pretreatment with glyburide 180 min after reperfusion (16 +/- 10% of baseline). Improvement of functional recovery of stunned myocardium by isoflurane, and the blockade of this action by glyburide, was not associated with changes in hemodynamics or regional myocardial perfusion.     

Continuous monitoring of myocardial acid–base status during intermittent warm blood cardioplegia

Objective: Intermittent warm blood cardioplegia (IWBC) is a well-established technique for myocardial protection during cardiac operations. According to standardized protocols, IWBC administration is currently performed every 15–20 min regardless of any individual variable and in the absence of any instrumental monitoring. We devised a new system for continuous measurement of the acid–base status of coronary sinus blood for on-line evaluation of myocardial oxygenation during IWBC. Methods: In 19 patients undergoing cardiac surgery for coronary artery bypass graft and/or valve surgery and receiving IWBC (34–37°C) by antegrade induction (3 min) and retrograde or antegrade maintenance (2 min) every 15 min, continuous monitoring of myocardial oxygenation and acid/base status was performed by means of a multiparameter PO₂, PCO₂, pH, and temperature sensor (Paratrend7 ®, Philips Medical System) inserted into the coronary sinus. Results: Mean cross-clamping time was 76±26 min; ischemic time was 13±0.2 min. pH decline was not linear, showing an initial fast decline, a point of flexus, and a progressive slow decline. After every ischemic period, the pH adaptation curve showed a complex pattern reaching step-by-step lower minimum levels (7.28±0.14 during the first ischemic period, to 7.16±0.19 during the third ischemic period – P=0.003). PO₂ decreased rapidly at 90% in 5.0±1.2 min after every reperfusion. During ischemia, PCO₂ increased steadily at 1.6±0.1 mmHg per minute, with progressively incomplete removal after successive reperfusion, and progressive increase of maximal level (42±12 mmHg during the first ischemic period, to 53±23 mmHg during the third ischemic period – P=0.05). Conclusions: Myocardial oxygen, carbon dioxide, and pH show marked changes after repeated IWBC. Myocardial ischemia is not completely reversed by standardized reperfusions, as reflected by steady deterioration of PCO₂ and pH after each reperfusion. Progressive increase of reperfusion durations or direct monitoring of myocardial oxygenation could be advisable in cases of prolonged cross-clamping time.     

Myocardial outflow of prostacyclin in relation to metabolic stress during off-pump coronary artery bypass grafting

BACKGROUND: The metabolic changes, possible myocardial damage, and influence on the vascular endothelium during off-pump coronary artery bypass grafting have been investigated. METHODS: Coronary sinus and arterial blood samples were obtained before coronary arterial occlusion, after 10 minutes of ischemia, and after 1 and 10 minutes of reperfusion in 9 patients who had an anastomosis performed to the left anterior descending coronary artery off-pump bypass RESULTS: The mean ischemic time was 14 +/- 1 minutes. The arteriovenous difference in lactate decreased during ischemia to reach a minimum at 1 minute of reperfusion (-0.15 +/- 0.06 micromol/L compared to 0.21 +/- 10 micromol/L before ischemia; p < 0.01). Myocardial lactate extraction decreased from 14.2 +/- 6.8 micromol/min before ischemia to -10.9 +/- 6.5 micromol/min after 1 minute of reperfusion (p < 0.01). Simultaneously, the arteriovenous difference in 6-keto-PGF(1alpha), the stable metabolite of prostacyclin, decreased from -30 +/- 26 pg/mL to -258 +/- 80 pg/mL at 1 minute of reperfusion (p < 0.05), and the 6-keto-PGF(1alpha) extraction over the heart decreased -556 +/- 466 pg/min to -18,560 +/- 5,683 pg/min (p < 0.01). CONCLUSIONS: The localized myocardial ischemia associated with these procedures causes changes in the myocardium and endothelial influence. Coronary bypass surgery performed on the beating heart may not be superior in preventing cardiac ischemia and endothelial disturbance, compared with conventional bypass surgery.     

Improvement of myocardial function by trifluoperazine, a calmodulin antagonist, after acute coronary artery occlusion and coronary revascularization

Activation of an intracellular calcium-calmodulin complex may play an important role in myocardial injury induced by ischemia and reperfusion. Trifluoperazine, a calmodulin antagonist, was used before ischemia to enhance myocardial preservation by preventing intracellular calcium accumulation. The experimental model used an isolated in situ pig heart (19 control animals and 15 trifluoperazine-treated animals) subjected to occlusion of the left anterior descending coronary artery for 60 minutes followed by 60 minutes of hypothermic potassium crystalloid cardioplegic arrest and 60 minutes of reperfusion. Myocardial segmental function measured by ultrasonic crystals showed that active systolic segment shortening was abolished in the distribution of the left anterior descending artery after 60 minutes of occlusion irrespective of the treatment, whereas that not in the distribution of the left anterior descending artery increased by about 15% in both groups of animals. Restoration of systolic segment shortening in the distribution of the left anterior descending artery 60 minutes after reperfusion was 12% and 42% of baseline levels in untreated and trifluoperazine-treated animals, respectively (p less than 0.01). This improvement in segmental function by trifluoperazine was reflected in significantly (p less than 0.05) better global myocardial contractility and compliance and in significantly (p less than 0.01) greater total coronary blood flow and myocardial oxygen consumption. Trifluoperazine also increased myocardial creatine phosphate content in the distribution of the left anterior descending artery (p less than 0.01) during reperfusion, and creatine kinase release was reduced (p less than 0.05). Our results suggest that trifluoperazine improved regional myocardial function after acute occlusion of the left anterior descending artery and reperfusion and that global cardiac performance was thereby improved. The beneficial effects of trifluoperazine may be exerted by prevention of myocardial injury associated with the calcium-calmodulin complex in ischemic and reperfused myocardium.     

Coronary blood flow and myocardial metabolism during reperfusion after hypothermic cardioplegia in the dog

There have been many studies of reperfusion injury after normothermic ischemia. However, there have been few clinically relevant studies on the nature and time course of recovery of the myocardium during reperfusion after hypothermic cardioplegia. We studied reperfusion in the isolated dog heart supported by another dog. After 2 h of cardioplegic arrest at 20 degrees C, 11 normal hearts were reperfused for 30 min at optimal coronary pressures (60-100 mm Hg mean). The following events occurred: rapid rewarming, a transient hyperemia followed by a rapid return of both coronary blood flow and myocardial oxygen consumption to normal, washout of lactate, recovery of contractility and a slight decline in ATP. Most of these events occurred during the first 15 min of reperfusion. We concluded that, in normal hearts which are well protected during hypothermic cardioplegia, reperfusion at optimal coronary pressure results in recovery of the myocardium within 15 min, with the exception of recovery of ATP levels.     

A novel peroxynitrite decomposer catalyst (FP-15) reduces myocardial infarct size in an in vivo peroxynitrite decomposer and acute ischemia-reperfusion in pigs

BACKGROUND: Reactive oxygen and nitrogen species generated after reperfusion injury result in organ dysfunction. Peroxynitrite, a reactive nitrogen molecule produced from the reaction of superoxide anions and nitric oxide, is thought to be a causative agent in oxidative reperfusion injury. The aim of this study was to investigate the effects of a novel peroxynitrite decomposition catalyst (FP-15) in an acute myocardial ischemia/reperfusion model. METHODS: Pigs were subjected to 60 minutes of regional ischemia by reversibly ligating the left anterior descending coronary artery followed by 180 minutes of reperfusion. In the treatment group (n = 6), an FP-15 (1 mg/kg) bolus was infused through the jugular vein after 30 minutes of ischemia followed by a continuous infusion (1 mg x kg(-1) x h(-1)) during reperfusion. Vehicle was infused in the control group (n = 6). Coronary flow was recorded by an ultrasonic flow probe and infarct size determined by tetrazolium staining. Arterial and left ventricular pressures were monitored continuously and regional myocardial function determined by sonomicrometry. RESULTS: No significant differences were observed in either hemodynamics or ischemic area at risk. However, the infarct size was significantly reduced (35.3% +/- 3.5% versus 21.6% +/- 2.6% of the ischemic area, control versus FP-15-treated groups, respectively, p < 0.05). +dP/dt was transiently improved in the FP-15-treated groups while during most of the reperfusion period coronary flow, and was significantly lower in the FP-15-treated group as compared to the control group (p < 0.01). CONCLUSIONS: FP-15 administration reduces myocardial infarct size and reactive hyperemia. These data support the pathogenic role of endogenously produced peroxynitrite and that FP-15 is effective in preventing myocardial reperfusion injury.     

Deep hypothermia during ischemia improves functional recovery and reduces free-radical generation in isolated reperfused rat heart.

BACKGROUND: We investigated the influence of deep hypothermia (4 degrees C) during ischemia-reperfusion in the isolated rat heart model. METHODS: Isolated, perfused rat hearts underwent either 30 minutes of normothermic ischemia (control group) or 30 minutes of hypothermic ischemia (hypothermia-treated group), followed by 30 minutes of reperfusion in both groups. We recorded functional parameters and used electron spin resonance (ESR) spectroscopy to detect ascorbyl radicals, as markers of free-radical production, in samples of coronary effluents. RESULTS: Functional parameters were stable in the 2 groups during pre-ischemic and ischemic periods. During reperfusion, coronary flow, left diastolic ventricular pressure, left ventricular developed pressure, and heart rate more rapidly recovered to values close to those obtained during the pre-ischemic period in the hypothermia-treated group than in the control group. Moreover, the post-ischemic contracture observed in the control group did not appear in the hypothermia-treated group. Finally, ESR analysis showed that the post-ischemic release of ascorbyl radicals decreased in the hypothermia-treated group. CONCLUSIONS: These results demonstrate that the protective effect of hypothermia against functional injury caused by ischemia-reperfusion may decrease the free-radical burst at reperfusion.     

Cardiac performance during reperfusion improved by pretreatment with oxygen free-radical scavengers

We studied the effects of oxygen free radicals on cardiac performance during reperfusion of ischemic myocardium. The pig heart, isolated in situ, was subjected to 60 minutes of regional ischemia at normothermia by occlusion of the left anterior descending coronary artery followed by 60 minutes of hypothermic cardioplegic arrest and 60 minutes of normothermic reperfusion. The oxygen free-radical scavengers, superoxide dismutase and catalase, were administered before occlusion of the left anterior descending coronary artery in the experimental group. The generation of free radicals in the untreated group, estimated by the measurement of malondialdehyde in the perfusate, was significant during reperfusion and was associated with a corresponding increase in creatine kinase. Superoxide dismutase and catalase significantly slowed the appearance of malondialdehyde and the release of creatine kinase during reperfusion. Superoxide dismutase and catalase did not alter coronary flow and myocardial oxygen extraction or consumption during occlusion of the left anterior descending coronary artery; however, coronary flow and oxygen consumption were significantly higher (p less than 0.05) during reperfusion in hearts treated with antioxidants. Left ventricular developed pressure and its maximum first derivative were measured under isovolumic conditions. In the untreated group, left ventricular developed pressure and its maximum first derivative declined to 61.1% and 57.1% of baseline values, respectively, after 60 minutes' occlusion of the left anterior descending, and to 45% of baseline values after 15 minutes of reperfusion. The decline in left ventricular developed pressure and its maximum first derivative during reperfusion was significantly (p less than 0.05) inhibited by superoxide dismutase and catalase, but left ventricular end-diastolic pressure was not significantly altered. These results implicate oxygen-derived free radicals in the injury resulting from reperfusion of ischemic myocardium and suggest that oxygen free-radical scavengers effectively protect against such injury.