Altered load dependence of postischemic myocardium

Intermittent myocardial ischemia can produce areas of postischemic ("stunned") myocardium in the heart of the human with coronary artery disease. These areas are no longer ischemic, but have diminished contractile performance. Although the effects of loading conditions on systolic contraction of normal, ischemic, and failing myocardium have been investigated in great detail, the way in which load affects contraction of postischemic myocardium is not known. The aim of this study was to determine in anesthetized dogs how loading conditions affect the systolic function of a region of myocardium after 10 min of ischemia and 1 h of reperfusion. Sets of piezoelectric crystals were implanted in a test zone and in a remote zone of myocardium. Measurements of systolic wall thickening were made during nine combinations of left atrial pressure (3, 6, and 9 cmH2O) and mean arterial pressure (70, 90, and 110 mmHg). One set of measurements was made under baseline conditions, and a second set was made after 10 min of coronary occlusion and 1 h of reperfusion. Ischemia and reperfusion reduced wall thickening in the test zone 36 +/- 3% and diminished the response to increases in preload. In contrast, the response of the test zone to changes in afterload was unchanged. An interaction between the test zone (in which depressed contraction was observed) and the surrounding myocardium (in which enhanced function was observed) produced the appearance of a regional wall motion abnormality as afterload increased. These results emphasize that the load dependence of postischemic myocardium differs from that of normal myocardium and must be taken into account in clinical studies in which regional contraction is used to monitor the heart for ischemia.     

Intracellular sodium and calcium in the postischemic myocardium

Intracellular sodium and calcium were measured in 30 isolated perfused rat hearts exposed to normothermic ischemic intervals varying from 0 to 40 minutes followed by 35 minutes of reperfusion. Accumulation of these elements was correlated with alterations in postischemic isovolumic contractile function. There were increases in calcium of 207%, 390%, and 681% of the non-ischemic control following reperfusion after respective ischemic intervals of 30, 35, and 40 minutes. These corresponded to decrements in peak developed pressure of 23.8% after 30 minutes, 68.6% after 35 minutes, and no recovery of function after 40 minutes of ischemia. Thirty-five and 40 minutes of ischemia produced 138% and 170% increases in intracellular sodium, respectively. These data show that there is a graded accumulation of intracellular sodium and calcium that correlates with the duration of ischemia and the degree of functional impairment in the postischemic heart. Measurement of intracellular sodium and calcium may, therefore, serve as an adjunct to other biochemical and functional factors used to quantitate postischemic and postcardioplegic damage in the development of new myoprotective regimens.     

The influence of infused calcium on the postischemic myocardium

Despite evidence for calcium-induced damage in the postischemic myocardium, calcium remains a frequently used inotropic agent following cardiopulmonary bypass surgery with cardioplegic arrest. The purpose of this study was (1) to challenge the postischemic myocardium with incremental doses of ionized calcium, and (2) to relate postischemic calcium reperfusion concentration to final recovery of left ventricular contractile function. Rabbit hearts (N = 38) were perfused and equipped with a ventricular balloon to monitor developed pressure (DP) ±dp/dt, and left ventricular end diastolic pressure (LVEDP). Hearts underwent 40 min of global ischemia. Hearts were then assigned to one of four groups to receive a variable calcium concentration (0.6, 1.2, 2.5, 5.0 mM) for the initial 5 min of reperfusion followed by 55 min of reperfusion (Ca⁺² = 1.25 mM). No differences were found between groups for final recovery of DP ±dp/dt, or final LVEDP. It was concluded that: (1) within the physiologic range, variable calcium infusions during the first 5 min of postischemic reperfusion do not impair final recovery of LV contractile function, (2) irreversible partial recovery of left ventricular function appears due to mechanisms other than mitochondrial or myofibrillar calcium loading during reperfusion, and (3) infused calcium is a safe inotropic agent even in the postischemic myocardium.     

甲状腺激素T3增补于心脏停搏液中对心肌的保护作用

目的　探讨Ｔ３ 增补于停搏液中的心肌保护作用。方法　离体鼠心（ ｎ ＝ １６） 在改良的ＬａｎｇｅｎｄｏｒｆｆＮｅｅｌｙ 灌注模型上、３７ ℃下经历２０ 分钟预灌注、２０ 分钟停搏、３０ 分钟再灌注。结果　再灌注３０ 分钟时,左室功能指标（ＬＶＤＰｄｐ／ｄｔ）百分恢复率治疗组显著高于对照组（ Ｐ ＜０ ．０１）,心肌超氧化物歧化酶（ＳＯＤ） 治疗组显著高于对照组（ Ｐ＜ ０．０１）,过氧化脂质（ＬＰＯ） 治疗组显著低于对照组（ Ｐ ＜０．０５）;心肌酶（ＨＢＤＨ．ＬＤＨ）释放量再灌注期对应时点组间比较,治疗组显著低于对照组（ Ｐ＜ ０ ．０１） ;电镜观察心肌超微结构,治疗组显著优于对照组。结论　Ｔ３ 增补于心脏停搏液中可以显著地促进缺血后左室功能的恢复,显著减轻心肌缺血再灌注损伤,具有良好的心肌保护作用。     

Free radicals and cardioplegia. Free radical scavengers improve postischemic function of rat myocardium

Oxygen-derived free radicals, such as the superoxide (O2-) anion, hydrogen peroxide (H2O2) and the hydroxyl (OH.) radical, may be involved in exacerbating myocardial injury during reoxygenation of ischemic tissue. The naturally occurring antioxidant enzymes, superoxide dismutase (SOD) and catalase (CAT), prevent the formation of the cytotoxic OH. radical during physiological conditions but may not be able to cope with the free radical generation that follows ischemia and reperfusion. We have used the isolated perfused working rat heart model of cardiopulmonary bypass and ischemic arrest to assess whether exogenous addition of SOD (20 IU/ml) and CAT (100 IU/ml) during ischemia and/or reperfusion can improve postischemic recovery of function following normothermic or hypothermic global ischemic arrest induced by St. Thomas' Hospital cardioplegic solution. Under conditions of normothermia, the addition of SOD alone or CAT alone to both the cardioplegic solution (CS) and the reperfusion solution (RS) had no effect on postischemic recovery (after 20-min working reperfusion) of aortic flow (27.9 +/- 2.7% and 16.1 +/- 6.3%, respectively) when compared with the nontreated control value of 28.1 +/- 3.7%. However, recovery was improved when SOD plus CAT were added to the CS alone (39.3 +/- 8.7%) and was significantly improved when they were added either to both the CS and the RS (48.4 +/- 6.0%; P = less than 0.02) or to the RS alone (51.3 +/- 3.7%; P = less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Adenosine preconditioning reduces both pre and postischemic arrhythmias in human myocardium

INTRODUCTION: Consistently, clinical series record supraventricular tachyarrhythmias in approximately 30% of patients following coronary artery bypass surgery (CABG). Ischemic preconditioning and adenosine preconditioning (Ado-PC) decrease postischemia/reperfusion (I/R) myocardial stunning, infarct size, and pharmacologically induced arrhythmias in all species including man. We hypothesized that adenosine preconditioning would decrease spontaneous pre- and postischemic atrial arrhythmias in human myocardium. The purposes of this study were to determine the effect of in vivo and in vitro Ado-PC on atrial arrhythmias. METHODS: Human atrial trabeculae were harvested from CABG patients, placed in organ baths, and paced (1 Hz). Developed force (DF) was recorded during simulated I/R (30/45 min). Prior to I/R, trabeculae were treated with Ado (125 microM) for 5 min (in vitro), or patients were treated with Ado (12 mg iv) 5 min (in vivo) prior to harvest of trabeculae. Contraction frequency >4 Hz (defined as atrial tachyarrhythmias) was recorded in all groups pre- and postischemia. RESULTS: Control trabeculae exhibited increased tachyarrhythmias pre- and postischemia. In vivo and in vitro Ado-PC suppressed both pre- and postischemic arrhythmias. CONCLUSIONS: Adenosine preconditioning suppresses the frequency of pre- and postischemic tachyarrhythmias against an ischemia/reperfusion insult in human myocardium. This antiarrhythmic effect occurs with both in vitro and in vivo administration of adenosine. Preconditioning with adenosine prior to elective ischemia/reperfusion is a promising strategy of reducing spontaneous atrial arrhythmias in patients undergoing myocardial revascularization.     

Effect of halothane and isoflurane on postischemic "stunned" myocardium in the dog

Short periods of coronary artery occlusion are known to produce prolonged periods of ventricular dysfunction. The effects of halothane or isoflurane on contractility and metabolism in postischemic "stunned" myocardium were studied in an open-chest canine model in which the left anterior descending artery (LAD) was occluded for 15 min and then reperfused. Regional function in the LAD and circumflex artery (CIRC) areas were measured with sonomicrometry, and metabolic data were determined from simultaneous arterial and venous measurements of oxygen and lactate. Halothane and isoflurane produced equivalent decreases in systolic shortening in both normal (CIRC) and stunned (LAD) areas of the heart. Furthermore, the amount of depression was similar with either halothane or isoflurane. Halothane 0.75 MAC significantly decreased systolic shortening in both the LAD region (from 38.8 +/- 25.9% to 11.0 +/- 21.8%) and in the CIRC region (from 116.7 +/- 24.7% to 87.5 +/- 23.3%). At equivalent MAC concentrations of isoflurane, the values were 42.5 +/- 45.7 to -7.0 +/- 49.9% in the LAD region and 91.5 +/- 11.9% to 66.9 +/- 23.9% in the CIRC area. At 1.5-MAC halothane, systolic shortening in the LAD region decreased from 47.9 +/- 47.2% to -0.6 +/- 20.3% and in the CIRC area from 114.6 +/- 16.8% to 76.0 +/- 18.7%. Isoflurane at 1.5 MAC produced significant decreases, from 23.4 +/- 54.5% to -15.6 +/- 27.1% in the LAD region and from 94.4 +/- 33.2% to 61.3 +/- 28.2 in the CIRC area.(ABSTRACT TRUNCATED AT 250 WORDS)     

异丙酚和硫喷妥钠对离体缺血后心脏左室功能的影响

目的 在离体灌注兔心比较了异丙酚和硫喷妥铵对缺血后心脏左室收缩、舒张功能作用的差异。方法 分别在非缺血心脏和缺血２０分再灌注１５分心脏给予异丙酚（２０μｍｏｌ／Ｌ、５０μｍｏｌ／Ｌ）或硫喷妥钠（２００μｍｏｌ／Ｌ、５００μｍｏｌ／Ｌ）,观察左室收缩功能（ＬＶ＋ｄｐ／ｄｔｍａｘ、ＬＶＤＰ）、舒张功能（ＬＶ－ｄｐ／ｄｔ ｍａｘ、ＬＶＤＥＰ）及灌出液出ＬＤＨ、ＣＰＫ活性的变化。结果 ２０μｍｏｌ／Ｌ异丙     

Continuous Hydralazine Infusion for Afterload Reduction

Impedance reduction with a continuous infusion of hydralazine was evaluated in 20 patients following cardiopulmonary bypass. Patients were selected for therapy when the cardiac index (CI) was less than 2.2 L/m²/min, when the systemic vascular resistance index (SVRI) was greater than 2,500 dyne sec cm^?5, or when both conditions were present. No other vasoactive or cardiotonic drugs were used intraoperatively or postoperatively. Responses were measured at 15, 30, 60, 120, 180, and 240 minutes and compared with control measurements. Significant responses appeared by 15 minutes in the mean arterial pressure, CI, and SVRI, which were maximal by 2 hours. At 4 hours, the SVRI was 1,520 ± 276 dyne sec cm^?5 (control, 3,235 ± 222) and pulmonary vascular resistance index, 365 ± 102 dyne sec cm^?5 (control, 592 ± 71). The CI was 3.20 ± 0.29 L/m²/min (control, 1.96 ± 0.16) and mean arterial pressure, 75 ± 2.3 mm Hg (control, 92 ± 2.4). Left atrial, pulmonary artery diastolic, and right atrial pressures increased from control but not significantly: 11.4 ± 0.8 to 13.3 ± 1.2 mm Hg, 13.6 ± 1.6 to 17.2 ± 1.5 mm Hg, and 6 ± 1.6 to 9.4 ± 1.7 mm Hg, respectively. In 16 patients, hydralazine was continued for 24 hours and in 11, the transition to oral therapy was made. Hydralazine by infusion effectively reduces after-load, avoids the fluctuations of bolus therapy, and allows the transition to oral therapy if needed.     

Pharmacologic modulation of experimental postischemic hepatic function.

The present study evaluated and compared the effects of SRI 63-441, a potent platelet activating factor antagonist, superoxide dismutase (SOD), an oxygen free radical scavenger, and ibuprofen, a cyclooxygenase inhibitor on hepatic function after 90 minutes of warm ischemia. After warm ischemia, livers were harvested and underwent 90 minutes of warm, oxygenated, sanguinous perfusion on an isolated liver perfusion apparatus. Pretreatment of donor animals with 20 mg/kg intravenous (I.V.) SRI 63-441 5 minutes before induction of total hepatic ischemia resulted in significantly increased bile production, a significant decrease in transaminase release, and a higher tissue adenosine triphosphate (ATP) content when compared with ischemic nontreated controls. SOD resulted in improved bile production and decreased transaminase liberation only when present in the perfusate at the time of in vitro reperfusion. Ibuprofen did not improve postischemic hepatic function in this model. Electron microscopy revealed patchy hepatocellular vacuolization with an intact sinusoidal endothelium in all ischemic livers. However, the degree of damage was less severe in the livers from those rats pretreated with 20 mg/kg SRI 63-441. This study demonstrates that SRI 63-441 pretreatment significantly reduces hepatic warm ischemic injury, and in the present model, appears superior to two other agents that have been advanced in the treatment of ischemic injury. The use of such agents singly or in combinations have important implications as regards gaining a better understanding of the basic mechanisms in organ ischemia, and moreover, for therapeutic applications in organ ischemia and preservation.     

Free radical-mediated postischemic injury in renal transplantation.

Oxygen free radicals are generated during reperfusion of ischemic organs. Studies employing several species of laboratory animal (rat, dog, pig, rabbit, mouse) have documented protective effects of a variety of free-radical scavengers and antioxidants when administered before or immediately preceding reperfusion of ischemic kidneys. These protective agents include superoxide dismutase, dimethylthiorea, dimethyl sulfoxide, alpha-tocopherol, glutathione, the iron chelator deferoxamine, probucol, allopurinol and oxypurinol, and the spin-trapping agent PBN. Furthermore, deficiency of antioxidants (selenium, alpha-tocopherol, or catalase) exacerbates postischemic renal injury. These findings have been applied to renal transplantation in an attempt to decrease the incidence of posttransplantation acute renal failure. This is important because acute renal failure results in morbidity, increases hospital stay and the cost of transplantation, and complicates the use of cyclosporine. In porcine and in canine kidney transplantation, superoxide dismutase and allopurinol have provided renal protection. Transplantation is complicated because there may be prolonged hypoperfusion before harvesting plus a brief period of total ischemia during harvesting, followed by a prolonged period of cold ischemia and/or reperfusion, then followed by another brief period of ischemia and reperfusion during transplantation. Injury may occur at each of these phases by different mechanisms.     

Controlled vasoregulation of postischemic liver microcirculation--a therapeutic approach.

One of the changes produced by ischemia and reperfusion is endothelin (ET)-mediated constriction of the hepatic vascular bed. This leads to microcirculatory disturbances and reduced blood flow, thereby causing local hypoxia and liver damage. Our aim was to induce stepwise changes of microvascular vessel diameters so as to define the best protective vessel width that could be produced by drug therapy and thereby to minimize ischemia/reperfusion injury. The mixed ET receptor antagonist bosentan was used in different dosages in a rat liver ischemia/reperfusion model with splenocaval shunt. In vivo microscopy was performed 30-90 min after reperfusion and local hepatic tissue pO2 was determined, together with aspartate aminotransferase/alanine aminotransferase (AST/ALT). After ischemia, sinusoidal diameters were significantly reduced to 76 +/- 7% of those in the control group. After the administration of bosentan in dosages of 0.1, 1, and 10 mg/kg body weight iv and 10 mg/kg body weight intraportally we found diameters of 83 +/- 4, 98 +/- 2, 109 +/- 6, and 137 +/- 19%, respectively. Perfusion rate and leukocyte-endothelium interactions showed dependence on sinusoidal diameters, with the best results in the group where preischemic sinusoidal vessel width had been maintained. Local tissue pO2 and transaminase levels also showed that oxygen supply was sufficient and that hepatocellular injury was most minimized in this group. Graduated blocking of ET receptors allows stepwise regulation of sinusoidal and postsinusoidal venular vessel width and offers a treatment strategy for pathophysiological situations that are associated with ET-induced vasoconstriction. The results suggest that maintenance of preischemic microvascular diameter is the best therapeutic approach.     

The role of magnesium in postischemic cardiac dysfunction.

BACKGROUND. The biochemical basis for postischemic myocardial stunning is not fully elucidated. Magnesium is an important regulator of cellular energetic processes and excitation-contraction coupling. We hypothesized that the decrease in function in the postischemic period may be the result of an alteration in magnesium regulation. METHODS. In a Langendorf perfused rabbit heart model, we used 31P nuclear magnetic resonance spectroscopy to noninvasively determine intracellular Mg2+ and high-energy phosphate levels in the preischemic period and after a 30-minute period of normothermic ischemia. We measured adenosine triphosphate (ATP), phosphocreatine, and the phosphocreatine/inorganic phosphate ratio and calculated the free energy of ATP hydrolysis (delta GATP). On reperfusion, hearts were divided into three groups (n = 7 per group)--those receiving unmodified Krebs-Henseleit (control), 192 ng/ml dobutamine, or 5 mmol/L pyruvate. RESULTS. Function (expressed as the rate-pressure product) was approximately 77% of preischemic values in the control group, whereas in both dobutamine and pyruvate groups it returned to preischemic levels. ATP was decreased similarly in all groups in the postischemic period. Phosphocreatine/inorganic phosphate ratio and delta GATP were higher in the pyruvate group compared with the other groups. Intracellular Mg2+ was elevated significantly in the unmodified control postischemic group compared with preischemic, postischemic dobutamine, and pyruvate groups (1.0 +/- 0.12 vs 0.80 +/- 0.08, 0.64 +/- 0.08, and 0.70 +/- 0.05 mmol/L, respectively; p less than 0.05). CONCLUSIONS. We conclude that (1) postischemic "stunned" hearts have elevated Mg2+ levels in association with impaired contractile function, (2) inotropic agents improve contractile function in association with a decline in Mg2+ to preischemic levels despite differing effects on intracellular energetics, and (3) Mg2+ may play an important regulatory role in the heart after ischemia.     

Enhancement of low coronary reflow improves postischemic myocardial function.

The effect of reperfusion coronary vasodilatation on postischemic myocardial mechanical function has been investigated in the isolated working rat heart. After a working period to assess control function, all the hearts were subjected to a single infusion (10 ml) of St. Thomas' Hospital cardioplegic solution No. 1 at 4 degrees C and were kept immersed in the same solution for 4 hours at 4 degrees C. Then hearts (six in each group) were initially reperfused at 37 degrees C for 10 minutes, either with ordinary reperfusate (Krebs-Henseleit bicarbonate buffer) or with reperfusate containing additional coronary dilator. After this period, all hearts were subjected to a further 5 minutes of ordinary reperfusate before being put back into the working mode to assess functional recovery. Mean reperfusion coronary flows and the steady coronary flow measured after 10 minutes of reperfusion in ml/min +/- SEM were--Krebs (control): 17.4 +/- 0.39 and 13.4 +/- 0.40; adenosine (3.75 mumol/L): 19.9 +/- 0.6 and 16.7 +/- 0.8; papaverine (0.05 mmol/L): 21.8 +/- 2.3 and 17.3 +/- 1.8; dipyridamole (2 mmol/L): 20.7 +/- 1.7 and 17.9 +/- 1.0; nitroglycerin (15 mg/L): 20.5 +/- 0.45 and 19.9 +/- 1.4; diltiazem (0.05 mmol/L): 19.6 +/- 2.98 and 17.7 +/- 1.8; calcitonin gene-related peptide (0.03 mmol/L): 20.8 +/- 0.69 and 18.0 +/- 1.3; 5-hydroxytryptamine (0.01 mmol/L): 19.2 +/- 0.53 and 16.9 +/- 0.80. Mean postischemic recovery of cardiac output, peak aortic pressure, and differentiation of pressure were expressed as percent of preischemic control +/- SEM were--Krebs: 54.1 +/- 2.8, 69.1 +/- 2.8, and 53.9 +/- 3.0; adenosine: 78.0 +/- 5.6, 89.5 +/- 2.9, and 69.1 +/- 1.9; papaverine: 81.8 +/- 3.9, 91.8 +/- 3.1, and 71.0 +/- 4.1; dipyrdamole: 67.3 +/- 3.3, 84.3 +/- 2.3, and 75.0 +/- 2.7; nitroglycerin: 83.1 +/- 4.8, 79.7 +/- 2.7, and 69.0 +/- 0.5; diltiazem: 76.5 +/- 3.7, 85.9 +/- 2.9, and 73.3 +/- 1.7; calcitonin gene-related peptide: 79.5 +/- 3.6, 90.0 +/- 4.9, and 75.4 +/- 3.9; 5-hydroxytryptamine: 71.6 +/- 3.2, 85.5 +/- 3.5, and 67.9 +/- 4.8. There was a positive correlation between mean reperfusion coronary flow, steady coronary flow, and postischemic recovery of cardiac output, peak aortic pressure, and differentiation of pressure. Mean reperfusion coronary flow, steady coronary flow, and postischemic recovery of cardiac output, peak aortic pressure, and differentiation of pressure were significantly greater in groups reperfused with vasodilators (p < 0.05) compared with control values.(ABSTRACT TRUNCATED AT 400 WORDS)     

Acadesine (AICA-riboside) improves postischemic cardiac recovery.

To test if acadesine (5-aminoimidazole-4-carboxamide riboside), a purine precursor, has cardioprotective effects, 16 dogs were placed on total cardiopulmonary bypass and subjected to global myocardial ischemia. Hemodynamic recovery was compared between a control (n = 8) group receiving standard cardioplegia and an acadesine (n = 8) group pretreated with intravenous acadesine (2.5 mg.kg-1.min-1 for 5 minutes, then 0.5 mg.kg-1.min-1) before ischemia, during ischemia, and until 10 minutes after removal of the aortic cross-clamp. Additionally, in the acadesine group the cardioplegia also contained 20 mumol/L acadesine. While the dogs were on cardiopulmonary bypass, global warm myocardial ischemia was induced by aortic cross-clamping for 5 minutes under normothermic conditions to simulate an angioplasty accident. Five minutes after aortic cross-clamping, hypothermic cardioplegia (30 mL/kg) was administered. The left anterior descending coronary artery was occluded before the first infusion of cardioplegia to simulate poor cardioplegia delivery that can occur during an emergency coronary artery bypass procedure after an angioplasty accident. The left anterior descending artery occlusion was released, and additional cardioplegia (15 mL/kg) infusions were made every 30 minutes thereafter during 120 minutes of cardioplegic ischemia. Thirty minutes after reperfusion, all animals in both groups were weaned from bypass and recovery data were obtained to compare with baseline preischemic values. There were no significant differences in heart rate, left atrial pressure, or systemic vascular resistance between groups after weaning from bypass. Peak developed pressure recovered to 79% +/- 19% (mean +/- standard deviation) of baseline in the acadesine group compared with 56% +/- 22% in the control group (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute severe postischemic myocardial depression reversed by triiodothyronine.

The purpose of this study was to determine the effects of triiodothyronine (T3) on postischemic left ventricular performance and high-energy phosphate content in a severe injury model. Isolated working rat hearts (n = 63) received 20 mL of hyperkalemic NIH No. 1 cardioplegia and were subjected to 20 minutes of ischemia at 37 degrees C. Treated hearts were reperfused with T3-supplemented modified Krebs-Henseleit buffer. Control hearts did not receive T3 supplementation. All treated hearts (n = 44) performed work after ischemia, whereas 26% (5/19) of the control hearts were not able to perform any left ventricular work after ischemia. Comparisons with preischemic values demonstrated significant progressive hemodynamic recovery with increasing concentrations of T3 (0, 0.06, 0.15, and 0.60 ng/mL) with concomitant recovery of left ventricular stroke work index (63%, 72%, 89% [p less than 0.05], and 99% [p less than 0.05], respectively). There were corresponding increases in recovery of aortic flow, systolic pressure, cardiac index, and stroke volume index (p less than 0.05). There were no significant changes in coronary sinus flow or heart rate in any group compared with preischemic values. Comparisons of postischemic high-energy phosphate concentrations also demonstrated no change between treated and untreated groups (p greater than 0.05). We conclude that administration of T3 in a severe left ventricular injury model significantly augments rapid ventricular recovery with no change in postischemic high-energy phosphate concentrations.     

Osmotic diuretics and hemodilution in postischemic renal failure.

In the acute phase of ischemic renal failure, the severe depression of the glomerular filtration rate (GFR) is due to obstruction of the tubules by cells and cell debris rejected from the proximal tubules, a blockade which can be prevented at least partly, by treatment with osmotic diuretics. The isosthenuria, the second typical sign in ischemic acute renal failure, probably derives from the medullary ischemia that results from an intracapillary trapping of red cells. This, in turn, is suggested to be caused by oxygen-derived free radicals, which via increasing the capillary macromolecular permeability result in a massive extravasation of plasma and hence in hemoconcentration. As expected from this hypothesis, scavengers may ameliorate both the trapping and the consequent medullary ischemia. Unfortunately, however, a therapy using both osmotic diuretics and scavengers fails to improve the long-term outcome. Hemodilution would seem more promising, since it will both prevent the medullary ischemia seen in the acute phase and substantially improve the long-term outcome. At a hematocrit of 0.30, rat kidneys exposed to 45-min ischemia will show a GFR 1 month after the insult of more than 50% of the normal GFR as against 15% in untreated animals.     

Amino acid substrate preloading and postischemic myocardial recovery.

During induced myocardial ischemia for cardiac surgery, myocardial stunning occurs and aerobic metabolism of glucose, fatty acids, and lactate is inhibited as anaerobic pathways predominate. Even following reperfusion, stunned myocardium uses oxygen and substrate inefficiently leading to poor functional recovery as less mechanical work is developed per oxygen utilized. Amino acids potentially can act as cardiac metabolic substrates during and after ischemia, utilizing the transamination of amino acids by the malate-aspartate shuttle to form high energy phosphates via the tricarboxylic acid cycle. We investigated if "preloading" hearts with a physiologic spectrum of amino acids could increase postischemic myocardial recovery. Isolated perfused rabbit hearts were subjected to 120 min of 34 degrees C cardioplegic ischemia. Hearts received cardioplegia alone as controls or were "preloaded" with a 0.05% amino acid perfusion for 30 min prior to cardioplegic ischemia. Following reperfusion, analysis of functional recovery revealed that contractility and cardiac efficiency were improved with amino acids substrate preloading. The mechanism of this may be due to uptake of amino acids prior to ischemia, which are later utilized for internal reparative work during ischemia and external contractile work after ischemia.     

Protective effect on postischemic renal edema by anticoagulation.

The effect of anticoagulation upon renal edema and plasma protein accumulation in acute ischemic renal damage was studied. Rats were subjected to unilateral renal artery occlusion for 60 min and 15 min of reflow. The kidney weight and the content of 125-I-fibrinogen and 131-I-albumin, injected 24 h priorly, were measured and the renal morphology studied. Groups of rats were pretreated with a heparin analogue with low anticoagulant effect, standard heparin, warfarin or saline. A marked increase in fibrinogen and albumin content and of the weight of the damaged kidney was noted. Heparin and warfarin both significantly attenuated these changes, whereas the heparin analogue did not. Microscopically, fibrin-positive material was seen in the peritubular capillaries, vasa recta and in the tubules of rats pretreated with saline or the heparin analogue, but not in rats pretreated with heparin or warfarin. The results support the hypothesis that fibrin deposition in the kidney is of importance for the development of renal edema in this model of ischemic renal damage.