Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes.

AIMS/HYPOTHESIS: Glucagon-like peptide-1 (GLP-1) has various extra-pancreatic actions, in addition to its enhancement of insulin secretion from pancreatic beta cells. The GLP-1 receptor is produced in kidney tissue. However, the direct effect of GLP-1 on diabetic nephropathy remains unclear. Here we demonstrate that a GLP-1 receptor agonist, exendin-4, exerts renoprotective effects through its anti-inflammatory action via the GLP-1 receptor without lowering blood glucose. METHODS: We administered exendin-4 at 10 µg/kg body weight daily for 8 weeks to a streptozotocin-induced rat model of type 1 diabetes and evaluated their urinary albumin excretion, metabolic data, histology and morphometry. We also examined the direct effects of exendin-4 on glomerular endothelial cells and macrophages in vitro. RESULTS: Exendin-4 ameliorated albuminuria, glomerular hyperfiltration, glomerular hypertrophy and mesangial matrix expansion in the diabetic rats without changing blood pressure or body weight. Exendin-4 also prevented macrophage infiltration, and decreased protein levels of intercellular adhesion molecule-1 (ICAM-1) and type IV collagen, as well as decreasing oxidative stress and nuclear factor-κB activation in kidney tissue. In addition, we found that the GLP-1 receptor was produced on monocytes/macrophages and glomerular endothelial cells. We demonstrated that in vitro exendin-4 acted directly on the GLP-1 receptor, and attenuated release of pro-inflammatory cytokines from macrophages and ICAM-1 production on glomerular endothelial cells. CONCLUSIONS/INTERPRETATION: These results indicate that GLP-1 receptor agonists may prevent disease progression in the early stage of diabetic nephropathy through direct effects on the GLP-1 receptor in kidney tissue.

Immediate functional benefits after controlled reperfusion during surgical revascularization for acute coronary occlusion.

This study tests the hypothesis that contractile dysfunction that often develops after acute coronary occlusion despite emergency revascularization can be avoided by careful control of the composition of the initial reperfusate and the conditions of the reperfusion. Between January 1987 and May 1989, 31 consecutive patients with acute coronary occlusion (90% resulting from percutaneous transluminal coronary angioplasty failures) were reperfused during emergency myocardial revascularization according to one of two different protocols. In 23 patients the reperfusate was normal blood given at systemic pressure ("uncontrolled reperfusion"); in eight patients the ischemic segment was reperfused during the first 20 minutes with a regional blood cardioplegic solution (substrate-enriched, hyperosmotic, hypocalcemic, alkalotic, diltiazem-containing) at 37 degrees C at a pressure of 50 mm Hg. Thereafter total bypass was prolonged for an additional 30 minutes before extracorporeal circulation was discontinued ("controlled reperfusion"). Assessment of regional contractility (echocardiography, radionuclide ventriculography), electrocardiographic evidence of myocardial infarction, release of creatine kinase and isoenzyme of creatine kinase, and hospital mortality was performed. Regional contractility was quantified with a scoring system from 0 (normokinesis) to 4 (dyskinesis). Data are expressed as mean +/- standard error of the mean. Both groups were well matched for age, sex, and the distribution of the occluded artery. In the controlled-reperfusion group there was a greater prevalence of previous infarctions (63% versus 43%), additional significant stenosis (1.3 +/- 0.2 versus 0.8 +/- 0.2), and cardiogenic shock (38% versus 17%) compared with the uncontrolled-reperfusion group. Furthermore, the interval between coronary occlusion and reperfusion was significantly longer in the controlled-reperfusion group (4.0 +/- 0.5 versus 2.3 +/- 0.3 hr; p less than 0.05). Regional contractility returned to normal in all patients treated by controlled reperfusion (wall motion score = 0.8 +/- 0.3, normokinesis = 0, slight hypokinesis = 1). In contrast, regional contractility remained severely depressed after uncontrolled reperfusion with normal blood (score 2.5 +/- 0.2; p less than 0.05), with only four of 23 patients with a score less than 2 (2 = severe hypokinesis). Postoperatively enzymes and electrocardiographic changes were similar in both groups. One patient died of mitral insufficiency in the controlled-reperfusion group, despite complete recovery of wall motion in the angioplasty-related artery. Conversely, the four of 23 deaths after uncontrolled reperfusion occurred in patients who sustained infarct in the area of the coronary occlusion (mortality 13% versus 17%). In conclusion, these preliminary clinical results indicate that immediate recovery of segmental contractility can be achieved after acute coronary occlusion if the initial reperfusion is controlled.(ABSTRACT TRUNCATED AT 400 WORDS)

Normoxic cardiopulmonary bypass reduces oxidative myocardial damage and nitric oxide during cardiac operations in the adult.

OBJECTIVE: Hyperoxic cardiopulmonary bypass is widely used during cardiac operations in the adult. This management may cause oxygenation injury induced by oxygen-derived free radicals and nitric oxide. Oxidative damage may be significantly limited by maintaining a more physiologic oxygen tension strategy (normoxic cardiopulmonary bypass). METHODS: During elective coronary artery bypass grafting, 40 consecutive patients underwent either hyperoxic (oxygen tension = 400 mm Hg) or normoxic (oxygen tension = 140 mm Hg) cardiopulmonary bypass. At the beginning and the end of bypass this study assessed polymorphonuclear leukocyte elastase, nitrate, creatine kinase, and lactic dehydrogenase, antioxidant levels, and malondialdehyde in coronary sinus blood. Cardiac index was measured before and after cardiopulmonary bypass. RESULTS: There was no difference between groups with regard to age, sex, severity of disease, ejection fraction, number of grafts, duration of cardiopulmonary bypass, or ischemic time. Hyperoxic bypass resulted in higher levels of polymorphonuclear leukocyte elastase (377 +/- 34 vs 171 +/- 32 ng/ml, p = 0.0001), creatine kinase 672 +/- 130 vs 293 +/- 21 U/L, p = 0.002), lactic dehydrogenase (553 +/- 48 vs 301 +/- 12 U/L, p = 0.003), antioxidants (1.97 +/- 0.10 vs 1.41 +/- 0.11 mmol/L, p = 0.01), malondialdehyde (1.36 +/- 0.1 micromol/L,p = 0.005), and nitrate (19.3 +/- 2.9 vs 10.1 +/- 2.1 micromol/L, p = 0.002), as well as reduction in lung vital capacity (66% +/- 2% vs 81% +/- 1%,p = 0.01) and forced 1-second expiratory volume (63% +/- 10% vs 93% +/- 4%, p = 0.005) compared with normoxic management. Cardiac index after cardiopulmonary bypass at low filling pressure was similar between groups (3.1 +/- 0.2 vs 3.3 +/- 0.3 L/min per square meter). [Data are mean +/- standard error (analysis of variance), with p values compared with an oxygen tension of 400 mm Hg.] CONCLUSIONS: Hyperoxic cardiopulmonary bypass during cardiac operations in adults results in oxidative myocardial damage related to oxygen-derived free radicals and nitric oxide. These adverse effects can be markedly limited by reduced oxygen tension management. The concept of normoxic cardiopulmonary bypass may be applied to surgical advantage during cardiac operations.

Role of pericardial constraint for right ventricular function in humans.

STUDY OBJECTIVE: To analyze the extent of pericardial constraint on right ventricular function in humans. PATIENTS AND METHODS: Twenty patients, 59 +/- 2 (mean +/- SEM) years old, undergoing coronary bypass surgery. Right ventricular volumes and pressures were evaluated using a rapid response Swan-Ganz thermodilution catheter. INTERVENTIONS: Parameters were determined before and after pericardiotomy, both before and during increased right ventricular systolic pressure by partial compression of the pulmonary artery (before pulmonary compression: 25 +/- 1 mm Hg; during: 39 +/- 1 mm Hg). RESULTS: Pericardiotomy alone did not significantly affect right ventricular end-diastolic volume (before: 79 +/- 4 mL m-2; after: 78 +/- 3 mL m-2), right ventricular ejection fraction (before: 48 +/- 1%; after: 48 +/- 2%), and right atrial pressure (before: 4.3 +/- 0.8 mm Hg; after: 4.3 +/- 0.7 mm Hg). Before pericardiotomy, the increase in right ventricular afterload significantly increased right atrial pressure (to 5.5 +/- 0.7 mm Hg, p < 0.05) and reduced right ventricular ejection fraction (to 43 +/- 2%, p < 0.01). Right ventricular end-diastolic volume remained unchanged. After pericardiotomy, the increase in right ventricular afterload significantly increased right ventricular end-diastolic volume (to 85 +/- 3 mL m-2, p < 0.01) and also reduced right ventricular ejection fraction (to 42 +/- 2%, p < 0.01), while right atrial pressure was not significantly changed. During increased right ventricular afterload, the right ventricular diastolic pressure-volume relation was shifted rightward. CONCLUSIONS: At normal levels of right ventricular diastolic filling, the pericardium does not exert constraining effects on right ventricular function. However, with increasing levels of right ventricular preload, pericardial constraint significantly influences right ventricular function in humans.

Controlled limb reperfusion in patients having cardiac operations.

HYPOTHESIS: Severe limb ischemia in patients having cardiac operations may occur after intraaortic balloon pump insertion, prolonged femoral vessel cannulation, percutaneous cardiopulmonary bypass, dissecting aneurysms, or emboli. Normal blood reperfusion can cause a postischemic syndrome that increases morbidity and mortality. This clinical study is based on an experimental infrastructure patterned after controlled cardiac reperfusion. (1) It tests the hypothesis that controlled limb reperfusion (i.e., modifying the composition of the initial reperfusate and the conditions of reperfusion) reduces the local and systemic complications seen after normal blood reperfusion. (2) It reports initial clinical application of this strategy in three cardiac surgery centers. METHODS: Controlled limb reperfusion was applied to 19 patients with signs of severe prolonged unilateral or bilateral ischemia (including paralysis, anesthesia, and muscle contracture); six patients (32%) were in cardiogenic shock. The mean ischemic duration was 26 +/- 6 hours. The reperfusion method includes a 30-minute infusion into the distal vessels of a normothermic reperfusate solution mixed with the patient's arterial blood (obtained proximal to the obstruction) in a 6:1 blood/reperfusate ratio. Data are mean +/- standard error of the mean. RESULTS: Sixteen patients (84%) survived with salvaged and functional limbs at the time of discharge. No renal, cardiac, pulmonary, cerebral, or hemodynamic complications developed in the survivors. The three deaths occurred in patients undergoing controlled limb reperfusion while in profound postoperative cardiogenic shock; neither postischemic edema nor contracture developed in any of them. CONCLUSIONS: These findings show that controlled limb reperfusion can be applied readily with standard equipment that is used for cardiac surgery and may salvage limbs while reducing postreperfusion morbidity and mortality.

Changing patterns of patients undergoing emergency surgical revascularization for acute coronary occlusion. Importance of myocardial protection techniques.

Between 1977 and 1992 a total of 163 consecutive patients underwent emergency coronary artery bypass grafting after acute coronary occlusion (94% after failed angioplasty). Patients were divided into four groups according to the method used for myocardial protection. The crystalloid cardioplegia group included 30 patients operated on from 1977 to 1980; the hypothermic fibrillation group included 60 patients (1980 to 1986); the blood cardioplegia group included 36 patients (1986 to 1989); and the blood cardioplegia with controlled reperfusion group included 37 patients (1989 to 1992). Preoperative data, ischemic time interval, collateral blood flow, intraoperative data, regional wall motion, global ejection fraction, myocardial infarct-specific electrocardiographic changes, enzyme release, rhythm disturbances, mortality, prevalence of intraaortic balloon pumping, and inotropic support were assessed in this retrospective study. Our data indicate that the current spectrum of patients undergoing emergency coronary artery bypass grafting after acute coronary occlusion are at a significantly higher risk compared with those 15 years ago, that is, increase in age (53 +/- 1 versus 59 +/- 2 years; p < 0.05), three-vessel disease (38% versus 3%; p = 0.004), acute occlusion of the left main coronary artery (11% versus 0%; p = 0.02), preoperative cardiogenic shock (35% versus 3%; p = 0.007), prevalence of acute two-vessel occlusion (22% versus 3%; p = 0.05), prevalence of previous infarction (59% versus 23%; p = 0.04), and duration of ischemia (3.0 +/- 0.2 versus 4.1 +/- 0.3 hours; p < 0.05). Despite the increase in patients with severely compromised ventricular function during recent years, the overall hospital mortality decreased to 5% (2/37) when maximal protection of the ischemic and remote myocardium was performed (preoperative intraaortic balloon pump, combined antegrade/retrograde substrate-enriched blood cardioplegia, warm induction, controlled reperfusion, prolonged vented bypass). Single-vessel disease was always associated with a low mortality, whereas mortality could be reduced with controlled blood cardioplegia in patients with multivessel disease (6%) and cardiogenic shock (15%). The immediate return of regional contractility in the previously ischemic area after controlled reperfusion might serve as an explanation for these favorable results. After unmodified blood reperfusion, normokinesis or slight hypokinesis occurs in only 34% to 46% in the early postoperative period (1 to 4 weeks) in comparison with 86% after controlled blood cardioplegia reperfusion (p < 0.05). We conclude that there is a significant increase in risk factors in patients undergoing emergency coronary artery bypass grafting and that improved methods of intraoperative myocardial protection are needed for these compromised patients.

Successful orthotopic pig heart transplantation from non-heart-beating donors.

BACKGROUND: With the aim to expand the severely limited donor pool by use of non-heart-beating donors we developed a technique for successful transplantation of hearts after 30 minutes of normothermic ischemia without donor pretreatment. METHODS: In control groups hearts were transplanted in a conventional fashion using crystalloid cardioplegia (Group I, n = 6) or BCP (Group II, n = 8) for induction of cardiac arrest. In the ischemic groups hearts were harvested after 30 minutes of normothermic ischemia, perfused with blood cardioplegia (BCP) (Group III, n = 9) or BCP containing the Na(+)-H(+)-exchange inhibitor HOE 642 (Group IV, n = 8) and transplanted orthotopically. RESULTS: All animals could be weaned from cardiopulmonary bypass. Low dose inotropic support was necessary in the ischemic groups only. Recovery of the maximal left ventricular stroke work index (LVSWImax) in Groups I vs II was 62.6+/-19.6% vs 73.3+/-23.3% (NS), maximal right ventricular stroke work index (RVSWImax) averaged 61.1+/-18.8 vs 87.8+/-31.7% (NS) as compared to the preoperative level. In the ischemic groups (III vs IV) LVSWImax was 27.3+/-11.7 vs 59.5+/-32.4% (p = 0.038), RVSWImax was 27.4+/-20.9 vs 64.2+/-46.6% (NS). CONCLUSIONS: The results indicate that (a) successful pig heart transplantation after 30 minutes of normothermic ischemia is possible without donor pretreatment, and (b) that HOE 642 improves posttransplant LVSWImax significantly.

Effects of chronic sultopride treatment on endocrine systems in psychotic women.

The effects of chronic sultopride treatment on endocrine systems were studied using five schizophrenic women. Sultopride, an antipsychotic drug, was administered orally three times daily for 5 weeks in a daily dose of 300-600 mg. The serum prolactin levels increased significantly after 1 day of treatment, reaching a maximum at 1 week and remaining elevated during treatment. The serum GH levels declined temporarily after 1 week of treatment and then returned to normal values after 3-5 weeks of treatment. Sultopride had no significant effects on LH, FSH, TSH, insulin, estradiol-17 beta and cortisol basal levels. Serum sultopride levels measured by radioimmunoassay remained steady during treatment. These results showed that sultopride stimulates prolactin secretion in schizophrenic women, probably by blocking pituitary dopamine receptors.

A preliminary double-blind study on the efficacy of carbamazepine in prophylaxis of manic-depressive illness.

A preliminary double-blind controlled study on the prophylactic effect of carbamazepine on recurrent manic-depressive psychotics was conducted with 22 patients using an inert placebo in ten subjects as a control drug. Carbamazepine in the dosage of 200-600 mg was administered for 1 year. Among the 22 carbamazepine subjects, carbamazepine was found to be effective in 60% of the cases and inert placebo in 22.2% (U-test, P less than 0.10). It is suggested that carbamazepine is a useful drug for the prophylaxis of manic-depressive illness.

MEDOS HIA-VAD biventricular assist device for bridge to recovery in fulminant myocarditis.

Successful weaning from biventricular mechanical support with full recovery of the myocardial function is extremely rare in fulminant myocarditis. We report on our experience with the MEDOS HIA-VAD ventricular assist device. The device worked for 17 days and provided adequate hemodynamics. Despite anticoagulation therapy, we had to change both ventricles because of clot formation on the surface of the outflow tract. After 17 days the myocardial function had recovered and we could remove the assist system.

Oriental medicine as therapy for resistant depression: use of some herbal drugs in the far east (Japan).

1. The advantage of oriental medicine are described. 2. For those whose anxious-depressive state are prolonged, despite several changes in combining drugs, five herbal medicines were introduced. Although their mechanism of action were still unknown, some effects were explained by modern pharmacological techniques.

Serum neuroleptic activities required to inhibit relapse in schizophrenic patients--a study by radioreceptor assay.

1. The serum levels of antidopaminergic (anti-D2), anti-alpha-adrenergic (anti-NA) and antiserotonergic (anti-5HT2) activities of neuroleptics were determined in schizophrenic patients on maintenance treatment. 2. The patients whose conditions remained stable had significantly higher serum levels of anti-D2 and anti-5HT2 activities than those who were considered to be in unstable conditions after a period of remission. 3. However, the serum levels of anti-5HT2 activity in patients whose conditions remained stable varied as much as those of anti-NA activities did, so it appeared that from a pharmacological viewpoint anti-D2 activity of neuroleptics was the most important in preventing a relapse in schizophrenic patient. 4. The serum levels of anti-D2 activity required to prevent relapses differed for each neuroleptic. 5. The frequency of side effects increased concordant with increasing serum levels of anti-D2, anti-NA and anti-5HT2 activities, and unfortunately even minimum effective serum levels of anti-D2 activity elicited slight side effects in the majority patients.

Effects of acute and chronic toluene inhalation on behavior and (3H)-serotonin binding in rat.

Toluene inhalation (0.7% in air) induced in rats abnormal neurological states resembling the serotonin syndrome, such as hindlimb abduction, resting tremor and head weaving. The frequency and intensity of these responses were unchanged after two weeks of exposure (0.7% in air, 15 min/day for 14 days), indicating an absence of tolerance development. An examination of specific serotonin (3H-5HT) binding to crude synaptic membranes prepared from brains of rats subjected to acute and chronic toluene exposure revealed that while no changes in either apparent Kd or apparent Bmax occurred in acutely exposed animals, in chronically treated animals specific (3H)-5HT binding decreased in hippocampus and pons + medulla oblongata. These results indicate that serotonergic mechanisms may play a role in some of the effects of toluene inhalation in rats, but cannot explain the absence of tolerance development after chronic exposure to toluene.

Potentiation of bleomycin cytotoxicity by high molecular weight polyacrylic acid. II. Involvement of rapid conformational change of polyacrylate.

We report that bleomycin (BLM) cytotoxicity is dramatically potentiated in the presence of high molecular weight polyacrylic acid (A119). For potentiation, an appropriate amount of divalent cations such as Ca++, Mg++, or Ba++ was required, in addition to vortex - stirring of the reaction mixture. There was no potentiation when A119 alone was pre-stirred or left standing for several days in the presence of divalent cations prior to use. Taking into account of kinematic viscosity of A119 observed during the treatment, a rapid conformational change of A119 in the presence of divalent cations might be involved in the potentiation mechanism.

Potentiation of bleomycin cytotoxicity in cultured mammalian cells by polyacrylic acid. III. Induction of DNA strand breakage and suppression of cellular heat production.

The 2E cytotoxicity of bleomycin toward cultured mammalian cells was synergistically enhanced by vortex-stirring in the presence of a low dose of high molecular weight polyacrylic acid. Cellular DNA isolated immediately after the above treatment suffered from severe single strand breaks. Heat production of the treated cells also decreased sharply immediately after the treatment, indicating that some functional disorder was probably induced on the cell membrane leading to cell death, possibly resulting from enhanced DNA strand breaks.

Pharmacokinetics of amitriptyline and its demethylated metabolite in serum and specific brain regions of rats after acute and chronic administration of amitriptyline.

The concentrations of amitriptyline (AMT) and its demethylated metabolite nortriptyline (NRT) in the serum and in specific brain regions were determined periodically after acute or chronic administration of 20 mg/kg of AMT in rats. Both AMT and NRT declined from the serum in a biexponential manner and were eliminated monoexponentially from the brain regions, with no significant difference in elimination among the eight brain regions examined. In the brain, both AMT and NRT were unevenly distributed after chronic administration, whereas an even distribution was observed after acute administration. The AUCbrain:AUCserum ratio of AMT was higher than that of NRT, indicating greater transport of AMT into the brain regions. The AUCAMT value in the serum increased 1.6 times after chronic administration, whereas no significant changes were observed in the brain regions. The AUCNRT values increased 9.0 times in the serum and 6.8 times in the brain, with the increase in the serum being greater. These results suggest inhibited distribution of the drugs into the tissues, including the brain regions, and enhanced metabolism of AMT.

Pulmonary artery banding with a novel percutaneously, bidirectionally adjustable device.

Pulmonary artery banding is commonly performed as a palliative procedure in complex congenital heart disease, when pulmonary blood flow is increased. However, the hemodynamics may change postoperatively requiring readjustment of the band, which may necessitate a second operation. We report a new system for pulmonary artery banding which allows precise placement of the band intraoperatively, as well as bidirectional percutaneous adjustment of the band postoperatively. Via left lateral thoracothomy the new device was implanted without complications into a neonate with congestive heart failure due to tricuspid atresia (IIc) and coarctation of the aorta. Although optimal placement of the band had been achieved intraoperatively the band had to be tightened 25 h after the operation and released 85 h after the operation in order to optimize hemodynamics. The bidirectionally adjustable device for banding of the pulmonary artery is superior to previously used devices with either no or unidirectional adjustability of the band because it is safe and easy to implant and has the potential to reduce the number of reoperations associated with this type of procedure.

Transmyocardial laser-revascularization: experimental studies on prolonged acute regional ischemia.

OBJECTIVE: This experimental study in pigs was undertaken to answer the question whether TMLR after acute myocardial infarction may improve regional myocardial perfusion, left ventricular function and diminish myocardial necrosis in the area at risk. METHODS: Thirty open-chest anesthetized pigs were observed for 6 h, six pigs served as controls. In 24 pigs, occlusion of the left anterior descending artery (LAD) beyond the first diagonal branch was performed: seven pigs had LAD occlusion only (ischemia group), and 17 pigs were treated by TMLR (using a CO2-laser, energy: 40 J) prior to coronary occlusion; nine pigs received one laser channel (1 mm diameter) per cm2 (laser group 1) and eight pigs two channels per cm2 in the LAD territory (laser group 2). Regional myocardial blood flow by microspheres, function (franc starling curves), histochemical assessment (triphenyl tetrazolium chloride, TTC and histology), were performed. RESULTS: The lased pigs were less prone to ventricular fibrillation (laser group 2, 38%; laser group 1, 56%; ischemic group, 100%; P < 0.05), and showed a significant smaller area of necrosis (TTC) in the area at risk (laser group 1, 23%; laser group 2, 14%; vs. ischemia group, 31%; P < 0.01). There was no significant difference between laser-treated and ischemia hearts regarding the amount of blood flow into the infarcted LAD region and the maximal left ventricular stroke work index after 6 h (P = n.s). Regional myocardial blood flow: ischemia group, 4 +/- 5 ml/100 g/min; laser group 1, 3 +/- 10 ml/100 g/min, and laser group 2, 2 +/- 10 ml/100 g/min; maximal left ventricular stroke work index: ischemia group, 1.8 mJ/g; laser group 1, 2.1 mJ/g and laser group 2, 2.1 mJ/g. CONCLUSIONS: This model of acute regional ischemia demonstrates that CO2-laser revascularization diminish significantly the incidence of ventricular fibrillation and necrosis in the area at risk, and does not change regional myocardial perfusion and global left ventricular function. This experiment indicates that TMLR may be an alternative in treating advanced ischemic heart disease.

Orthotopic transplantation of pig hearts harvested after 30 min of normothermic ischemia: controlled reperfusion with blood cardioplegia containing the Na+-H+-exchange inhibitor HOE 642.

OBJECTIVES: The aim of our study was to develop a surgical technique for a successful transplantation of hearts harvested after 30 min of normothermic ischemia without donor pretreatment. Successful transplantation of ischemic compromised hearts could help to expand the severely limited donor pool. We used the pig model because this species is very susceptible to myocardial ischemia. Na+-H+-exchange (NHE) inhibitors have shown excellent protective properties in several in vitro and in vivo models of myocardial ischemia and reperfusion. METHODS: In group I (n=12) hearts were harvested after 30 min of normothermic ischemia following cardiac arrest induced by exsanguination. Hearts were perfused with warm blood cardioplegia and transplanted orthotopically. In group II (n=9) controlled reperfusion with cold leucocyte-depleted blood cardioplegia was performed after 30 min of normothermic ischemia. In group III (n=8) the same procedure was performed as in group II but blood cardioplegia contained 1 mmol/l HOE 642. RESULTS: In group I massive myocardial oedema was observed and none of the animals could be weaned from cardiopulmonary bypass (CPB). In contrast, all animals in groups II and III could be weaned from CPB with low dose inotropic support. In groups II and III the contractility of the hearts, expressed as maximal left and right ventricular stroke work index was significantly impaired after transplantation as compared with the preoperative value. Supplementation of blood cardioplegia with HOE 642 resulted in a significantly better recovery of the LVSWImax (Group II vs. III). CONCLUSIONS: Successful transplantation of pig hearts is possible after 30 min of normothermic ischemia without donor pretreatment if a controlled reperfusion with cold leucocyte-depleted blood cardioplegia is performed. HOE 642 given during reperfusion only improves posttransplant left ventricular function.

Evaluation of the indirect revascularization method after 3 months chronic myocardial ischemia.

OBJECTIVE: The long-term effectiveness of transmyocardial laser revascularization (TMLR) was evaluated in the setting of a severe left anterior descending artery (LAD) stenosis. METHODS: To employ the chronic ischemic model, pigs underwent three operative procedures over a 13-week period. In the first operation, an operative stenosis of the LAD was created. One week later, the animals were studied at baseline by analyzing different parameters of perfusion (microspheres), function and ECG changes. Afterwards, pigs were randomized into one of three different experimental groups: animals in laser group 1 received one laser channel (n=9) and laser group 2 two channels per cm(2) (n=6) in the LAD territory (using a CO(2)-laser). Animals of the ischemic group (n=12) underwent the same procedures without TMLR-treatment. Twelve weeks later, the animals were re-studied (third operation) and killed. Additional analysis of myocardial water content and histochemistry was performed. RESULTS: Chronic myocardial ischemia and regional myocardial blood flow (RMBF) in laser group 2 revealed relatively higher RMBF values compared with the ischemic group (P=0.015), after 3 months, but no absolute improvement of perfusion at rest compared with baseline was observed in all experimental groups. Left ventricular stroke work index (LVSWI) at rest and under stress did not show any improvement compared with initial values in all study groups (P not significant). However, laser group 1 demonstrated relatively higher LVSWI(max) values in comparison with the ischemic group (P=0.013) as did laser group 2 (P=0.017). Regional contractility of the laser groups recovered after 3 months (which was deteriorated shortly after TMLR, P<0.001) and increased under stress compared with baseline (laser 1: P=0.015, laser 2: P=0.017). In contrast, the ischemic group did not show any difference from initial values (P not significant). The lased pigs of group 2 were less prone to intractable ventricular fibrillation (P=0.036 vs. ischemic group), and showed a significant smaller area of necrosis in the area at risk (P=0.012 vs. ischemic group). CONCLUSIONS: This model of chronic regional ischemia demonstrates that CO(2)-laser revascularization significantly ameliorates microperfusion and regional contractility, and diminishes the incidence of ventricular fibrillation and necrosis in the area at risk. However, it does not change the overall perfusion and global LV function.