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Biomedical subjects

I Tritto

Publications and source records attributed to I Tritto.

26 records · Page 2Linked to original sources
PubMed1993

The effects of calcium channel antagonist treatment and oxygen radical scavenging on infarct size and the no-reflow phenomenon in reperfused hearts.

Calcium antagonists reduce ischemic injury, and anti-free-radical interventions may reduce reperfusion injury. However, the effects of treatment with both interventions have never been investigated. In the present study, anesthetized rabbits underwent 30 minutes of coronary artery ligation, which was followed by 5.5 hours of reflow. Eight animals in each group received: (1) the calcium antagonist gallopamil during ischemia, (2) the oxygen radical scavenger superoxide dismutase during reperfusion, (3) combined treatment with gallopamil and superoxide dismutase, and (4) saline solution. All groups were similar with respect to collateral flow during ischemia and extent of risk region. Infarct size averaged 60.2% +/- 5.5% of risk region in controls and was significantly smaller (p < 0.001) in rabbits that were treated with either gallopamil (28.1% +/- 3.4%) of superoxide dismutase (29.3% +/- 3.2%). Little further reduction in infarct size was observed with combination therapy (22.9% +/- 3.2% of risk region; p = NS). Superoxide dismutase had no effects on hemodynamics, whereas gallopamil significantly reduced heart rate, mean arterial pressure, and rate-pressure product. However, the reduction in infarct size that was observed in gallopamil-treated rabbits significantly exceeded the expected value in this group after corrections were made for changes in these determinants of ischemic injury. Therefore we investigated whether other factors may have contributed to the beneficial effects of gallopamil. In vitro the drug had no oxygen radical scavenging activity, nor did it exert antioxidant effects. In addition, gallopamil did not affect neutrophil function. In conclusion, in this acute model myocardial cell necrosis was significantly reduced either by administration of a calcium antagonist during ischemia or by removing oxygen radicals during reperfusion. However, superoxide dismutase administration did not further reduce infarct size when given to animals that had been treated with gallopamil. Since gallopamil has no direct effect on several mechanisms of reperfusion injury, these data suggest that calcium antagonists, by decreasing myocardial oxygen demand during ischemia, may indirectly reduce oxygen radical damage during subsequent reperfusion.

Analysis of Variance↗
PubMed1992

Effects of ischemia and reperfusion on cardiac tolerance to oxidative stress.

Oxidative stress may affect cardiac function and metabolism. Oxidants are normally inactivated by reacting with reduced glutathione (GSH), with resulting formation and release of oxidized glutathione (GSSG). However, ischemia might affect glutathione metabolism. This might render ischemic hearts less resistant against subsequent oxidant injury during reperfusion, and it might also affect the reliability of GSSG measurements as a means to investigate oxidative stress in reperfused hearts. We compared the metabolic and functional consequences of an oxidant load in control rabbit hearts and in hearts reperfused after 30 min of normothermic total ischemia. In controls, H2O2 infusion (H2O2; 5-30 microM) induced a dose-dependent stimulation of GSSG release and a progressive impairment of cardiac function. At these doses, H2O2 challenge of postischemic hearts resulted in biochemical and functional changes identical to those observed in controls. Release of lactate dehydrogenase (LDH) and of GSH was negligible, similar in both groups. In additional experiments, infusion of H2O2 at a much higher dose (200 microM) elicited a further increase in GSSG release from both groups, although GSSG concentrations were lower in postischemic hearts. The functional effects of the 200 microM H2O2 infusion were similar in both groups, all hearts showing rapid and irreversible deterioration of function. Occurrence of irreversible cell injury was also manifested by a large release of LDH and GSH to a similar extent in both groups. These data demonstrate that cardiac tolerance toward oxidants is largely unaffected by a relatively brief episode of severe ischemia and indicate that GSSG release can be reliably used to investigate oxidative stress in reperfused hearts.

Animals↗
PubMed1991

Oxygen radicals generated at reflow induce peroxidation of membrane lipids in reperfused hearts.

To test whether generation of oxygen radicals during postischemic reperfusion might promote peroxidation of cardiac membrane lipids, four groups of Langendorff-perfused rabbit hearts were processed at the end of (a) control perfusion, (b) 30 min of total global ischemia at 37 degrees C without reperfusion, (c) 30 min of ischemia followed by reperfusion with standard perfusate, (d) 30 min of ischemia followed by reperfusion with the oxygen radical scavenger human recombinant superoxide dismutase (h-SOD). The left ventricle was homogenized and tissue content of malonyldialdehyde (MDA), an end product of lipid peroxidation, was measured on the whole homogenate as well as on various subcellular fractions. Reperfusion was accompanied by a significant increase in MDA content of the whole homogenate and of the fraction enriched in mitochondria and lysosomes. This phenomenon was not observed in hearts subjected to ischemia but not reperfused, and was similarly absent in those hearts which received h-SOD at reflow. Reperfused hearts also had significantly greater levels of conjugated dienes (another marker of lipid peroxidation) in the mitochondrial-lysosomal fraction. Again, this phenomenon did not occur in ischemic hearts or in reperfused hearts treated with h-SOD. Unlike the effect on tissue MDA and conjugated dienes, reperfusion did not significantly stimulate release of MDA in the cardiac effluent. Treatment with h-SOD was also associated with significant improvement in the recovery of cardiac function. In conclusion, these data directly demonstrate that postischemic reperfusion results in enhanced lipid peroxidation of cardiac membranes, which can be blocked by h-SOD, and therefore is most likely secondary to oxygen radical generation at reflow.

Acetylglucosaminidase↗
PubMed1990

Reduction in infarct size by the phospholipase inhibitor quinacrine in dogs with coronary artery occlusion.

It has been suggested that activation of tissue phospholipases may contribute to the development of ischemic cell injury. In the present study we sought to assess whether administration of the phospholipase inhibitor quinacrine would reduce the extent of myocardial necrosis after coronary artery occlusion. In open-chest, anesthetized dogs the left anterior descending coronary artery was ligated, and technetium-99-labeled albumin microspheres were injected into the left atrium to measure the area at risk. The animals were then randomly divided into a control group (n = 8) and a group receiving quinacrine (5 mg/kg intravenous bolus followed by a 40 micrograms/kg/min infusion for 6 hours; n = 9). The animals were killed 6 hours after occlusion, and the infarcted area was delineated by triphenyltetrazolium chloride staining. The extent of the risk region was similar in the two groups (32.3 +/- 2.1% of the left ventricle in control dogs and 34.2 +/- 3.4% in quinacrine-treated dogs). Infarct size was 86.4 +/- 8.8% of the risk region in control animals, whereas in treated dogs it averaged 62.3 +/- 6.4% of the risk region (p = 0.05). No differences were found in heart rate, arterial pressure, and rate-pressure product between the two groups. Thus administration of the phospholipase inhibitor quinacrine reduced the extent of myocardial necrosis in a model of fixed coronary artery occlusion. Preservation of membrane phospholipids, reduced formation of lipoxygenase metabolites, or both may mediate this phenomenon.

Animals↗
PubMed1988

Reduction in infarct size by the prostacyclin analogue iloprost (ZK 36374) after experimental coronary artery occlusion-reperfusion.

In this study we attempted to determine whether administration of iloprost (ZK 36374), a chemically stable prostacyclin analogue, would reduce infarct size after experimental coronary artery occlusion and reperfusion. One hour of coronary artery occlusion was performed in 28 open-chest, anesthetized rabbits++, followed by 5 hours of reperfusion. Two minutes after occlusion, 99mTc-labeled albumin microspheres were injected into the left atrium for later assessment of the area at risk of infarction. Fifteen minutes after occlusion animals were randomly assigned to either the treatment group (iloprost, 1.2 micrograms/kg/min intravenously for 6 hours; n = 14) or the control group (n = 14). In vitro platelet aggregation was inhibited in rabbits receiving iloprost. In 10 rabbits (five treated and five control) regional myocardial blood flow was also measured by means of differentially labeled radioactive microspheres. Infarct size was significantly smaller in treated rabbits (53.6 +/- 4.1% of the risk zone vs 89.4 +/- 3.8% in control rabbits; p less than 0.001). Flow to the nonischemic myocardium was higher in treated animals, that is, 1.87 +/- 0.20 ml/min/gm of tissue 50 minutes after occlusion and 1.90 +/- 0.20 ml/min/gm of tissue 4 hours after reperfusion, compared with 1.54 +/- 0.20 and 1.64 +/- 0.30 ml/min/gm of tissue, respectively, in control rabbits (p less than 0.01). Collateral flow to the ischemic region was not affected by the drug. Mean arterial blood pressure, heart rate, and pressure-rate product in treated rabbits were not significantly different from values in control rabbits. In conclusion, administration of iloprost reduced myocardial infarct size in this model of myocardial ischemia and reperfusion in absence of major hemodynamic effects.

Animals↗
PubMed1985

[Limitation of the area of necrosis induced by quinacrine after coronary occlusion in the dog].

Phospholipase activation has been suggested to represent one of the most relevant biochemical steps toward irreversible myocardial injury during ischemia. Accordingly, the time-course of myocardial phospholipid degradation was studied in 167 rats surviving coronary artery occlusion randomly divided into 83 controls and 84 treated with the phospholipase inhibitor quinacrine (75 mg/Kg s.c. every 8 h). The animals were sacrificed at different times ranging from 2 to 48 h post-occlusion and phospholipids and creatine kinase activity (CK) were measured on the supernatant of the left ventricular homogenates. In control animals a rapid fall in phospholipid concentration (from 1.33 +/- 0.12 to 0.67 +/- 0.05 microgram P/mg of protein) and CK activity (from 9.84 +/- 0.49 to 6.93 +/- 0.60 IU/mg of protein) was observed within 4 hours post-occlusion; these parameters remained almost unchanged throughout the rest of the study. In quinacrine-treated animals left ventricular phospholipids and CK also fell during the first hours post-occlusion; however, 24 and 48 h after the occlusion they were significantly higher than in controls (phospholipids: 0.99 +/- 0.05 vs 0.62 +/- 0.04 microgram P/mg of protein, p less than 0.001, and CK: 7.76 +/- 0.54 vs 4.99 +/- 0.37 IU/mg of protein, p less than 0.001, at 48 h). The effect of quinacrine on the extent of necrosis was then assessed in 13 anesthetized dogs undergoing ligation of the left anterior descending coronary artery. To measure the area at risk (RZ), 99Tc-PP labeled albumin microspheres were injected into the left atrium 5 min after coronary occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Mepindolol reduces myocardial necrosis in rats with coronary artery occlusion.

Mepindolol is a newly developed beta-adrenergic blocking agent reported to counteract the chronotropic effect of catecholamines, with only little effect on contractility. This study was designed to assess whether or not mepindolol is effective in reducing infarct size. Accordingly, 16 rats, serving as controls, underwent coronary artery occlusion and did not receive any treatment; an additional 19 were treated with mepindolol (1 mg/kg s.c. t.i.d.) for 48 h. Finally, a third group (n = 18) underwent sham operation. Forty-eight hours later, infarct size was calculated from left ventricular creatine phosphokinase activity and found to average 52.4 +/- 7.8% (mean +/- SEM) of the left ventricle in control rats and 35.6 +/- 5.4% in treated rats (p less than 0.05). Left ventricular phospholipid content averaged 0.79 +/- 0.08 microgram P/mg protein in sham-operated rats and 0.61 +/- 0.04 microgram P/mg protein in control animals. In contrast, in mepindolol-treated rats, phospholipid concentration was 0.70 +/- 0.04 microgram P/mg protein (p less than 0.05), this suggesting a protective effect of the drug on ischemia-induced phospholipid degradation. The long-term effect of mepindolol on left ventricular hydroxyproline concentration was assessed 21 days post-coronary occlusion. Infarct size calculated by this method was 30.2 +/- 4.8% of left ventricle in 21 control animals and 18.2 +/- 4.2% in 28 treated rats (p less than 0.05), indicating that, as for the acute necrosis, the extent of scar development after coronary artery occlusion can be reduced by mepindolol.

Adrenergic beta-Antagonists↗