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Biomedical subjects

A M Lefer

Publications and source records attributed to A M Lefer.

At least 397 records · Page 22Linked to original sources
PubMed1978

Anti-endotoxin actions of methylprednisolone in the isolated perfused cat liver.

The efficacy of the synthetic glucocorticoid, methylprednisolone, was examined in vitro using an isolated cat liver perfused with a blood-free medium. Addition of endotoxin (75 microgram/g tissue) to the perfusate did not change perfusion pressure or total oxygen consumption. However, cellular integrity was severely compromised as reflected by increases in perfusate lactate dehydrogenase and cathepsin D activities, increases in tissue lysosomal fragility, and enlargement and vacuolization of lysosomes. Addition of methylprednisolone (1 x 10(-3) M) to the perfusion medium prevented the endotoxin-induced changes in hepatocyte integrity. It is suggested that a major action of endotoxin in the liver is to increase lysosomal fragility, and the protective action of methylprednisolone appears to be related to its lysosomal stabilizing action. The potent anti-endotoxin action of glucocorticoids in vivo may be due in part to the stabilization of lysosomal membranes in tissues such as the liver.

Animals↗
PubMed1978

Properties of cardioinhibitory factors produced in shock.

The widespread occurrence of circulating cardioinhibitory factors in many types of circulatory shock and in a variety of mammalian species is impressive. This review summarizes the properties of the nine best-known factors with regard to their occurrence, chemical properties, sites of origin, biological actions, and pharmacological modification. Cardioinhibitory factors appear to play a significant role in the pathogenesis of circulatory shock. There now are pharmacological means available with which to prevent the formation of such factors. With knowledge on the chemistry of cardioinhibitory factors rapidly accumulating, it is anticipated that specific antagonists to the action of these factors will become available in the near future.

Animals↗
PubMed1978

Comparison of the cytotoxic actions of hypoxia and endotoxin in the perfused cat liver.

The isolated cat liver perfused at a constant flow with Krebs-Henseleit solution containing low-molecular-weight dextran was employed to ascertain the direct effects of hypoxia or endotoxin on hepatic integrity. Hypoxia resulted in large increases in circulating lactate dehydrogenase (LDH) activity and in amino-nitrogen concentration, whereas endotoxin at a dose of 0.75 microgram/gm liver wet weight resulted in only small changes in these variables after 150 minutes of perfusion. Perfusion pressure and perfusate pH did not change significantly in response to either intervention. Both hypoxia and endotoxin significantly compromised lysosomal stability as evidenced by large increases in circulating levels of cathepsin D, large increases in the nonsedimentable fraction of tissue cathepsin D (ie, increased percentage of free activity), and changes in the ultrastructural appearance of liver lysosomes associated with enhanced fragility (eg, swelling, increased vacuolization). Both interventions also significantly impaired phagocytosis by reticuloendothelial cells within the liver. However, neither intervention altered BSP clearance, indicative of a lack of effect on parenchymal cell clearance. These findings indicate that both endotoxin and hypoxia induce direct cellular damage within the liver; however, endotoxin exerted a more selective action on lysosomes, whereas hypoxia produced more of a diffuse cytotoxic effect.

Amines↗
PubMed1978

Preservation of cellular integrity as a protective mechanism of dexamethasone in hemorrhagic shock in the cat.

Anesthetized cats were hemorrhaged to a mean arterial blood pressure of 40 mm Hg for 120 minutes. Cats given dexamethasone (6 mg/kg, i.v.) at the time of hemorrhage and again (3 mg/kg, i.v.) at the time of reinfusion maintained post-reinfusion arterial blood pressure at a higher level than cats given the steroid vehicle. In addition, dexamethasone treated cats exhibited higher post-reinfusion liver blood flows than vehicle treated hemorrhaged cats. Dexamethasone significantly retarded the rise in plasma cathepsin D and amino-nitrogen activities during hemorrhage, and prevented the accumulation of a myocardial depressant factor (MDF) in the circulating blood. Dexamethasone had no significant effect on isolated cat papillary muscle or aortic strips. It appears that dexamethasone exerts its beneficial effect in hemorrhage shock primarily by stabilizing lysosomal membranes and the subsequent prevention of proteolysis and MDF formation rather than by a direct vasodilator or inotropic effect.

Amines↗
PubMed1977

Isolation of myocardial depressant factor from plasma of dogs in hemorrhagic shock.

Starting with 31 of plasma from dogs in hemorrhagic shock, we have purified the myocardial depressant factor and found that the activity is separate from salts and free amino acids. Moreover, the myocardial depressant factor is present in shock plasma in concentrations of about 1 nmol/ml of plasma. The depressant factor exists as multiple chromatographic forms. The best characterized forms are the anionic forms. A preliminary amino acid composition of the anionic forms has been obtained. These findings should allow more rapid processing of plasma containing high myocardial depressant factor activity to separate the factor and to completely identify this small peptide of great physiologic interest.

Amino Acids↗
PubMed1977

Protective action of timolol in acute myocardial ischemia.

Timolol, a beta-adrenoceptor blocking agent with little or no cardiodepressant activity, was studied in acute myocardial ischemia in cats. Timolol, at a dose of 25 mug/kg, blocked 75 to 80% of the cardiac response to isoproterenol. This dose also significantly reduced heart rate in cats subjected to acute myocardial ischemia by ligation of the left coronary artery. Timolol significantly prevented the spread of ischemic damage in the myocardium as assessed by (a) curtailing the increase in plasma creatine phosphokinase (CPK) activity, (b) preventing the loss of CPK from the ischemic portion of the myocardium, and (c) restoring the elevated S-T segment of the electrocardiogram toward normal. Timolol did not significantly retard the increase in fragility of lysosomes in ischemic myocardial tissue. The mechanism of the protective effect to timolol on the ischemic myocardium appears to be via reducing myocardial oxygen demand by decreasing heart rate.

Adrenergic beta-Antagonists↗
PubMed1977

Beneficial effect of arachidonic acid during hemorrhagic shock in the dog.

Arachidonic acid (AA), precursor of the bisenoic prostaglandins was infused at a rate of 120 mug/kg per min into the vena cava of dogs subjected to hemorrhagic shock to assess the effects of stimulation of the prostaglandin (PG) synthetase system on the shock state. Hemorrhagic shock was induced by bleeding to a mean arterial blood pressure (MABP) of 40 mm Hg for 150 minutes followed by reinfusion of all remaining shed blood. In sham shock dogs receiving AA vehicle (0.1 M Na2C03), there were no significant changes in MABP, superior mesenteric artery flow (SMAF), renal artery flow (RAF), PGF2 or PGF2alpha concentrations, or in cathepsin D or myocardial depressant factor (MDF) activities during a 260-minute experimental period. During oligemia, untreated hemorrhagic shock dogs exhibited dramatic reductions in MABP, SMAF, and RAF which were transiently restored following reinfusion, but markedly decreased 100 minutes after reinfusion. Cathepsin D, MDF, PGE2, and PGF2alpha values increased significantly in these dogs. AA given during oligemia did not prevent changes in SMAF or RAF, but maintained MABP at near-normal values after reinfusion. AA also significantly protected against the plasma accumulation of both cathepsin D an MDF is hemorrhagic shock dogs. Circulating PGF2alpha and PGE2 values increased rapidly in AA-treated dogs and plateaued at 3.6 and 4.8 times control values, respectively, during oligemia. Hemorrhagic shock dogs receiving AA plus Na meclofenamate, a PG synthetase inhibitor, were not significantly different from shock dogs receiving vehicle except that the circulating PG concentrations did not increase. Thus, products of the PG synthetase system appear to prevent the plasma accumulation of lysosomal hydrolases nand of MDF, and may significantly preserve MABP after hemorrhagic shock in the dog.

Animals↗
PubMed1977

Tissue uptake of isotopically labeled aprotinin in early myocardial ischemia.

The tissue uptake of 3H-aprotinin was studied in anesthetized cats during acute myocardial ischemia (MI) 1 an 2 hr after injection of the tracer. Several tissues exhibited a rapid uptake of the protease inhibitor. Kidney, lung and liver demonstrated the greatest uptake with tissue/plasma ratios of 1.6 to 4.8. Spleen, adrenals, intestine, heart and pancreas exhibited tissue/plasma ratios of 0.28 to 0.58, whereas abdominal aorta, skeletal muscle and omentum had tissue/plasma ratios below 0.17. The rate of clearance of 3H-aprotinin from cat plasma was unaltered by myocardial ischemia. Although ischemic myocardial tissue took up less aprotinin than the non-ischemic myocardial tissue in the same hearts, ischemic tissue accumulated significant amounts of aprotinin relative to the non-ischemic region (82%). These data show that aprotinin reaches ischemic myocardial tissue during the first 2 hr of acute ischemia and would be available to antagonize some of the proteases which may be liberated during these critical early hours of the ischemic process.

Animals↗
PubMed1977

Influence of dopamine on liver dynamics in hemorrhagic shock.

The present study was conducted to examine the effect of dopamine on arterial blood pressure, liver blood flow, cathepsin D activity, and free amino nitrogen concentration in hemorrhagic shock. Dopamine at a dose of 4 microgram/kg/min increased both mean arterial blood pressure and liver blood flow in postoligemic shock, but failed to prevent the marked increases in circulating cathepsin D and free amino nitrogen. In fact, dopamine infusion resulted in an increased plasma cathepsin D activity in shock. This increased accumulation of a lysosomal marker enzyme probably results from increased washout of the enzyme from the splanchnic or hepatic vascular bed in response to increased blood flow in these areas rather than from a direct effect of dopamine on lysosomal integrity. The increase in hepatic artery and portal vein flows appeared to result from stimulation of dopaminergic receptors since the dopamine dose was in the dopaminergic range and because haloperidol, a dopamine blocker, abolished the improved hemodynamic effects of dopamine. This study suggests that dopamine benefits the animal in hemorrhagic shock hemodynamically, but does not reverse the metabolic and cellular problems in shock. Perhaps, in combination with a drug opposing the biochemical basis of shock, dopamine may provide a greater anti-shock action.

Amino Acids↗