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Biomedical subjects

P Libby

Publications and source records attributed to P Libby.

At least 253 records · Page 14Linked to original sources
PubMed1980

Effects of chymostatin and other proteinase inhibitors on protein breakdown and proteolytic activities in muscle.

To learn more about the enzymes involved in protein catabolism in skeletal and cardiac muscle and to identify selective inhibitors of this process, we studied the effects of proteinase inhibitors on protein turnover in isolated muscles and on proteolytic activities in muscle homogenates. Chymostatin (20mum) decreased protein breakdown by 20-40% in leg muscles from normal rodents and also in denervated and dystrophic muscles. These results are similar to our previous findings with leupeptin. The related inhibitors pepstatin, bestatin, and elastatinal did not decrease protein breakdown; antipain slowed this process in rat hind-limb muscles but not in diaphragm. Chymostatin did not decrease protein synthesis and thus probably retards proteolysis by a specific effect on cell proteinase(s). In homogenates of rat muscle, chymostatin, in common with leupeptin and antipain, inhibits the lysosomal proteinase cathepsin B, and the soluble Ca(2+)-activated proteinase. In addition, chymostatin, but not leupeptin, inhibits the chymotrypsin-like proteinase apparent in muscle homogenates. In muscles depleted of most of this activity by treatment with the mast-cell-degranulating agent 48/80, chymostatin still decreased protein breakdown. Therefore inhibition of this alkaline activity probably does not account for the decrease in protein breakdown. These results are consistent with a lysosomal site of action for chymostatin. Because of its lack of toxicity, chymostatin may be useful in maintaining tissues in vitro and perhaps in decreasing muscle atrophy in vivo.

Animals↗
PubMed1978

Leupeptin, a protease inhibitor, decreases protein degradation in normal and diseased muscles.

The protease inhibitor leupeptin decreases protein degradation in rat skeletal and cardiac muscle incubated in vitro, while protein synthesis remains unaltered. Leupeptin also lowers protein breakdown in denervated rat muscles and affected muscles from mice with hereditary muscular dystrophy. Leupeptin may thus be useful in retarding tissue atrophy. Since homogenates of leupeptin-treated muscles had decreased cathepsin B activity, this lysosomal protease may play a role in protein turnover in normal and diseased muscles.

Animals↗
PubMed1977

Favorable effects of hyaluronidase on electrocardiographic evidence of necrosis in patients with acute myocardial infarction.

To evaluate hyaluronidase's effect in reducing post-infarction myocardial necrosis, we randomized 91 patients with anterior infarction to control (45) or to hyaluronidase-treatment (46) groups. A 35-lead precordial electrocardiogram was recorded on admission and seven days later. Hyaluronidase was administered intravenously after the first electrocardiogram and every six hours for 48 hours. QRS-complex changes were analyzed to assess the drug's effect. Precordial sites with ST-segment elevation (larger than or equal to 0.15 mV) on the initial electrocardiogram that retained an R wave were considered vulnerable for the development of electrocardiographic signs of necrosis. The sum of R-wave voltages of vulnerable sites fell more in the control group than in the hyaluronidase group (70.9 +/- 3.6 per cent [+/- 1 S.E.M.] vs 54.2 +/- 5.0 per cent P less than 0.01). Q waves appeared in 59.3 +/- 4.9 per cent of the vulnerable sites in control versus 46.4 +/- 4.9 per cent in hyaluronidase-treated patients (P less than 0.05). Thus, hyaluronidase reduced the frequency of electrocardiographic signs of myocardial necrosis.

Acute Disease↗
PubMed1975

The effect of hypoglycemia on myocardial ischemic injury during acute experimental coronary artery occlusion.

To determine the effect of hypoglycemia on myocardial ischemic injury following coronary artery occlusion epicardial electrograms were recorded 15 minutes after two 20-minute coronary artery occlusions in seven anesthetized dogs. The first occlusion was a control (blood glucose 85 plus or minus 5(sd) mg per cent). Before the second occlusion hypoglycemia was induced (blood glucose 40 plus or minus 5 mg per cent) by the intravenous administration of insulin (2 units/kg). The average ST-segment elevation in leads during control was 3.5 plus or minus 1.0 mV which rose to 6.1 plus or minus 1.4 mV during the second occlusion (P smaller than 0.05). The number of sites showing ST-segment elevation exceeding 2 mV increased from 7.6 plus or minus 1.6 during control to 10.6 plus or minus 1.4 (P smaller than 0.05) during the occlusion with hypoglycemia. In other dogs, a coronary artery was occluded for 24 hours. Epicardial ST-segment elevations were compared to creatine phosphokinase (CPK) activity and histological appearance from the same sites. CPK activity in sites with normal ST segments (0-2 mV) was 33.1 plus or minus 6.0 IU/mg protein. Six additional dogs received insulin following the 15 minute epicardial map and blood sugar was maintained at a level of 46 plus or minus 6 mg per cent for the 24 hours. These dogs showed more myocardial necrosis than predicted by the ST-segment elevation prior to insulin administration. Forty-six percent of sites, which in control dogs would have been expected to have normal CPK and histological appearance, showed depressed CPK activity and histological evidence of early myocardial necrosis. Thus, hypoglycemia increases myocardial damage, as reflected by enzymatic and histological analyses.

Animals↗
PubMed1975

Effects of hyaluronidase administration on myocardial ischemic injury in acute infarction. A preliminary study in 24 patients.

The effect of hyaluronidase on myocardial ischemic injury was examined in 13 patients with acute myocardial infarction, and the results were compared with 11 patients who did not receive hyaluronidase. A 35-electrode precordial mapping method was used to assess the rate of resolution of ST segment elevations. In the 11 control patients, the sum of ST segment elevations (sigmaST) fell after 2 hours to an average of 93.5% plus or minus 17.3% (SEM) and after 24 hours to 89.6% plus or minus 7.6% of the initial values, while the number of electrodes exhibiting ST segment elevations exceeding 0.1 mV (NST) fell to 98.0% plus or minus 12.3% and 94.3% plus or minus 10.4% of the initial values respectively. In the hyaluronidase-treated group, at the same time sigmaST fell significantly more (P less than 0.05), to 54.1% plus or minus 5.0% and 51.3% plus or minus 11.8% and NST was also more markedly reduced (P less than 0.05) to 50.7% plus or minus 7.8% and 50.1% plus or minus 12.4%, thus indicating that hyaluronidase can accelerate the reduction of myocardial ischemic injury in patients with acute myocardial infarction.

Acute Disease↗
PubMed1973

Reduction of experimental myocardial infarct size by corticosteroid administration.

The influence of the administration of pharmacologic doses of hydrocortisone on the extent and severity of acute myocardial ischemic injury and on subsequent necrosis after acute coronary occlusion was investigated in 28 dogs. In order to study acute myocardial injury, repeated epicardial electrocardiograms were recorded from 10 to 15 sites on the anterior surface of the left ventricle. Average ST segment elevation (ST) and the number of sites in which ST segment elevation exceeded 2 mV (NST), indices of the magnitude and extent of myocardial injury, respectively, were analyzed at 30 and 60 min after coronary occlusion. In the control group ST and NST did not change significantly in this time interval while in the treated group, which received 50 mg/kg hydrocortisone just after the 30 min recording, ST fell from 3.5+/-0.8 to 1.1+/-0.4 mV (P<0.01) and NST was reduced from 6.7+/-1.1 to 1.4+/-0.8 (P<0.01). In order to study the influence of hydrocortisone on necrosis, epicardial ST segment elevation 15 min after coronary occlusion was compared to myocardial creatine phosphokinase activity (CPK) and histologic appearance 24 h later in each site. In a control group (14 dogs) a relationship was established between ST segment elevation at 15 min (in millivolts) and CPK activity (in international units per milligram of protein) 24 h later: log CPK = -0.0611ST + 1.26 (N = 102 specimens, r = -0.79). In the treated groups, hydrocortisone (50 mg/kg i.v.) was given either at 30 min after occlusion (seven dogs) or at 6 h after occlusion (six dogs). Both groups received supplementary doses of hydrocortisone (25 mg/kg) 12 h after occlusion. The two treated groups exhibited less CPK depression than that expected from ST segment elevation at each site, with slopes of the regression lines which were significantly less steep: log CPK = -0.0288ST + 1.26 (N = 48, r = -0.71) and log CPK = -0.0321ST + 1.31 (N = 48, r = -0.76) in the (1/2) h and 6 h groups, respectively. Histologically, sites with ST segment elevations of less than 2 mV at 15 min after occlusion exhibited normal appearance 24 h later. Sites with ST segment elevations (> 2 mV) in the control group showed histologic changes compatible with early myocardial infarction in 96% of specimens, while this occurred only in 61% and 63% of specimens, respectively, in the treated groups, showing that over one third of the sites were protected from undergoing necrosis due to the intervening hydrocortisone treatment. Thus pharmacological doses of hydrocortisone prevent myocardial cells from progressing to ischemic necrosis even when administration is initiated 6 h after coronary occlusion.

Animals↗
PubMed1973

The effect of glucose-insulin-potassium on cardiac ultrastructure following acute experimental coronary occlusion.

The effects of glucose-insulin-potassium (GIK) on cardiac ultrastructure following acute experimental coronary occlusion were studied in dogs. Epicardial ST segment elevations at multiple sites on the anterior surface of the left ventricle 15 minutes after ligation of the left anterior descending coronary artery were used to predict infarct development. Biopsies removed from sites of known ST segment elevation were examined with the electron microscope, and the degree of injury was correlated with the ST segment elevation. The animals receiving GIK showed significantly less necrosis than was seen in dogs with occlusion alone at corresponding levels of ST segment elevation. Other evidence suggesting a beneficial effect of GIK was the presence of a fibrillar material in several biopsies from the treated animals, which may indicate the regeneration of myofilaments.

Animals↗
PubMed1972

Coronary artery reperfusion. I. Early effects on local myocardial function and the extent of myocardial necrosis.

The effects of coronary artery reperfusion 3 hr after coronary occlusion on contractile function and the development of myocardial damage at 24 hr was studied experimentally. In 14 control and 6 reperfused dogs, relationships between epicardial ST segment elevation 15 min after coronary occlusion and myocardial creatine phosphokinase activity (CPK) and histologic appearance 24 hr later were examined. The electrocardiograms were recorded from 10 to 15 sites on the left ventricular epicardium and transmural samples for CPK and histology were obtained from the same sites where epicardial electrocardiograms had been recorded. An inverse relation existed between ST segment elevation (mv) 15 min after occlusion and log CPK activity (IU/ mg of protein) 24 hr later, log CPK = - 0.06ST + 1.26. In dogs subjected to coronary artery reperfusion, there was significantly less CPK depression (log CPK = - 0.01ST + 1.31, [P < 0.01]) than that expected from the control group. In the control group 97% of specimens showing ST segment elevations over 2 mv at 15 min showed abnormal histology 24 hr later. In contrast, in the reperfused group 43% of sites exhibiting elevated ST segment at 15 min showed abnormal histology 24 hr later. In six additional dogs it was shown that the paradoxical movement of the left ventricular wall could be reversed within 1 hr of perfusion. Therefore, by enzymatic and histologic criteria, as well as by functional assessment, coronary artery reperfusion 3 hr after occlusion resulted in salvage of myocardial tissue.

Animals↗