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Biomedical subjects

A M Lefer

Publications and source records attributed to A M Lefer.

At least 325 records · Page 18Linked to original sources
PubMed1982

Infarct size restriction in cats by the beta-adrenergic blocker timolol.

The beta-adrenergic antagonist, timolol, was previously shown to exert a protective effect in cats subjected to 5 h of myocardial ischemia. The present study was designed to determine the effect of timolol on infarct size in cats 24 h after coronary occlusion. Timolol (25 microgram/kg) or vehicle (0.9% NaCl) was administered 0.5, 5, 10, 15 and 20 h after acute ligation of the left anterior descending coronary artery. There was no significant difference in arterial blood pressure or heart rate in MI cats receiving timolol or vehicle. Timolol markedly decreased S-T segment elevation at 2-12 h (P less than 0.05). Left ventricular weights in MI + vehicle cats (8.5 +/- 0.7 g, n = 6) were similar to timolol-treated MI cats (8.9 +/- 0.4 g, n = 7). However, the percent of the left ventricular myocardium infarcted, determined by nitroblue tetrazolium staining, was significantly less (P less than 0.001) in timolol MI cats compared to saline-treated cats, 9.8 +/- 1.2% (n = 7) vs. 18.9 +/- 1.8% (n = 6), respectively. Hemodynamic or cytoprotective actions of timolol do not appear to explain these results. Rather, the mechanism of infarct size reduction by timolol is probably explained by antagonism of beta-receptor-mediated metabolic effects.

Animals↗
PubMed1982

Salutary actions of thromboxane synthetase inhibition during global myocardial ischemia.

Isolated cat hearts were perfused with blood-free Krebs-Henseleit solution for 165 min. Ischemia was induced by reducing perfusion to 0.02 ml/min/g wet heart weight for 2 h followed by reperfusion at controls flows for 30 min. Hearts perfused with the thromboxane synthetase inhibitor OKY-1581 at concentrations of 5 X 10(-6) M were spared from the increases in circulating thromboxane B2 occurring in untreated ischemic hearts. After reperfusion, cardiac contractile force increased to a higher level in OKY-1581 treated hearts. This was associated with a lower coronary vascular resistance than in untreated ischemic hearts. OKY-1581 treated ischemic hearts exhibited lower perfusate and higher myocardial creatine kinase (CK) activity than untreated ischemic hearts, indicative of preservation of cellular integrity. Also, OKY-1581 treated ischemic hearts showed improved lysosomal stability as evidenced by a lower tissue percent free cathepsin D activity than untreated ischemic hearts. These results are consistent with a significant role of thromboxanes in the propagation of myocardial cellular damage during ischemia.

Acrylates↗
PubMed1982

Anti-thromboxane A2 actions of pinane thromboxane A2 derivatives.

Six pinane-thromboxane A2 analogs have been synthesized and tested for their ability to antagonize carbocyclic thromboxane A2 (CTA2) induced coronary vasoconstriction and prostaglandin endoperoxide analog induced platelet aggregation. Two of the derivatives, 5C-15S BPTA2 and 5T-15S BPTA2 and 5T-15S BPTA2 (1 microM) showed 76 +/- 3 and 72 +/- 9 percent inhibition of CTA2 (15 nM) induced vasoconstriction of cat coronary arteries respectively, while the other compounds showed between 15 and 50 percent inhibition at 1.0 and 2.0 microM. 5C-15S BPTA2 also antagonized prostaglandin-endoperoxide analog induced human platelet aggregation, although the other compounds showed little or no antagonism of aggregation in this system.

Animals↗
PubMed1982

Cardiac effects of prostaglandins during global ischemia in isolated perfused cat hearts.

Prostaglandin E1,PGD2, and 16,16 dimethyl prostaglandin E2 were studied in an isolated perfused cat heart preparation during normal conditions and in myocardial ischemia. Under ischemic perfusion, prostaglandin E1 showed some protective action on the release of creatine kinase into perfusate during ischemia, but none of the prostaglandins studied prevented increases in perfusate creatine kinase after reperfusion. Prostaglandin E1 also showed significant membrane stabilizing activity reducing the rate of lysosomal hydrolase release from cat liver lysosomes. Prostaglandin E1 may be beneficial in myocardial ischemia due to its membrane stabilizing action and perhaps to other effects but it did not exert significant protective effects on reperfusion injury of the ischemic myocardium under conditions of these experiments.

16,16-Dimethylprostaglandin E2↗
PubMed1982

Anti-aggregatory actions of calcium channel blockers in cat platelets.

Four calcium channel blockers, verapamil, nifedipine, nisoldipine and nimodipine were studied in terms of their ability to inhibit platelet aggregation in cat platelet rich plasma by optical aggregometry. Only verapamil and nisoldipine significantly inhibited aggregation in cat platelets to ADP (2 microM). None of the calcium channel blockers exerted marked inhibition of aggregation induced by 1mM arachidonic acid. However, verapamil produced a moderate but significant inhibition of aggregation to arachidonic acid. Increasing the calcium ion concentration could reverse this inhibition. Thus, there are significant differences in the anti-aggregatory activity of calcium channel blockers in cat platelet rich plasma.

Adenosine Diphosphate↗
PubMed1982

Protective actions of dexamethasone in acute cerebral ischemia.

The effects of glucocorticoids on cerebral integrity during cerebral ischemia (CI) are not clear. We induced CI in rabbits by occlusion of the left external carotid artery and injection of sodium arachidonate (NaAr) in the left internal carotid artery. We investigated the effect of dexamethasone (DEXA) on NaAr--induced CI. We examined four groups: a) Sham CI, b) CI, c) CI + Dopamine (80 micrograms/kg/min), and d) CI + Dopamine + DEXA (6 mg/kg). The EEG was recorded over the hemisphere injected with NaAr. After 240 min of observation, the brain was sampled to measure water content and to examine the cerebral vasculature microscopically. The dose of NaAr was similar in all ischemic groups (ie, 0.45 to 0.50 mg). In both CI, and CI + Dopamine groups, the EEG became flat in all 13 rabbits. Moreover, the water content of the left hemisphere increased (P less than 0.01 vs Sham CI), but that of the right side only slightly. In the CI + Dopamine + DEXA group, only one rabbit out of seven showed a flat EEG. Water content of the left side increased slightly and that of the right side not at all. Microscopic examination of the brain showed obstruction of cerebral arterioles in the left hemisphere in rabbits given NaAr. Thus, DEXA protects the brain from edema induced by NaAr, when blood pressure is maintained by dopamine. This is associated with preservation of cerebral electrical activity. However, dopamine alone was unable to preserve the EEG or protect against edema formation during cerebral ischemia.

Acute Disease↗
PubMed1982

Protective actions of nafazatrom in traumatic shock.

3-Methyl-(1-[2-naphthyloxy]-ethyl)-2-pyrazolin-5-one (nafazatrom), a new antithrombotic agent, at doses of 0.5 to 2.0 mg/kg significantly prolonged survival of rats after induction of traumatic shock. Nafazatrom did not exert significant effects on arterial blood pressure in either control or shock animals. However, nafazatrom significantly prevented the plasma accumulation of the lysosomal protease cathepsin D and of the cardiotoxic peptide, myocardial depressant factor (MDF). In addition, nafazatrom (10 microgram/ml) significantly stabilized lysosomal membranes in isolated liver lysosomal suspensions, and inhibited proteolysis in pancreatic homogenates. Thus, nafazatrom exerts significant anti-shock activity which appears to be related to its favorable cellular and metabolic effects.

Animals↗
PubMed1982

Tissue uptake of 3H-naloxone in control and in hemorrhagic shock cats.

Tissue uptake and plasma levels of 3H-naloxone were studied in normotensive control cats, as well as in hemorrhagic hypotensive cats. Intravenous injection of naloxone resulted in a rapid and extensive uptake of naloxone label from plasma by several tissues. Plasma half-life of the radiolabel was determined to be 137 min. One and two hours after injection, large amounts of naloxone label were found in the liver, pancreas, adrenal, kidney and lung, with tissue/plasma ratios ranging from 2 to 30. Brain tissue displayed the lowest tissue/plasma ratios of any organ sampled. Infusion of 8 mg/kg -1.hr-1 naloxone resulted in an increase in concentration of radiolabel over a 2 hr period. Hemorrhagic shock did not significantly retard uptake of naloxone by tissues. Splanchnic organs displayed high uptake of naloxone even during hemorrhagic shock. Brain tissue in cats subjected to hemorrhagic shock had the lowest uptake naloxone of all tissues sampled. The degree of uptake of naloxone by tissues is consistent with its proposed role in lysosomal membrane stabilization and prevention of proteolysis during hemorrhagic shock.

Animals↗
PubMed1981

Thromboxane synthetase inhibitors differentially antagonize thromboxane receptors in vascular smooth muscle.

A number of thromboxane (Tx) synthetase inhibitors have been found to prevent thromboxane release in acute cardiopulmonary disorders. However, little is known about Tx receptor antagonism by these substances. Imidazole, UK-37,248 and pinane thromboxane A2 (PTA2) were tested in isolated perfused cat coronary arteries, spirally cut rabbit pulmonary artery strips, and in rabbit and cat platelets for their ability to antagonize vasoconstrictor and aggregatory effects of a stable Tx agonist, carbocyclic thromboxane A2 (CTA2). Imidazole, at concentrations that completely inhibit thromboxane synthesis, failed to antagonize the vasoconstrictor effects of CTA2 in both systems. UK-37,248, at 10 to 1000 micrograms/ml, failed to inhibit CTA2-induced coronary constriction but at 1 microgram/ml reduced rabbit pulmonary artery constriction by 80 +/- 8% (P less than 0.0005). In comparison, 1 micro M PTA2 completely prevented PTA2-induced constriction in both coronary and pulmonary arteries. PTA2 did not antagonize KCl and angiotensin II responses. In platelets, PTA2 but not UK-37,248 prevented arachidonate induced aggregation in rabbit and cat platelets. Some of the beneficial effects of thromboxane synthetase inhibitors may be associated with thromboxane receptor antagonism. Inhibitors structurally similar to TxA2 appear to have greater thromboxane receptor antagonistic activity. This additional activity may be of importance in therapeutics of coronary and pulmonary disorders.

Animals↗
PubMed1981

Protective effect of nifedipine in the hypoxic perfused cat liver.

The effects of the calcium antagonist nifedipine on isolated perfused cat livers were studied during 150 min of normoxic or hypoxic perfusion with Krebs-Henseleit solution. Hypoxic livers perfused with the nifedipine vehicle exhibited significantly higher increases in perfusion pressure, perfusate lactate dehydrogenase and cathepsin D activities, as well as amino-nitrogen concentrations compared to the control normoxic group. In contrast, the nifedipine + hypoxia group showed no significant difference in any of these variables from the control livers. Nifedipine (0.3 microgram/ml) protected the liver during hypoxia and that this protection may have stemmed from its inhibition of Ca++ influx which has been linked in irreversible cell death.

Animals↗
PubMed1981

Stabilization of cardiac lysosomal and cellular membranes in protection of ischemic myocardium due to coronary occlusion:efficacy of the nonsteroidal anti-inflammatory agent, naproxen.

The combined cellular membrane stabilizing and prostaglandin-inhibiting agent, naproxen, administered either 30 minutes before or after left coronary occlusion, induced significant preservation of the acutely ischemic experimental animal myocardium. A consistent extent of myocardial protection was provided as measured by ST segment elevation, plasma accumulation of CK activity, tissue CK activities, and amino-nitrogen concentrations, and ultrastructural integrity. Protection did not appear to be via hemodynamic mechanisms since naproxen neither altered pressure-rate product nor decreased coronary resistance. While the degree that inhibition of platelet thromboxane A2 generation contributes to these salutary results requires clarification due to possible simultaneous decrease of coronary endothelial PGI2 formation, the present study emphasizes the value of the concomitant special lysosomal and cellular stabilizing actions of naproxen. In contrast to acetylsalicylic acid, meclofenamate, and indomethacin which do not effect such benefit in the same experimental conditions, our results indicate that naproxen resembles the nonsteroidal anti-inflammatory agents which also possess membrane stabilizing properties, such as ibuprofen and flurbiprofen, and protects ischemic myocardium in similar adverse circumstances.

Animals↗
PubMed1981

Mechanism of protection against arachidonate induced sudden death by glucocorticoid.

Dexamethasone at a dose of 6 mg.kg-1 given to rabbits for three days prior to challenge with sodium arachidonate (2 mg.kg-1) intravenously, improved survival from 0% to 90% (p less than 0.01). Dexamethasone, given for shorter periods prior to arachidonate injection resulted in survival rates from 17% to 40%. In dexamethasone (3 days) treated rabbits, plasma thromboxane B2 concentrations were only increased by 30% compared with increases of 950% in untreated rabbits (p less than 0.001). Dexamethasone treated rabbits did not exhibit pulmonary thrombosis as did untreated rabbits given arachidonate. However, platelet rich plasma from both control and treated rabbits was aggregated by 0.2 mM arachidonate in vitro. The mechanism of the protective effect of dexamethasone appears to be related to induction of enzymes or stimulation of clearance of injected arachidonic acid, since steroid treated rabbits cleared labeled arachidonic acid more rapidly than untreated rabbits.

Animals↗
PubMed1981

Carbocyclic thromboxane A2: aggrevation of myocardial ischemia by a new synthetic thromboxane A2 analog.

In vitro experiments indicate that thromboxane A2 (TA2) is a potent platelet aggregator and vascular constrictor. However, it is unclear what roles these specific actions may contribute in the pathophysiology of myocardial ischemia. Carbocyclic thromboxane A2 (CTA2), a TA2 analog, constrict isolated perfused cat coronary arteries, but does not aggregate platelets, and thus appeared useful to clarify these separate actions of TA2. In anesthetized cats, radioactive labeled microspheres were injected into the left atrium for measurement of cardiac output and tissue blood flows. Compared to control measurements, CTA2 infusion (4.8 microgram.kg-1.min-1 for 10 min) significantly decreased cardiac output from 347 to 16 ml.min-1 to 248 +/- 16 ml.min-1 (p less than 0.025). Furthermore, CTA2 also significantly reduced blood flow to the left ventricle by 33 +/- 7%, but did not alter heart rate or MABP in the intact cat. In cats subjected to left anterior descending coronary artery occlusion, infusion of CTA2 (1 microgram.min-1 for 120 minutes) 30 min after ligation resulted in a significantly reduced myocardial cellular integrity as measured by myocardial creatine kinase activity (p less than 0.01) or percent bound myocardial cathepsin D (p less than 0.01). Thus, these data suggest that activation of vascular thromboxane receptors as well as direct cellular damage may play a role in the pathophysiology of myocardial ischemia.

Animals↗