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Biomedical subjects

A M Lefer

Publications and source records attributed to A M Lefer.

At least 271 records · Page 15Linked to original sources
PubMed1985

Beneficial effects of a neutral protease inhibitor in traumatic shock.

Eglin C is a polypeptide inhibitor of the neutral proteases elastase and cathepsin G. We have investigated its action in traumatic shock in rats. Eglin C (2 mg/kg) given following trauma prolonged survival time from 2.3 +/- 0.5 h to 3.6 +/- 0.4 h (p less than 0.05) in traumatized rats. Although eglin C treatment had no significant effect on the increase in plasma cathepsin D activity, eglin C administration significantly blunted plasma myocardial depressant factor (MDF) accumulation, 54 +/- 3 vs 79 +/- 8 U/ml (p less than 0.02). Our findings indicate a potential role for neutral proteases in toxic factor formation.

Anesthesia↗
PubMed1985

Modulation of leukotriene synthesis and actions by synthetic derivatives of arachidonic acid.

Seven analogs of arachidonic acid were tested for their coronary vasoactivity and their ability to inhibit LTC4 and LTD4 synthesis by lung tissue and to antagonize LTD4 induced coronary constriction. None of the seven arachidonic acid analogs significantly altered peptide leukotriene production by minced cat lung. Two of the analogs (i.e., 7, 13-diethanoarachidonic acid and 7, 10, 13-triethanoarachidonic acid) exerted modest but significant coronary vasodilation in isolated cat coronary arteries, and significantly antagonized the coronary vasoconstrictor response to LTD4. These analogs may be of interest in modulating leukotriene actions.

Animals↗
PubMed1985

Protective action of a thromboxane synthetase inhibitor in preventing extension of infarct size in acute myocardial infarction.

U-63,557A, a new selective thromboxane synthetase inhibitor, was evaluated for its ability to prevent the extension of myocardial infarct size. Left coronary arteries of male Sprague-Dawley rats (230 - 270 g) were acutely ligated, producing a consistent model of myocardial infarction (MI) in rats analyzed 48 hours later. Left ventricular free wall (LVFW), creatine kinase (CK) activity, and amino-nitrogen concentrations were assayed as indices of infarct size. U-63,557A was administered intravenously in two doses (4 and 8 mg/kg) with a split schedule (2 min post-ischemia and either 4 or 24 hrs later). Administration of the thromboxane synthetase inhibitor significantly reduced both myocardial CK and amino-nitrogen loss at a dose of 8 mg/kg, but it was only slightly effective at 4 mg/kg. Drug treatment significantly increased the percent LVFW spared; 27 +/- 3% (vehicle) vs 43 +/- 7% and 52 +/- 7% (8 mg/kg). U-63,557A is an effective agent in myocardial ischemia for limiting the extension of infarct size after acute coronary artery ligation. Previous studies of other thromboxane synthetase inhibitors showed effectiveness in the early stages of MI. This study shows an effect on true infarct size 48 hours post-ligation, and suggests that inhibition of thromboxane A2 plays an important role in the pathogenesis of ischemic damage in the myocardium.

Animals↗
PubMed1985

In vivo interaction of prostacyclin with an inhibitor of cyclic nucleotide phosphodiesterase, HL 725.

Prostacyclin (PGI2) inactivates platelets by stimulation of adenylate cyclase, and its effect can be potentiated in vitro by simultaneous inhibition of cyclic AMP phosphodiesterase. The interaction of synthetic PGI2 and the potent phosphodiesterase inhibitor HL 725 was studied in a model of systemic platelet activation by intravenous injection of collagen. Platelet aggregate formation was evaluated by continuous on-line measurement of the circulating platelet count. Collagen injection in rabbits receiving vehicle caused a 30 +/- 3% decrease in the circulating platelet count. Infusion of PGI2 (0.05, 0.1 and 0.75 micrograms kg-1 min-1) dose-dependently inhibited this decrease. HL 725 (0.5, 1 and 3 micrograms kg-1 min-1) caused a slight but significant effect. Combinations of PGI2 and HL 725, respectively, at 0.25 + 1.0 and 0.1 + 0.5 micrograms kg-1 min-1 inhibited platelet aggregate formation to a greater extent than when either substance was used alone and produced a comparable inhibition to PGI2 at 0.75 micrograms kg-1 min-1. Collagen induced an acute fall in the mean arterial blood pressure (MABP) which also was inhibited by PGI2, HL 725 and their combinations. The infusion of a combination of PGI2 and HL 725 before collagen produced a decrease in the MABP which was greater than when either compound was used on its own. Thus, PGI2 and the phosphodiesterase inhibitor HL 725 interact in vivo to inhibit platelet aggregation and lower MABP.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1985

Effects of peptide leukotrienes on cardiac dynamics in rat, cat, and guinea pig hearts.

The purpose of the present investigation was to examine potential inotropic effects of leukotrienes C4 (LTC4) and D4 (LTD4) in relation to their potent coronary constricting effects. The experiments were carried out in isolated Langendorff perfused hearts and isolated electrically driven isometrically contracting papillary muscle preparations. Tissues from cat, rat, and guinea pig were used in the study. Both LTC4 and LTD4 at 50 ng/ml had no effect on papillary muscles isolated from the rat, guinea pig, or cat. These papillary muscles responded to known negative inotropic agents including pentobarbital sodium and methanol. In isolated hearts perfused under constant flow, both LTC4 and LTD4 at 50 ng/ml increased coronary perfusion pressure and decreased contractile force of the heart in all three species. In hearts perfused under constant pressure perfusion, both LTC4 and LTD4 decreased coronary flow with concomitant decreases in contractile force. The leukotriene antagonist, FPL 55712, blocked both the coronary constrictor and the cardiodepressant effects of both leukotrienes. Pentobarbital (100 micrograms/ml) significantly decreased cardiac contractile force without inducing coronary vasoconstriction. These findings demonstrate that LTC4 and LTD4 do not possess direct negative inotropic activity in cardiac muscles of these three species. However, LTC4 and LTD4 are potent coronary constrictors that can secondarily decrease myocardial contractile force via their coronary constrictor action.

Animals↗
PubMed1985

Blockade of thromboxane and the prevention of eicosanoid-induced sudden death in mice.

We studied the effects of thromboxane-receptor antagonism and thromboxane synthetase inhibition in a thrombotic model of sudden death in mice. Intravenous injection of arachidonic acid (AA; 80 mg/kg) or the prostaglandin-endoperoxide analog U-46,619 (2.3 mg/kg) results in sudden death in approximately 90% of the animals. Pretreatment with the thromboxane receptor antagonist SQ-29,548 (0.3-10 mg/kg) protects dose-dependently against AA and U-46,619-induced sudden death. In contrast, CGS-13,080, a thromboxane synthetase inhibitor, shows a dose-dependent beneficial effect in AA-induced sudden death only. Although PTA2 has partial thromboxane agonistic properties in the rabbit, it protected the mice against AA-induced sudden death, thus demonstrating TxA2 antagonistic properties in this species. These data emphasize the importance of thromboxane A2 as a major mediator of arachidonic acid-induced sudden death and the effectiveness of thromboxane-receptor antagonists in endoperoxide-induced sudden death.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1985

Eicosanoids as mediators of ischemia and shock.

A variety of eicosanoids are produced in ischemic and circulatory shock. Many of these constrict arteries, induce platelet aggregation or adherence of other blood cells to the vasculature, and contribute to increased membrane permeability. Thromboxane A2, leukotriene C4, and leukotriene D4 fulfill all the criteria stipulated for humoral mediators of ischemia and shock. Moreover, pharmacologic modulation of these mediators by either specific inhibition of their synthesis or antagonism of their arteries at their receptor sites protects against tissue and cell damage during ischemia and shock as well as enhances survival in these life-threatening states.

Animals↗
PubMed1985

Beneficial effects of a new potent and specific thromboxane receptor antagonist (SQ-29,548) in vitro and in vivo.

SQ-29,548, a newly synthetized thromboxane receptor antagonist, was investigated for its effects on platelet and vascular thromboxane receptors in vivo and in vitro. Arachidonic acid (AA)-induced sudden death in rabbits was dose-dependently inhibited by SQ-29,548 at doses ranging from 0.2 to 2 mg/kg. Sudden death was accompanied by a 46 +/- 6% decrease in continuously measured circulating platelet count, which was also dose-dependently inhibited by SQ-29,548. The AA-induced increase in continuously recorded whole blood ATP content was 1.2 +/- 0.4 microM and was significantly diminished by all SQ-29,548 doses used. Platelet aggregation induced by AA, the endoperoxide analog U-46,619 or collagen in platelet-rich plasma was dose-dependently inhibited by SQ-29,548 which exerted an IC50 of 0.8, 0.3 or 2.9 microM, respectively. In contrast, ADP and platelet-activating factor acether-induced platelet aggregation were unaffected at concentrations of SQ-29,548 up to 260 microM. Thromboxane B2 formation was not significantly altered by SQ-29,548 (1-100 microM) in platelet-rich plasma stimulated with AA or in spontaneously clotting whole blood. Thromboxane synthetase, cyclooxygenase and lipoxygenase product formation were unaffected by SQ-29,548 when washed rabbit platelets were stimulated with radiolabeled AA and the products were measured after separation by thin-layer chromatography. U-46,619 (500 nM), carbocyclic thromboxane A2 (15 nM) and prostaglandin F2 alpha (3 microM)-induced contractions of rabbit pulmonary artery were antagonized by SQ-29,548 exerting a IC50 value between 120 and 40 nM, whereas norepinephrine-induced contractions were unaltered.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗
PubMed1985

Beneficial actions of two novel calcium entry blockers in the isolated perfused hypoxic cat liver.

The effects of two new calcium entry blockers, anipamil and ronipamil, were studied during 150 min of normoxic or hypoxic perfusion in isolated perfused cat livers. Hypoxic livers in which the vehicle for these inhibitors (i.e., ethanol) was injected intravenously prior to isolation of the liver, exhibited significantly higher increases in perfusion pressure, perfusate lactate dehydrogenase and cathepsin D activities, compared to control normoxic perfused livers. In contrast, the livers isolated from cats pretreated with calcium entry blocker anipamil and subsequently perfused under hypoxic conditions showed no significant difference in any of these variables from the control normoxic perfused livers. Ronipamil given intravenously 30 minutes prior to isolation also significantly protected the liver during hypoxia. The protection afforded by anipamil and ronipamil appears to be related to their inhibition of Ca++ influx which has been linked to cell death in hepatocytes.

Animals↗
PubMed1985

Protective effects of a new LTD4 antagonist (LY-171883) in traumatic shock.

We studied the effects of a selective antagonist of LTD4 (LY-171883, 2 and 4 mg/kg) in traumatic shock. Anesthetized rats subjected to Noble-Collip drum trauma developed a shock state characterized by a survival time of 1.7 +/- 0.3 h, a sixfold increase in plasma cathepsin D activity, and a fourfold increase in plasma myocardial depressant factor (MDF) activity. Administration of LY-171883 did not significantly inhibit the release of the lysosomal hydrolase cathepsin D during traumatic shock. However, LY-171883 (2 mg/kg) significantly attenuated the accumulation of MDF activity in the plasma (51 +/- 2 vs 37 +/- 3 U/ml), vehicle vs drug, respectively, and significantly (p less than 0.02) prolonged survival time to 2.7 +/- 0.2 h. Administration of the antagonist at a dose of 4 mg/kg further improved survival time (3.4 +/- 0.6 h, p less than 0.01) and additionally blunted circulating MDF activities compared to traumatized rats given only the vehicle. LY-171883 was found to antagonize the bronchoconstrictor effect of LTD4 given intravenously to anesthetized rats as well as the coronary vasoconstrictor actions of LTD4 in vitro. The beneficial effect of LTD4 antagonism in the present study is consistent with the concept that peptide leukotrienes are important mediators of the pathogenesis of traumatic shock.

Acetophenones↗
PubMed1985

Protective actions of propyl gallate, a lipoxygenase inhibitor, on the ischemic myocardium.

Products of the lipoxygenase pathway of arachidonate metabolism, including hydroperoxides, free radicals, and leukotrienes, are thought to mediate ischemic damage during acute myocardial ischemia (MI). Propyl gallate (1 mg/kg/h) was infused in anesthetized cats 0.5 h after coronary artery occlusion. Propyl gallate did not influence mean arterial blood pressure (MABP), heart rate (HR), or the product of these, the pressure-rate index. Treatment of MI with propyl gallate significantly reduced the plasma accumulation of creatine kinase (CK). This was confirmed by reduced CK loss in biopsies from the ischemic region of the heart, indicative of a protective effect. Propyl gallate also reduced the loss of compounds containing amino-nitrogen groups from the ischemic region, although it did not significantly reverse the S-T segment elevation in the electrocardiogram. These results are consistent with the concept that inhibition of formation of lipoxygenase products protects the myocardium from ischemic damage. This study also helps explain the work of others demonstrating that combined cyclooxygenase-lipoxygenase inhibitors or depletion of leukocytes is beneficial in MI.

Animals↗
PubMed1984

Protective actions of a new thromboxane synthetase inhibitor in arachidonate induced sudden death.

A new thromboxane synthetase inhibitor, OKY-046, at doses of 0.5 and 1.0 mg/kg prevented mortality induced by sodium arachidonate in 100% of the rabbits studied. Sodium arachidonate at a dose of 1.25 mg/kg uniformly decreased mean arterial blood pressure to values approximately 0 mm Hg, stopped respiration and produced sudden death within 3-5 minutes in all rabbits studied. OKY-046 prevented all these sequelae of the sodium arachidonate. Untreated rabbits challenged with sodium arachidonate develop large increases in circulating thromboxane B2 (TxB2) and 6-keto PGF1 alpha of about 12- to 18-fold. In contrast, OKY-046 prevented the increase in TxB2 concentrations and the pulmonary thrombosis, but did not block the rise in 6-keto PGF1 alpha following arachidonate injection. These results suggest that the protective mechanism of OKY-046 in arachidonate induced sudden death is via selective inhibition of thromboxane synthesis.

Acrylates↗
PubMed1984

Salutary effects of nitrendipine, a new calcium entry blocker, in hemorrhagic shock.

Intracellular accumulation of calcium is thought to play an integral role in the progression of ischemic injury and cell death. We infused the calcium entry blocker, nitrendipine (1.5 micrograms/kg per min), into cats in order to investigate the importance of extracellular Ca2+ influx during hemorrhagic shock. Nitrendipine proved to be a potent hypotensive agent in sham shock cats when infused over a 4 h period (156 +/- 9 to 90 +/- 5 mm Hg) (P less than 0.01). However, in hemorrhaged animals, nitrendipine treatment maintained the post-reinfusion MABP at a significantly higher (P less than 0.01) value than untreated controls (79 +/- 5 vs. 51 +/- 4 mm Hg, respectively). Superior mesenteric artery flow (SMAF) for hemorrhaged animals treated with nitrendipine was significantly higher (9.8 +/- 1.4 ml/min per kg) (P less than 0.01) than that for untreated cats (4.2 +/- 0.4 ml/min per kg), at 2 h post reinfusion. There was no significant increase in SMAF during oligemia in the nitrendipine-treated animals. Nitrendipine was also found to significantly retard the appearance of cathepsin D in the plasma of hemorrhaged cats as well as reduce plasma proteolysis to values not significantly different from sham shock animals. Furthermore, myocardial depressant factor (MDF) activity in the plasma of nitrendipine-treated shock cats was not significantly different from sham shock animals, while the plasma MDF activity for shock cats receiving vehicle increased 3-fold (P less than 0.001). The beneficial effects for nitrendipine in hemorrhagic shock are likely due to both its vasodilator function and its ability to reduce intracellular Ca2+ accumulation during ischemia, thereby reducing disruption of cell membrane systems.

Animals↗
PubMed1984

Beneficial effect of anisodamine in hemorrhagic shock.

Anisodamine , an alkaloid extracted from Anisodus tanguticus , is widely used in China in the treatment of septic shock, but its mechanism of action is unknown. We studied its antishock action in cats in a well controlled model of hemorrhagic shock. A bolus dose of 1 mg/kg was given intravenously 20 min after MABP was stabilized at 40-45 mm Hg, followed by i.v. infusion of 2 mg/kg/h during the oligemic period. Two hours post-reinfusion, MABP was significantly higher (106 +/- 10 mm Hg) in the drug-treated group than in shock cats receiving only vehicle (53 +/- 6 mm Hg, P less than 0.001). Anisodamine treated shock cats exhibited significantly lower cathepsin D activity (P less than 0.02) and amino-nitrogen concentration (P less than 0.001) than untreated shock animals. Plasma myocardial depressant factor (MDF) activity was significantly increased in the untreated shock cats (61 +/- 6 Units/ml), but the plasma accumulation of MDF was significantly blunted by anisodamine (32 +/- 5 Units/ml, P less than 0.01). Anisodamine did not increase superior mesenteric artery flow ( SMAF ) in this model of hemorrhagic shock as there was no significant difference in SMAF between the two shocked groups. Thus, the beneficial effect of anisodamine probably is not due to vasodilation of the splanchnic vasculature. In vitro analysis indicates that the drug has a direct anti-proteolytic action in cat pancreatic homogenates. This may partly explain the mechanism of its action, which appears to be complex.

Animals↗
PubMed1984

Potentiation of leukotriene formation in pulmonary and vascular tissue.

Leukotriene (LT) release from vascular and pulmonary tissue was assessed by a radioimmunoassay for peptide leukotrienes (i.e., LTC4, LTD4 and LTE4). The calcium ionophore A-23187 at 1-3 micrograms/ml and platelet activating factor (PAF) at 10 micrograms/ml produced marked formation of peptide leukotrienes in minced cat pulmonary tissue. This was also confirmed by bioassay of the incubates in isolated perfused cat coronary arteries. Rat pulmonary tissue was comparable to cat with regard to LT production, but guinea-pig lung produced about 30-50% less on a weight basis. In addition, aortic and coronary artery vessel walls produced significant amounts of LTs. The time course for maximal leukotriene production occurred at 45-60 min of incubation at 37 degrees C in both the radioimmunoassay and the bioassay. Cat coronary artery constricted markedly to LTC4 or LTD4 (30-40 mm Hg) and to the lung or blood vessel incubate. This constriction was virtually totally blocked by the leukotriene antagonist FPL-55712, but not by the thromboxane receptor antagonist, pinane thromboxane A2, the alpha-adrenergic receptor antagonist, phenoxybenzamine, or the angiotensin receptor antagonist, saralasin. Thus, pulmonary and vascular tissue produce leukotrienes that appear to exert coronary constrictor effects on specific leukotriene receptors. These results indicate that the ischemia of shock and anaphylaxis may be accentuated by the release of peptide leukotrienes.

Animals↗