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Biomedical subjects

A M Lefer

Publications and source records attributed to A M Lefer.

At least 253 records · Page 14Linked to original sources
PubMed1986

Anti-shock properties of the prostacyclin analog, iloprost, in traumatic shock.

The effects of iloprost, a synthetic carbacyclin derivative of prostacyclin (PGI2) was studied in a standardized model of traumatic shock. Pentobarbital anesthetized rats (35 mg/kg) subjected to Noble-Collip drum trauma were characterized by a 84 +/- 10 minute survival time, a 16-fold increase in plasma cathepsin D activity, and a 5-fold increase in plasma myocardial depressant factor (MDF) activity. Iloprost significantly attenuated the accumulation of MDF activity in the plasma (69 +/- 14 vs. 20 +/- 6 U/ml) vehicle vs. drug (p less than 0.01), respectively, and significantly prolonged survival time to 243 +/- 36 minutes (p less than 0.01). Plasma cathepsin D activity was also significantly attenuated (12 +/- 1.8 vs. 6.2 +/- 2.1 U/ml), vehicle vs. drug, respectively (p less than 0.02). Iloprost exhibited significant anti-proteolytic activity in pancreatic homogenates. Iloprost appears to exert a membrane stabilizing effect decreasing plasma cathepsin D activity and attenuating MDF production, probably secondarily to its anti-proteolytic effect and its maintenance of the splanchnic circulation. Iloprost may therefore prove to be a useful therapeutic agent in acute ischemic disorders including traumatic shock.

Animals↗
PubMed1986

Coronary vasoactivity of four 7,13-bridged analogs of arachidonic acid.

Four newly synthesized 7,13-bridged arachidonic acid analogs which have been shown to exert 5-lipoxygenase inhibitory activity were studied in isolated perfused cat coronary arteries. The two dehydro analogs constricted and the two non-dehydro analogs dilated the coronary arteries. None antagonized LTD4 induced constriction. Thus there is no direct connection between lipoxygenase inhibition and leukotriene inhibition or vasoactivity.

Animals↗
PubMed1986

Modulation of receptor mediated leukotriene release in the perfused heart.

The chemotactic peptide n-formyl-methionyl-leucyl-phenylalanine (FMLP) induces peptide leukotriene release at concentrations of 20-25 pmol/ml 3 min after the start of FMLP infusion. FMLP-induced leukotriene release in rabbit hearts is not blocked by the leukotriene receptor antagonist FPL-55712 at concentrations that totally antagonize the hemodynamic effects of exogenously infused peptide leukotrienes. Moreover, propyl gallate, a lipoxygenase inhibitor, does not block FMLP-induced leukotriene release. However, the chemotactic peptide antagonist (Boc-Phe-Leu-Phe-Leu-Phe-OH) totally antagonized FMLP-induced leukotriene release suggesting that the release is via a different mechanism, possibly a receptor mediated event.

Animals↗
PubMed1986

Beneficial effects of tissue-type plasminogen activator in acute myocardial ischemia in cats.

Tissue-type plasminogen activator is a new thrombolytic agent that dissolves intravascular thrombi in coronary and peripheral vessels with less pronounced systemic lysis than that produced by streptokinase. Plasminogen activator was shown to induce reperfusion, and to salvage ischemic myocardium, by lysing experimentally induced coronary artery thrombi. The effect of a melanoma cell-derived tissue-type plasminogen activator was studied in cat myocardium rendered ischemic by coronary artery ligation for 2 hours and reperfused for another 4 hours. Plasminogen activator was infused at a rate of 500 IU X kg-1 X min-1 for the first 30 minutes of reperfusion. The marked increase in plasma creatine kinase activity during reperfusion was significantly lower in plasminogen activator-treated cats at 4, 5 and 6 hours, with 7.7 +/- 1.5 X 10(-3) IU X mg protein-1 (n = 8) in the plasminogen activator group versus 17.8 +/- 3.5 X 10(-3) IU X mg protein-1 (n = 7) in the vehicle group at 6 hours (mean +/- SEM). The area at risk in the two ischemic groups was not different, being 14.6 +/- 1.5 and 16.6 +/- 1.4% of total left ventricular mass for the treated and untreated groups, respectively. However, the mass of necrotic tissue determined histochemically was significantly lower in the plasminogen activator-treated group, accounting for 29.5 +/- 3.9% of the area at risk compared with 46.8 +/- 4.2% of area at risk in cats receiving only the vehicle (p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Significance of production of peptide leukotrienes in murine traumatic shock.

We studied the formation of a leukotriene metabolite in plasma and bile during traumatic shock. Anesthetized rats subjected to Noble-Collip drum trauma developed a lethal shock state characterized by a survival time of 1.9 +/- 0.3 h, a 4.5-fold increase in plasma cathepsin D activity, and a reduction in mean arterial blood pressure to 45 +/- 2 mmHg compared with 108 +/- 5 mmHg in sham-shock controls. Plasma and bile samples were analyzed by reverse-phase high-pressure liquid chromatography (HPLC) for peptide leukotrienes (e.g., LTC4, LTD4, and LTE4), and their retention times were confirmed by co-elution with radioactive standards, radioimmunoassay (RIA), and UV spectrophotometry. No leukotrienes or metabolites were found in plasma. The major peptide leukotriene from bile was eluted between LTC4 and LTD4 and corresponds to a metabolite of LTE4, N-acetyl-LTE4, which is also produced during endotoxin shock. The metabolite increased nearly sevenfold in traumatic shock compared with sham trauma. The identity of the metabolite was confirmed by UV scan, which revealed a spectrum consistent with a peptide leukotriene and similar to that of previously reported spectra for N-acetyl-LTE4. In conclusion, peptide leukotrienes are rapidly cleared from the blood and appear in the bile as N-acetyl-LTE4, a metabolite of the peptide leukotrienes. These findings support a role of the peptide leukotrienes in the pathogenesis of traumatic shock.

Animals↗
PubMed1986

Mechanism of the pressor effect of the calcium agonist, BAY k 8644, in the intact rat.

The purported calcium agonist BAY k 8644 was tested as a pressor agent in pentobarbital anesthetized and conscious Sprague-Dawley rats. A dose of 10 micrograms/kg increased mean arterial blood pressure (MABP) by 47 +/- 3 mm Hg in anesthetized and 39 +/- 3 mm Hg in conscious rats. The calcium channel blockers nitrendipine or nisoldipine (180 micrograms/kg/h) blocked 62-84% of the pressor response of BAY k 8644 (p less than 0.001 from control responses). The alpha-adrenergic receptor antagonist phentolamine (400 micrograms/kg) failed to alter the Bay k 8644 induced pressor response either in the conscious or anesthetized state. Moreover, the thromboxane receptor antagonist, SQ-29,548 and the leukotriene D4 and E4 receptor antagonist LY-171,883 at doses that markedly block thromboxanes or leukotrienes, respectively, had no effect on the BAY k 8644 induced pressor response. Neither the angiotensin II receptor antagonist, saralasin nor an arginine vasopressin antagonist (AVP-A) modify the BAY k 8644 induced pressor response. Thus, BAY k 8644 appears to directly increase MABP in the rat by activation of calcium influx into vascular smooth muscle and/or cardiac muscle cells, probably without the action of any common secondary vasoconstrictor mediator.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1986

Inhibition of the platelet activating factor mediated component of guinea pig anaphylaxis by receptor antagonists.

The role of platelet activating factor (PAF) and its inhibition by specific receptor antagonists was studied in hypersensitivity reactions in guinea pig lung parenchymal strips and in guinea pigs in vivo. Immunological challenge of isolated lung parenchymal strips with ovalbumin resulted in a contractile response of 184 +/- 16 mg (n = 38). Pretreatment of the strips with a combination of the antihistamine diphenhydramine, the dual lipoxygenase and cyclooxygenase product synthesis inhibitor BW-755C, and the PAF receptor antagonist kadsurenone totally inhibited the increase in tension. The bronchoconstrictor effects induced by immunological challenge were also totally inhibited when the leukotriene receptor antagonist FPL-55,712 was used to replace BW-755C or another PAF receptor antagonist, alprazolam was used to replace kadsurenone. Ovalbumin challenge in sensitized guinea pigs in vivo resulted in airway constriction, circulatory failure and an abrupt fall in continuously measured platelet count by 75 +/- 12%, followed by death of all animals within 5-8 min. Pretreatment with diphenhydramine, BW-755C and kadsurenone (or alprazolam) improved survival to 64% (i.e., 7 of 11 animals) compared to a survival rate of 0% (i.e., 0 of 8 vehicle treated controls). Despite the improved survival, the severe thrombocytopenia was unaltered with the combined therapy. PAF, histamine and peptide leukotrienes appear to act in concert in mediating the anaphylaxis-induced airway constriction and circulatory failure in guinea pigs, but are not apparently responsible for the accompanying thrombocytopenia.

Alprazolam↗
PubMed1986

Inhibition of leukotriene actions by the calcium channel blocker, nisoldipine.

Nisoldipine, a calcium channel blocker having a highly potent effect on vascular smooth muscle relative to cardiac muscle, was tested to determine its anti-leukotriene properties. Nisoldipine, at concentrations from 1 to 300 ng/ml, significantly attenuated the vasoconstrictor effects of both LTC4 and LTD4 in isolated perfused cat coronary arteries and in isolated Langendorff perfused cat hearts. In isolated perfused coronary arteries, nisoldipine exerted a greater percentage inhibition of LTC4- and LTD4-induced constriction than of the constriction induced by the thromboxane analog, carbocyclic thromboxane A2 (CTA2). In isolated cat lung fragments, higher concentrations of nisoldipine were required to inhibit leukotriene formation (i.e., 10-200 microM). These concentrations of nisoldipine markedly inhibited the formation of the chemotactic leukotriene (LTB4) as well as the peptide leukotrienes (LTC4 and LTD4) stimulated by A-23187. Both types of leukotrienes were inhibited to a comparable degree. Thus, nisoldipine has significant anti-leukotriene actions. At normally employed concentrations, nisoldipine inhibits leukotriene actions on vascular smooth muscle, and at higher concentrations, it inhibits leukotriene formation.

Animals↗
PubMed1986

Beneficial actions of thromboxane receptor antagonism in hemorrhagic shock.

The new specific thromboxane receptor antagonist, BM-13505, was infused intravenously (1 mg/kg bolus and 1 mg/kg hr continuous infusion) to determine its effect in a feline model of hemorrhagic shock. Hemorrhaged cats treated with BM-13505 maintained post-reinfusion mean arterial blood pressure and superior mesenteric artery flow at significantly higher values compared to cats receiving only the vehicle. BM-13505 was also found to attenuate the increase in plasma cathepsin D activity in hemorrhaged cats as well as to curtail plasma proteolysis to values not significantly different from sham shock animals at the end of the post-reinfusion period. Furthermore, the plasma activity of a myocardial depressant factor (MDF) was significantly lower in BM-13505-treated shocked cats than in the vehicle group (37 +/- 4 vs 71 +/- 7 U/ml, P less than .01). Additionally, BM-13505 was shown to antagonize thromboxane-induced vasoconstriction in isolated perfused cat coronary arteries and to exert an anti-aggregatory effect in platelet-rich cat plasma induced by the endoperoxide analog, U-46619. However, BM-13505 failed to show a direct antiproteolytic effect in cat pancreatic homogenates. Thus, the beneficial effects of BM-13505 in hemorrhagic shock are likely due to both its prevention of thromboxane-induced vasoconstriction and its ability to attenuate thromboxane-induced platelet aggregation. Our results further substantiate the role of thromboxane A2 as a mediator of hemorrhagic shock and suggest that antagonism of thromboxane receptors may be useful in the treatment of hemorrhagic shock.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1986

Effects of lisinopril, a new angiotensin converting enzyme inhibitor in a cryo-injury model of chronic left ventricular failure.

The angiotensin converting enzyme inhibitor, lisinopril, was studied in a cryo-injury model of chronic heart failure. This model is characterized by a progressive decrease in cardiac output starting six weeks after cryo-injury to a 30% decrease in cardiac output 10 weeks after injury. Although histological damage to the myocardial tissue, particularly in the epicardial area, was observed, no significant changes occurred in body weight, mean arterial blood pressure, heart rate or central venous pressure. Daily intraperitoneal injection of 3 mg/kg lisinopril was instituted starting four weeks after injury for a duration of six weeks. Lisinopril completely restored the cardiac output to normal values at the end of this six week period. Thus, converting enzyme inhibition appears to be an effective therapeutic agent in this model of chronic cardiac failure.

Animals↗
PubMed1986

Cardioprotective actions of a new calcium channel blocker in acute myocardial ischemia.

The ability of anipamil, a calcium channel blocker, to protect ischemic myocardial tissue was investigated in pentobarbital anesthetized cats. Two bolus injections of anipamil (1.0 mg/kg i.v.) or their vehicle (i.e., 95% ethanol) were given 30 and 150 min post-ligation of the left anterior descending coronary artery. Anipamil significantly reduced the elevated S-T segment elevation and T wave amplitude suggesting a moderating influence on cellular ischemia. The drug also significantly blunted the loss in myocardial creatine kinase activity and amino-nitrogen concentrations from ischemic myocardial tissue, compared to cats receiving only the vehicle. These changes are suggestive of a cardioprotective effect of this calcium channel blocker. Since no significant change in the pressure rate index was seen with anipamil, a decrease in myocardial oxygen demand does not appear to be the major mechanism of the cardioprotective action of the agent. Therefore, anipamil protected the heart from ischemic damage, possibly by a direct cytoprotective action.

Animals↗
PubMed1986

In vivo anti-platelet properties of anipamil, a calcium channel blocker, in the rabbit.

The anti-platelet actions of anipamil, a new calcium channel blocker were studied in anesthetized rabbits using continuous on-line techniques to measure platelet count and platelet secretion by ATP release. Anipamil, at a dose of 0.5 mg/kg twice daily for three days, prior to challenge with collagen (100 micrograms/kg) or arachidonic acid (1.1 mg/kg), was without effect. However, 2 and 5 mg/kg of anipamil significantly retarded the decline in platelet count to both platelet activators, although anipamil failed to significantly diminish the hypotensive effect of these platelet activators, or significantly increase survival to arachidonic acid. Moreover, anipamil was without effect on the platelet effects of platelet activating factor (PAF). Thus, anipamil has the ability to partially inhibit the activation of platelets in vivo.

Adenosine Triphosphate↗
PubMed1986

Anti-shock actions of the pyrimido-pyrimidine derivative, RA-642.

The anti-shock actions of RA-642 were studied in traumatic shock in rats. The shock state was characterized by a significantly reduced mean arterial blood pressure (MABP), a five-fold increase in plasma cathepsin D activity, a three-fold increase in plasma myocardial depressant factor (MDF) activity, and a mean survival time of 1.6 +/- 0.3 h. Administration of 0.5 mg/kg of the pyrimido-pyrimidine derivative, RA-642, significantly prolonged survival time to 3.7 +/- 0.6 h (p less than 0.01). Plasma cathepsin D activity was not affected by RA-642 although accumulation of the cardiotoxic peptide MDF was significantly blunted (p less than 0.025). This effect on MDF accumulation may be related to the potent antiproteolytic action of RA-642 in vitro. Results indicate that RA-642 provides significant beneficial effects in a severe model of traumatic shock.

Animals↗
PubMed1986

CGS-12970, a thromboxane synthetase inhibitor, limits ischemic damage following coronary artery occlusion.

A new thromboxane synthetase inhibitor, CGS-12970, was evaluated for its ability to reduce the extension of myocardial infarct size in rats. CGS-12970 was given at either 4 or 8 mg/kg following acute coronary artery ligation. Both myocardial creatine kinase (CK) and amino-nitrogen loss from the left ventricular free wall (LVFW) were used as indices of ischemic damage at 48 hours. Rats given only the vehicle following coronary artery ligation lost 4.9 +/- 0.5 IU/mg protein (p less than 0.001) CK activity from the LVFW. This loss of CK activity was only slightly reduced by CGS-12970 at 4 mg/kg. However, at 8 mg/kg, the CK depletion from the LVFW was significantly reduced (p less than 0.05). This protective effect was confirmed by similar curtailment (p less than 0.05) of the loss of nitrogenous compounds from ischemic myocardium, at the high dose of CGS-12970. These findings represent a protective effect of CGS-12970 in reducing the extent of ischemic cardiac damage following experimental coronary artery ligation.

Animals↗
PubMed1985

Antiaggregatory effects of thromboxane receptor antagonists in vivo.

The antiaggregatory and antisecretory effects of two newly developed thromboxane receptor antagonists, BM-13,177 and SQ-29,548, were studied in an in vivo model of platelet activation. Arterial platelet count and whole blood ATP concentrations were measured continuously on-line in the arterial blood of anesthetized rabbits. Injections of collagen decreased peripheral platelet count by 25% of initial value. ATP concentrations increased 50 to 100 nM during collagen challenge. SQ-29,548 and BM-13,177 dose-dependently reduced platelet loss to about 50% of that observed in vehicle treated animals. Injection of arachidonic acid (AA) or 9,11-methanoepoxy-PGH2 resulted in sudden death of the animals associated with a 67 to 69% decrease in platelet count and a marked release of ATP. Pretreatment with SQ-29,548 or BM-13,177 increased survival rates from 0 to 100%, and reduced or totally inhibited ATP secretion and decreases in platelet count. In contrast, the thromboxane synthetase inhibitor, dazoxiben, was effective in inhibiting AA induced sudden death, but was without any effect when 9,11-methanoepoxy-PGH2 was used as the challenging agent. We conclude that SQ-29,548 and BM-13,177 are effective in antagonizing the effects of subsequent conversion to thromboxane A2. BM-13,177 and SQ-29,548 are generally considered as specific antagonists of endoperoxide/thromboxane receptors on platelets and smooth muscles in vitro. Preliminary clinical studies with BM-13,177 showed a marked inhibition of ex vivo platelet aggregation in human volunteers and patients (18, 19). These reports encourage further study of thromboxane receptor antagonists as effective anti-thrombotic drugs in the experimental and clinical setting.

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

Anti-ischemic actions of a new thromboxane receptor antagonist during acute myocardial ischemia in cats.

Thromboxane A2 (TxA2) production increases significantly during acute myocardial ischemia. Since TxA2 induces platelet aggregation, coronary vasoconstriction, and has a direct cytolytic effect, thromboxane receptor antagonism would be expected to be beneficial in acute myocardial ischemia. Thirty minutes after ligation of the left anterior descending coronary artery (LAD) in anesthetized cats, the TxA2 receptor antagonist BM-13,177 or its vehicle was given as a bolus injection at 20 mg/kg, followed by continuous infusion of 20 mg/kg/hr for 4.5 hours. ST segment elevation declined significantly (p less than 0.02) after BM-13,177 treatment, suggesting a reduction in cellular ischemia. The loss in myocardial creatine kinase (CK) activity and in free amino-nitrogen concentration in the ischemic area was also significantly reduced (p less than 0.01). No significant changes in blood pressure or heart rate were seen with BM-13,177 during myocardial ischemia or in nonischemic control cats. Blood levels of BM-13,177 were sufficient to inhibit ex vivo platelet aggregation induced by the prostaglandin endoperoxide analog, U-46,619. Data from isolated cat coronary arteries suggest that BM-13, 177 antagonizes the thromboxane/endoperoxide receptor in coronary vascular smooth muscle. These experiments indicate that TxA2 plays a significant role in propagating the extension of ischemic damage, and that thromboxane receptor antagonism is an effective means of reducing the damage provoked by TxA2 in acute myocardial ischemia.

Animals↗
PubMed1985

Preservation of ischemic myocardium by a new converting enzyme inhibitor, enalaprilic acid, in acute myocardial infarction.

Enalaprilic acid (MK-422), the biologically active diacid of the converting enzyme inhibitor enalapril, was studied in myocardial ischemia (MI). Acute left coronary artery ligation was produced in 62 male Sprague-Dawley rats, and infarct size was determined by left ventricular free wall (LVFW) creatine kinase (CK) activity. Administration of enalaprilic acid (2 mg/kg) 2 minutes and 24 hours after MI significantly blunted the reduction in LVFW CK activity at 48 hours after ligation, when compared to the MI rats given vehicle (6.4 +/- 0.5 vs 4.7 +/- 0.2 IU/mg protein, respectively; p less than 0.01). The percentage of LVFW spared was significantly (p less than 0.01) increased from 28 +/- 2% to 45 +/- 5% by MK-422. MK-422 also significantly blunted the loss of LVFW CK activity 48 hours after a coronary ligation (10 minutes) followed by reperfusion, when compared to vehicle (10.1 +/- 0.6 vs 8.3 +/- 0.6 IU/mg protein, respectively; p less than 0.05). This represents a significant increase in the percentage of LVFW spared, 65 +/- 5% vs 85 +/- 6% (p less than 0.05). These data indicate a significant protective action afforded by MK-422 in two different protocols of ischemic damage to the myocardium and suggest a role for the renin-angiotensin system in the extension of ischemic damage.

Angiotensin II↗