Biomedical subjects

A M Lefer

Publications and source records attributed to A M Lefer.

At least 289 records · Page 16Linked to original sources

PubMed1984

Thromboxane A2 in acute myocardial infarction.

We evaluated the presence of thromboxane B2, the stable metabolite of thromboxane A2, early in the course of acute myocardial infarction (AMI) in both animal and patient studies. In an open-chest model, the left anterior descending artery (LAD) was isolated and the great cardiac vein was cannulated in nine dogs. Following occlusion of the LAD, there was an increase in thromboxane B2 concentration from 0.77 +/- 0.0093 to 1.79 +/- 0.46 pmol/ml (p less than 0.05) and 1.96 +/- 0.48 pmol/ml (p less than 0.05) at 1 and 5 minutes, respectively, following coronary occlusion. At 30 and 60 minutes after occlusion there was no significant increase compared to the baseline. In 17 patients with AMI the mean thromboxane B2 concentration was 0.96 +/- 0.13 pmol/ml at 4.88 +/- 0.40 hours after the onset of chest pain. In 12 patients with sequential samples before and after restoration of patency of the occluded vessel, the initial concentration was 0.71 +/- 0.058 pmol/ml. At 5 minutes after restoration of patency thromboxane B2 concentration was 1.1 +/- 0.17 pmol/ml (p = 0.05). One hour later a return to baseline was noted (0.82 +/- 0.75 pmol/ml). Two patients with the highest thromboxane B2 concentrations (2.0 and 2.6 pmol/ml) were unable to have successful recanalization. We conclude that generation of thromboxane A2 occurs during the early stages of AMI and may be an important pathophysiologic phenomenon in AMI.

Animals↗

PubMed1984

Inhibitors of lipoxygenase products improve survival in traumatic shock.

We have used three selective inhibitors of arachidonic acid metabolism in order to investigate the role of lipoxygenase metabolites in the pathogenesis of traumatic shock (LD90). The following inhibitors were used: CGS-5391B (2.5 mg/kg), a cyclooxygenase and lipoxygenase inhibitor, CGS-5677 (2.0 mg/kg), a selective lipoxygenase inhibitor, and U-60,257 (0.3 mg/kg), a putative inhibitor of glutathione-s-transferase. These inhibitors did not alter arterial blood pressure or heart rate when given to sham shock rats. The traumatic shock model was characterized by a 4.5-fold increase in plasma cathepsin D activity, a 4-fold increase in plasma myocardial depressant factor (MDF) activity, and a mean survival time of 1.5 +/- 0.2 h. Only the dual inhibitor significantly blunted the accumulation of cathepsin D in the plasma (7.5 +/- 0.8 vs 11.3 +/- 0.8 U/ml, p less than 0.01). However, all three inhibitors significantly suppressed plasma MDF accumulation by 50-60%: CGS-5391B, CGS-5677, and U-60,257 (p less than 0.01). Moreover, these three agents significantly improved survival time in traumatic shock. The increased survival time and reduced MDF activity afforded by these inhibitors suggest a significant role for lipoxygenase metabolites, particularly LTC4 and LTD4, in the pathogenesis of traumatic shock.

Animals↗

PubMed1984

Leukotriene production in isolated tissues of diabetic rats.

We examined the ability of heart, aorta and lung obtained from alloxan diabetic rats as well as control rats to produce peptide leukotrienes (LT). The isolated perfused heart preparation as well as incubated minced tissue preparations were studied. Upon infusion of the Ca++ ionophore A23187, hearts from diabetic rats produced significantly less peptide LT when compared to control hearts. Lung tissue from diabetic animals incubated with A23187 also produced less immunoreactive peptide leukotrienes (iLT) when compared to the control group. In both preparations, incubation with the lipoxygenase inhibitor propyl gallate significantly inhibited the production of iLT in both the diabetic and control group. The observed differences in production of leukotrienes may alter vascular reactivity and thus play a role in the cardiovascular complications observed in diabetes.

Animals↗

PubMed1984

Specificity of anti-leukotriene actions of nicardipine.

The calcium channel blocker, nicardipine (100 ng/ml) markedly antagonized the coronary vasoconstrictor effect of the peptide leukotrienes LTC4 and LTD4 on the isolated perfused cat coronary artery. However, nicardipine even at 300 ng/ml failed to antagonize the leukotriene induced contraction of either tracheal or pulmonary parenchymal strips from guinea pigs. However, at higher concentrations (i.e., 10 micrograms/ml), nicardipine inhibited the production of peptide leukotrienes from minced cat lung incubated in the presence of A23187. Thus, nicardipine exerts some selectivity in its anti-leukotriene actions.

Animals↗

PubMed1984

Potentiation of coronary vascular platelet adhesion by atrial pacing in the presence of arterial stenosis in dogs.

The effect of atrial pacing on coronary hemodynamics and platelet adhesion was evaluated in 13 dogs. In all 13 dogs, a snare was placed around the circumflex artery and tightened so that distal coronary artery pressure decreased to 60 to 70 mm Hg. In 10 dogs, atrial pacing was instituted at twice the heart rate at rest for 10 minutes. In three dogs, observation was continued for 10 minutes without pacing. In the 10 dogs undergoing pacing, heart rate increased from 90.5 +/- 32.6 to 173.5 +/- 45.8 beats/min. Aortic pressure was unchanged. Distal coronary artery pressure decreased from 70.8 +/- 7.8 to 53.2 +/- 10.0 mm Hg (p less than 0.05) and the pressure gradient across the stenosis increased from 47.6 +/- 12.7 to 61.2 +/- 9.1 mm Hg (p less than 0.05). Stenotic resistance increased from 2.5 +/- 0.8 to 3.6 +/- 2.4 mm Hg/ml X min-1, but coronary flow was unchanged. In all three control dogs, there was no change in coronary dynamics for the 10 minute period. In 8 of the 10 dogs that underwent pacing, platelet deposition was observed at the site of coronary stenosis. In contrast, in the three control dogs there was no platelet deposition. Atrial pacing in the presence of coronary stenosis appears to alter coronary hemodynamics such that there are activation and deposition of platelets at the site of stenosis. This platelet deposition may be transient or could become the nidus for subsequent platelet-related events in the coronary vessel.

Animals↗

PubMed1984

Pathophysiological mechanisms of sudden death induced by platelet activating factor.

Platelet activating factor (Paf) (15-40 micrograms-1) kills male rabbits within 3 to 5 min. Intravenous injection of Paf at a dose of 15 micrograms kg-1 is uniformly lethal, and the rabbits died within 4.5 +/- 0.4 min. The sudden death is characterized by cessation of respiration, a marked decrease in mean arterial blood pressure (M.A.B.P.), and 8 fold increases in plasma thromboxane B2 (TxB2) concentrations with only modest elevation in plasma 6 keto-prostaglandin F1 alpha (6-keto PGF1 alpha) concentrations. Pretreatment with the cyclo-oxygenase inhibitor, ibuprofen (6.25 mg kg-1), or with the thromboxane synthetase inhibitors dazoxiben (2.5 mg kg-1), CGS-13080, or OKY-046 1 mg kg-1) increased survival rates to 83-100%. Protected rabbits showed only modest changes in M.A.B.P. and no significant increase in plasma TxB2 concentrations. The protective drugs showed a dose-related action on M.A.B.P., plasma TxB2 concentration and mortality rate in Paf-induced sudden death. The mechanisms of the protection appeared to be prevention of platelet aggregation (leading to pulmonary thrombosis) and pulmonary and coronary vasoconstriction. However, Paf does not appear to exert direct vasoconstrictor effects in isolated coronary or pulmonary arteries. The effects of Paf in vivo appear to be mediated by TxA2 released by activated platelets in the absence of the protective effects of prostacyclin. Inhibition of thromboxane synthesis effectively prevents the Paf-induced sudden death.

Animals↗

PubMed1984

Effects of lipoxygenase inhibitors in arachidonate-induced sudden death.

Both BW 755c, a cyclo-oxygenase and lipoxygenase inhibitor, and nordihydroguaiaretic acid (NDGA), a selective lipoxygenase inhibitor, were tested for their protection against arachidonate-induced sudden death in rabbits. 100% survival was seen with BW 755c (1 mg kg-1), while NDGA showed 0 and 17% survival (2 mg kg-1 and 4 mg kg-1). BW 755c prevented 12-fold increase in plasma thromboxane B2 concentrations and the formation of pulmonary artery thrombi normally seen with arachidonate-induced sudden death, while NDGA showed no such protective effect. Radioimmunoassay of rabbit plasma for leukotrienes (LTC4, LTD4 and LTE4) indicated that they do not accumulate in blood in the model and BW 755c had no effect, suggesting that the deleterious effects seen are caused by cyclo-oxygenase pathway metabolites such as thromboxane A2, but not by lipoxygenase pathway products such as leukotrienes.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗

PubMed1984

Preservation of ischemic myocardial tissue with an antagonist of vasoconstrictor eicosanoids.

A new antagonist of the vasoconstrictor eicosanoids, L-640,035, was studied in a standardized model of myocardial ischemia (MI) in anesthetized cats. This eicosanoid antagonist was not found to exert any overt hemodynamic action in cats subjected to a sham myocardial ischemia protocol. However, the antagonist markedly reduced the S-T segment of the electrocardiogram when administered 30 min after permanent occlusion of the left coronary artery. Moreover, circulating activities of the marker enzyme creatine kinase (CK) were markedly attenuated by L-640,035 3-5 h after the onset of MI. This was verified by cardiac biopsies 5 h post-MI since myocardial CK activities decreased much less in treated MI cats than in MI cats receiving only the vehicle for L-640,035 (i.e., ethanol). The active metabolite of the antagonist in biological fluids (i.e., L-636,499) markedly antagonized the vasoconstrictor actions of endoperoxide and thromboxane analogs, but not of noneicosanoids in isolated perfused coronary arteries.

Animals↗

PubMed1984

Role of AVP in maintenance of circulatory homeostasis during hemorrhagic shock.

Hemorrhagic hypotension produces significantly increased plasma arginine vasopression (AVP) concentrations. We have utilized a specific antagonist (AVP-A) of the pressor effects of endogenous AVP to investigate the role of this neurohypophyseal hormone on the pathogenesis of hemorrhagic shock. Infusion of the AVP-A (2 micrograms/kg bolus + 2 micrograms X kg-1 X h-1 infusion) into sham-shocked animals produced no significant changes in any of the observed experimental variables. Cats subjected to hemorrhagic shock given AVP-A had final superior mesenteric artery flow (SMAF) values significantly (P less than 0.05) higher than shock cats given vehicle (7.7 +/- 1.1 vs. 4.5 +/- 0.8 ml X kg-1 X min-1, respectively). Increases in postreinfusion plasma cathepsin D activities were significantly blunted in hemorrhaged animals treated with AVP-A (10.4 +/- 2.0 vs. 24.8 +/- 5.5 U/mg protein; P less than 0.05). Plasma proteolysis as well as the plasma accumulation of myocardial depressant factor (MDF) were also significantly modulated by AVP-A treatment in hemorrhaged animals. MDF activities were 75 +/- 6 and 53 +/- 4 U/ml (P less than 0.02) for shock cats given vehicle or AVP-A, respectively. However, these beneficial actions were not reflected in any significant improvement in postreinfusion mean arterial blood pressure (MABP). These findings suggest that endogenous AVP functions not only as a potent splanchnic vasoconstrictor but also as a key humoral factor in the maintenance of postreinfusion MABP, a profile that is different from the role of angiotensin II, the other major splanchnic vasoconstrictor, in shock.

Animals↗

PubMed1984

Cardioprotective effects of enalapril in acute myocardial ischemia.

Enalapril, a new potent orally active angiotensin-converting enzyme inhibitor, was studied in cats subjected to acute myocardial ischemia. Enalapril, administered intravenously (2 mg/kg, plus 2 mg/kg/h) 30 min after ligation of the left coronary artery, significantly reduced the pressure-rate index, an indicator of myocardial oxygen demand. This was confirmed in isolated cat papillary muscles where enalapril reduced contractile force by 5-10%. During myocardial ischemia, enalapril reversed the elevated S-T segment of the electrocardiogram toward normal 2 h after the onset of ischemia. Moreover, enalapril significantly blunted the increases in circulating creatine kinase (CK) activity, as well as significantly prevented the loss in myocardial CK activity. These changes correlated with reduced myocardial loss of compounds containing free amino-nitrogen. Enalapril effectively acted as a converting enzyme inhibitor over the 5-hour course of the observation period. However, enalapril also acted as an angiotensin antagonist in isolated coronary arteries, a finding that may help explain its efficacy in myocardial ischemia. Enalapril did not appear to stabilize the membranes of cat liver lysosomes, and thus probably does not protect the ischemic myocardium by lysosomal stabilization.

Acute Disease↗

PubMed1984

Altered coronary vascular responsiveness to leukotrienes in alloxan-diabetic rats.

Altered responsiveness to and metabolism of various eicosanoids in diabetic animals and patients has been reported by several investigators. The purpose of this investigation was to examine the coronary vascular responsiveness of alloxan-diabetic rats to the leukotrienes. Hearts from 12- to 16-week-old alloxan-diabetic rats and weight-matched controls were perfused at constant flow by the Langendorff method. Coronary vasoactivity to leukotrienes B4, C4, D4 and E4 was assessed by measuring the change in coronary perfusion pressure upon infusion of these eicosanoids. Hearts from diabetic rats showed increased responsiveness to leukotrienes C4 (4-40 nM) and D4 (10-100 nM). Both control and diabetic rat hearts were only slightly responsive to leukotriene E4, and no difference between the two groups existed in the reactivity to this leukotriene. Neither group was responsive to the chemotactic leukotriene, B4. Perfusion of the hearts with the cyclooxygenase inhibitor, ibuprofen, failed to alter the coronary vascular responses to the leukotrienes. The coronary constrictor effects of the leukotrienes are the primary effect of these agents on the rat heart, since heart rate does not change significantly, and changes in contractile force are secondary to the coronary vascular constriction. These alterations in responsiveness to leukotrienes may play a role in the cardiovascular complications associated with diabetes.

Aging↗

PubMed1984

Coronary vascular actions of the converting enzyme inhibitor, enalapril.

Enalapril, a potent angiotensin converting enzyme inhibitor, effectively blocked the constrictor actions of angiotensin I in isolated perfused cat coronary arteries. Enalapril, at concentrations of 25 to 100 micrograms/ml, inhibited angiotensin I by 65 to 80%. Moreover, enalapril at 100 to 200 micrograms/ml, markedly antagonized the coronary vasoconstrictor effects of angiotensin II. At 150 micrograms/ml, enalapril blocked the angiotensin II response by 80 +/- 5%, and at 200 micrograms/ml, it was blocked by 95 +/- 4%. Enalaprilic acid at 0.5 to 1.0 microgram/ml also blocked the angiotensin II response by 94 +/- 5%. Captopril, up to 250 micrograms/ml, failed to significantly antagonize angiotensin II, although it readily blocked angiotensin I in this preparation. The duration of this angiotensin II blockade lasted about 60-90 min. This angiotensin II antagonism may help explain the beneficial effects of enalapril in situations such as acute myocardial ischemia.

Angiotensin I↗

PubMed1984

Anti-shock actions of a new converting enzyme inhibitor, enalaprilic acid, in hemorrhagic shock in cats.

A new angiotensin converting enzyme inhibitor, enalaprilic acid (MK-422), was given in a bolus of 0.5 mg/kg i.v., followed by an infusion of 0.25 mg/kg/hr to determine its effects in hemorrhagic shock. MK-422 produced no significant hemodynamic effects in sham shock controls, yet it effectively blocked the pressor effect of exogenously administered angiotensin I throughout the 260-min experimental period and reduced angiotensin converting enzyme activity by 90% as determined by radiochemical assay. In vitro studies on cat papillary muscles and pancreatic homogenates revealed no direct inotropic or antiproteolytic effect of enalaprilic acid. Nevertheless, converting enzyme inhibitor treatment maintained postreinfusion mean arterial blood pressure at a significantly higher value (P less than .01) than that of untreated hemorrhaged animals (66 +/- 5 vs. 27 +/- 10 mm Hg, respectively). Superior mesenteric artery flow for hemorrhaged cats was significantly higher (P less than .05) in the treated group both during the end of the oligemic period (6.1 +/- 0.4 vs. 3.8 +/- 0.8 ml/kg/min) and during the postreinfusion period (6.5 +/- 0.7 vs. 1.9 +/- 1.0 ml/kg/min). Moreover, enalaprilic acid blunted the marked rise in plasma cathepsin D (P less than .01) and myocardial depressant factor activities (P less than .01), and plasma amino-nitrogen concentrations (P less than .05) observed in the untreated hemorrhaged cats. These results indicate that enalaprilic acid improved the hemodynamic and metabolic status of cats in hemorrhagic shock.

Angiotensin I↗

PubMed1984

Coronary vascular responsiveness to non-eicosanoid vasoconstrictors in the perfused diabetic rat heart.

We tested arginine vasopressin, and a dihydropyridine calcium agonist, BAY K-8644 in isolated perfused hearts from control and diabetic rats. Arginine vasopressin (1-100 ng/ml) and BAY K-8644 (100-500 ng/ml) significantly increased coronary perfusion pressure during constant flow perfusion indicative of coronary vasoconstriction. However, no significant potentiation was observed between diabetic rats and their weight matched controls for either vasoconstrictor.

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

PubMed1984

Beneficial effect of a thromboxane synthetase inhibitor in traumatic shock.

Traumatic shock was induced in anesthetized rats using the Noble-Collip method. This resulted in an abrupt decline in mean arterial blood pressure (MABP) and heart rate. Plasma cathepsin D activity increased sixfold, plasma thromboxane B2 (TxB2) concentration increased 2.5-fold, plasma myocardial depressant factor (MDF) activity increased 3.5 fold, and the mean survival time was 1.4 +/- 0.2 hours. Administration of the selective thromboxane synthetase inhibitor 5-(3-pyridinylmethyl) benzofuran-2-carboxylate (U-63,557A) (4 mg/kg) resulted in a significant improvement in survival time, 3.3 +/- 0.5, p less than 0.01. Plasma cathepsin D activity was not affected by U-63,557A (7.4 +/- 0.8 vs. 8.5 +/- 1.1 U/ml). However, both plasma and peritoneal fluid TxB2 concentration were significantly reduced and accumulation of the toxic peptide, MDF, was significantly blunted (69 +/- 6 vs. 40 +/- 5 U/ml, p less than 0.01). Our data indicate that blockade of thromboxane A2 (TxA2) production by selective synthetase inhibition is beneficial in trauma and support a role for TxA2 in the pathogenesis of circulatory shock.

Animals↗

PubMed1983

Role of thromboxanes and prostaglandin endoperoxides in the pathogenesis of eicosanoid induced sudden death.

Arachidonic acid (1 mg/kg) or 9,11-azo PGH2 (35 micrograms/kg) injected intravenously into anesthetized rabbits results in sudden death characterized by a marked loss of circulating platelets, a dramatic rise in circulating thromboxane B2 concentrations and a precipitous drop in blood pressure. Death ensues in 3 to 5 minutes from pulmonary thrombosis and pulmonary artery constriction. Administration of dazoxiben (2 mg/kg) prior to arachidonic acid, prevents all of these changes. However, dazoxiben failed to prevent any of these effects after injection of azo-PGH2, a synthetic agonist of the endoperoxide and thromboxane receptor. These results demonstrate the importance of endoperoxide-thromboxane accumulation in eicosanoid induced sudden death and suggests that there is no significant functional difference between the actions of these agents in the rabbit.

Animals↗

PubMed1983

Antagonism of platelet aggregation by 13-azaprostanoic acid in acute myocardial ischemia and sudden death.

The effects of 13-azaprostanoic acid (13-APA) were studied during acute myocardial ischemia in cats and in rabbit sudden death induced by sodium arachidonate (Na-Ar). To more clearly define the mechanism of action of 13-APA, we also examined its effects on isolated cat and rabbit coronary arteries, in vitro aggregation of cat and rabbit platelet-rich plasma (PRP) and circulating rabbit platelet count measured in vivo. 13-APA provided minimal protection during myocardial ischemia in cats, partially reversing ischemia-induced ST segment elevations by 3-5 hours after coronary artery occlusion. However, 13-APA was ineffective in inhibiting the rise in plasma creatine kinase (CK) activity or the loss of CK from ischemic myocardial tissue. 13-APA (1.0 - 100 microM) did not inhibit contraction of cat coronary arteries produced by a stable thromboxane A2 analog. However, 13-APA (100 microM) inhibited aggregation of cat PRP induced by AA (1.0 microM). 13-APA also provided significant protection against sudden death induced by Na-Ar in rabbits. While this agent was ineffective in reducing vasoconstriction of rabbit coronary arteries or inhibiting platelet aggregation in response to 500 microM AA, aggregation of rabbit PRP by 250 microM AA was completely inhibited. AA injection produced a significant decrease in circulating platelet count in vehicle-treated rabbits. However, 13-APA reduced the decrease in circulating platelet count in rabbits which survived AA injection during the 13-APA infusion. These results indicate that antagonism of thromboxane A2 receptors in platelets may be an important feature in protecting against sudden death. The difference in sensitivities of vascular and platelet thromboxane receptors as well as the accessability of 13-APA to these receptors may explain the lack of protection of 13-APA in myocardial ischemia.

Animals↗

PubMed1983

Beneficial effects of ibuprofen in pacing-induced myocardial ischemia.

Lysosomal membrane instability and platelet activation are both associated with acute myocardial ischemia. The effect of ibuprofen on cathepsin D as a marker of lysosomal membrane "leakiness" and thromboxane B2 as a marker of platelet activation was evaluated in 44 patients with angina pectoris. Samples of blood analyzed for cathepsin D, thromboxane B2, and lactate were withdrawn from the coronary sinus and brachial artery before and after pacing to 140 beats/min for 4 minutes. Myocardial ischemia was assessed by determination of transmyocardial lactate extraction or production. Ibuprofen (800 mg) or placebo was administered orally 2 hours before cardiac catheterization. Patients were classified into 4 groups on the basis of administration of placebo or ibuprofen and the presence or absence of myocardial ischemia as determined by demonstration of lactate extraction or production after atrial pacing. In patients with lactate extraction, no significant efflux of cathepsin D or thromboxane B2 occurred after pacing. In patients with lactate production given placebo, a 64 +/- 25% increase in the thromboxane B2 level and a 113 +/- 37% increase in cathepsin D activities occurred in the coronary sinus effluent sampled after pacing. In contrast, in patients with comparable coronary artery disease and comparable lactate production who were given ibuprofen, no release of thromboxane B2 (p = 0.05 compared with patients given placebo) or cathepsin D (p less than 0.01 compared with patients given placebo) occurred after pacing-induced ischemia. These findings suggest that ibuprofen stabilizes membranes and prevents platelet-activated release of thromboxane A2 in pacing-induced myocardial ischemia.

Angina Pectoris↗