Search PubMed⌕ Search

Biomedical subjects

A M Lefer

Publications and source records attributed to A M Lefer.

At least 181 records · Page 10Linked to original sources
PubMed1989

Protective effects of a specific platelet activating factor (PAF) antagonist, WEB 2086, in traumatic shock.

We have investigated the role of platelet activating factor (PAF) in the pathogenesis of a murine model of traumatic shock using WEB 2086, a specific antagonist of PAF. WEB 2086 (0.5 mg/kg) significantly reversed the decrease in mean arterial blood pressure (MABP) induced by PAF (0.3 micrograms/kg) in anesthetized rats. Anesthetized rats were subjected to Noble-Collip drum trauma. Traumatized rats treated with WEB 2086 (0.5 mg/kg bolus followed by infusion at 0.5 mg/kg/hr) maintained a higher MABP than those receiving only the vehicle (0.9% NaCl). Improvement in MABP paralleled a significant increase in overall survival time (p less than 0.01) in rats receiving WEB 2086 (0.5 mg/kg). WEB 2086 also significantly attenuated the plasma accumulation of the lysosomal hydrolase, cathepsin D and of free amino-nitrogen compounds, compared to shocked rats receiving only the vehicle. Furthermore, the production of the cardiotoxic peptide, myocardial depressant factor (MDF) was also blunted by WEB 2086. These results suggest that PAF may be an important mediator in the pathogenesis of traumatic shock in rats. Furthermore, PAF receptor antagonists may be useful as therapeutic agents when given early in the course of ischemic and shock states.

Animals↗
PubMed1989

Protective effect of the specific thromboxane receptor antagonist, BM-13505, in reperfusion injury following acute myocardial ischemia in cats.

The ability of BM-13505, 4-[2-(4-chlorobenzenesulfonylamino) ethyl]-benzene acetic acid), a specific thromboxane/endoperoxide receptor antagonist, to protect the myocardium against ischemia and reperfusion injury, was assessed in an anesthetized cat model. Cats were rendered ischemic by left anterior descending (LAD) coronary artery ligation for 1 1/2 hours followed by reperfusion for 4 1/2 hours. BM-13505 or its vehicle (i.e., Na2CO3) was administered intravenously 30 minutes before reperfusion at a rate of 1 mg/kg followed by 1 mg/kg/hr. BM-13505 significantly (p less than 0.001) reduced the area of ischemic tissue as a percent of total left ventricular mass and total area at risk, without altering basic hemodynamics (i.e., arterial blood pressure, heart rate, or their product) and thereby not influencing myocardial oxygen demand. The mechanism of the protective effect of the thromboxane receptor antagonist appears to be cytoprotective but may involve the prevention of neutrophil-induced cellular damage.

Acute Disease↗
PubMed1989

Acute effects of unsaturated fatty acids in splanchnic artery occlusion shock.

Diets enriched with omega-3 unsaturated fatty acids are associated with decreased hypercholesterolemia and decreased risk of ischemic and atherosclerotic diseases. We studied the acute intravascular effects of some of these unsaturated fatty acids (i.e., eicosapentaenoic acid, EPA; docosahexaenoic acid, DHA) along with omega-6 unsaturated fatty acids, (i.e., linoleic and linolenic acid) in splanchnic artery occlusion (SAO) shock in rats. Anesthetized rats subjected to total occlusion of the celiac and superior mesenteric arteries for 40 minutes followed by reperfusion usually resulted in a fatal outcome 90-120 minutes after releasing the clamps. SAO shock rats treated with the omega-3 unsaturated fatty acid, EPA, exhibited an improved survival time and rate (p less than 0.05 from vehicle) compared to those receiving only vehicle (i.e., 50% ethanol). EPA and DHA treated SAO rats also exhibited lower plasma activities of the lysosomal protease, cathepsin D, free amino-nitrogen compounds, and the cardiotoxic peptide, myocardial depressant factor. These results indicate that omega-3 unsaturated fatty acids, especially EPA, have some acute beneficial effects in SAO shock in rats.

Animals↗
PubMed1989

Lack of endothelium-dependent relaxation in coronary resistance arteries of cholesterol-fed rabbits.

The endothelium-dependent contractile responses of subepicardial coronary resistance arteries (286 +/- 18 microns ID, n = 22) from rabbits fed either a 0.5 or 2.0% cholesterol-enriched diet or a control diet for 10-12 wk were determined under isometric conditions at the optimum length for active force production (Lo). After the development of tone with 29 mM K+-Krebs, arteries from control rabbits treated with acetylcholine (0.1-10 microM) showed a concentration-dependent relaxation, with a maximum decrease in tone of 63%. In contrast, coronary arteries from animals fed 0.5 and 2.0% cholesterol contracted to acetylcholine (approximately 210% increase in tone). A similar phenomenon was seen with arteries precontracted with 10 nM 9,11-methanoepoxy-prostaglandin H2 (U 46,619), a thromboxane A2 mimetic. The contractile responses to acetylcholine occurred in arteries in which the endothelium was structurally intact and which were devoid of plaque. Arteries from cholesterol-fed animals were poorly responsive to ADP (0.01-10.0 microM), whereas arteries from normal animals relaxed. All arteries relaxed to an equal degree when exposed to acidified nitrite, which produces nitric oxide (NO). The data suggest that as a result of hypercholesterolemia, there may be a dysfunction in the synthesis or release of endothelium-derived relaxing factor (EDRF) by the endothelial cells of coronary resistance arteries, rather than an abnormality of the smooth muscle cells per se.

Acetylcholine↗
PubMed1989

Anti-EDRF effect of tumor necrosis factor in isolated, perfused cat carotid arteries.

Cat carotid arteries that have an intact endothelium were isolated and perfused with Krebs-Henseleit solution containing recombinant human tumor necrosis factor (rhTNF). Perfused arteries were preconstricted with KCl and then dilated with acetylcholine (ACh) or acidified NaNO2. After perfusion with TNF (4 micrograms/ml) for 120 min, the ACh-induced vasodilator response was markedly blunted, but the NaNO2 vasodilator response was not significantly affected. Arteries perfused with 2 micrograms/ml TNF for 60-120 min or with 4 micrograms/ml for 60 min did not develop a significantly impaired relaxation to ACh. Moreover, perfusion with 20-100 micrograms/ml cycloheximide, an inhibitor of protein synthesis, blocked the TNF-induced impairment of the relaxation to ACh. On the other hand, the vasodilator response to acidified NaNO2 did not change in any perfused carotid arteries. These results suggest that TNF promotes the synthesis of proteins that contribute to the damage of endothelial cells directly, probably by inhibiting endothelium-derived relaxing factor release.

Acetylcholine↗
PubMed1989

Thromboxane is produced in response to intracoronary infusions of complement C5a in pigs. Cyclooxygenase blockade does not reduce the myocardial ischemia and leukocyte accumulation.

Activated polymorphonuclear leukocytes (PMNs) contribute to myocardial injury during ischemia and reperfusion. There is evidence that activation of the complement pathway may be one of the mechanisms of PMN activation during ischemia. Intracoronary infusion of complement C5a during normal perfusion pressure is associated with decreased coronary flow, contractile dysfunction, and PMN accumulation. The mechanisms responsible for these changes have not been identified. Thromboxane A2 (TXA2) is a potential mediator of this myocardial ischemic response. Activated PMNs produce TXA2, a known coronary vasoconstrictor, and TXA2 was shown to be a mediator of the pulmonary hypertensive response to activated complement. The goal of the present study was to determine if an enhanced TXA2 production is associated with the myocardial response to C5a and whether cyclooxygenase blockade would reduce the myocardial ischemia. In open-chest pigs, intracoronary C5a (500 ng) caused reversible reductions in blood flow (50.0% of control), regional contractile function (25.8% of control), leukocyte trapping (1.0 x 10(6) cells/g myocardium or a peak artery-coronary venous difference of 5.3 x 10(3) cells/microliters blood), and increased coronary venous TXB2 (the TXA2 breakdown product) from 1.6 pmol/ml to a peak of 6.9 pmol/ml. Cyclooxygenase blockade with aspirin or indomethacin, which prevented TXB2 production, did not alter the response in flow, function, or PMN trapping. Ibuprofen, a known direct inhibitor of PMNs in addition to its cyclooxygenase blockade effect, reduced the response slightly. The pig coronary vascular bed was responsive to the TXA2 agonist U46619, which reduced flow and function without PMN trapping. Mechanical reductions in coronary flow to levels equivalent to those during the C5a infusions did not increase coronary venous TXB2 nor cause PMN trapping but did cause equivalent contractile dysfunction. Incubation of whole blood with C5a at concentrations equivalent to those achieved in vivo did not cause TXB2 production. We conclude that 1) TXA2 is produced in response to intracoronary C5a and 2) cyclooxygenase blockade does not prevent the C5a-induced myocardial ischemia, contractile dysfunction, and PMN trapping. The TXA2 production likely involves a vascular site or a blood cell-vascular interaction. This model system indicates the potential for persistently activated PMNs to cause continued ischemia during myocardial reperfusion.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1989

Cardiovascular effects of acute hypercholesterolemia in rabbits. Reversal with lovastatin treatment.

Hypercholesterolemia was induced in New Zealand white rabbits by feeding them a 0.5% cholesterol-enriched rabbit chow for 2 wk. Half of the cholesterol-fed rabbits were given lovastatin, a potent inhibitor of hydroxymethylglutaryl-coenzyme A reductase (HMG-CoA reductase), the rate limiting enzyme in cholesterol biosynthesis, and the other half were given its vehicle (i.e., DMSO). At the end of 2 wk, the rabbits underwent experimental myocardial ischemia or a sham ischemia procedure. Ischemic animals fed the cholesterol-enriched diet for 2 wk experienced much greater cardiac damage than ischemic rabbits fed the control diet, despite the absence of any atherosclerosis. Lovastatin was shown to protect the ischemic rabbit myocardium by three different indices of ischemic damage: (a) maintenance of creatine kinase (CK) activity in the ischemic myocardium; (b) reduced loss of free amino-nitrogen containing compounds from the ischemic myocardium; and (c) blunting the rise of plasma CK activity. These effects were not due to differences in myocardial oxygen demand between the groups. Arteries isolated from animals fed the cholesterol-enriched diet developed defects in endothelium-dependent relaxation in both large vessels as well as coronary resistance vessels. Acute hypercholesterolemia increases the severity of myocardial ischemia while at the same time impairing endothelium-dependent relaxation. These deleterious changes can be significantly attenuated by treatment with lovastatin.

Animals↗
PubMed1989

Vascular responsiveness of constant flow perfused arteries with intact endothelium.

We have devised a perfused artery preparation, in which one can conveniently assess vasoactivity to agents (a) in the presence and absence of a functionally intact endothelium within the same vessel, and (b) when added to the luminal or abluminal (i.e., adventitial) surface of the vessel. Moreover, utilizing stainless steel cannulas of various calibers, one can routinely perfuse vessels ranging from less than 1 mm to over 4 mm in internal diameter. By moderating the pulsatile nature of the constant flow perfusion, one can retain a functionally intact endothelium (i.e., at totally damped perfusion) or one can abolish endothelial modulation of vasoactive agents (i.e., a pulsatile perfusion). The integrity of the endothelium was confirmed by histological methods. Using perfused cat carotid arteries preconstricted with U-46619, a stable prostaglandin-endoperoxide analog which maintains a stable vasoconstriction, acetylcholine dilated carotid arteries perfused at non-pulsatile flows, but not at pulsatile flows, indicating the endothelium dependent nature of the vasodilation produced by ACh. This was confirmed with the calcium ionophore A-23187, a non-receptor endothelium dependent vasodilator. However, calcium channel blockers (e.g., nimodipine) prostacyclin analogs (e.g., iloprost) or vasodilator nitrates (e.g., sodium nitrite at pH 2.0) produced equivalent dilations in the presence and absence of a functional intact endothelium. This preparation allows for convenient use of single dose application of pharmacologic agents as well as cumulative dose-response relationships.

Acetylcholine↗
PubMed1989

Significance of lipid mediators in shock states.

Derivatives of fatty acids (e.g., arachidonic acid) and phospholipids (e.g., platelet activating factor) appear to be important mediators of a significant extent of the pathophysiology of circulatory shock. These lipid mediators are extremely potent substances having a variety of important biological effects contributing to cellular injury. Moreover, prevention of either the formation of these lipid mediators by synthesis inhibitors or blockade of their action via specific receptor antagonism improves these shock states. Also, using sensitive chemical and immunological detection methods, increased amounts of these lipid mediators have been identified in body fluids during shock states. Finally, several of these lipid mediators are linked to the activation of other lipid and non-lipid mediators of shock in a manner which amplifies the actions of the lipid mediators.

Animals↗
PubMed1989

Protective effects of a combination thromboxane synthesis inhibitor-receptor antagonist, R-68070, during murine traumatic shock.

The effects of R-68070 were studied in a well-characterized model of drum-induced traumatic shock in rats. R-68070 is a combination thromboxane A2 (TxA2) synthetase inhibitor-TxA2 receptor antagonist. Pentobarbital-anesthetized (50 mg/kg) rats subjected to Noble-Collip drum trauma developed a lethal circulatory shock state characterized by a marked decrease in mean arterial blood pressure (MABP) to about 75 mmHg, resulting in a survival time of 1.58 +/- 0.18 h. This compares with MABP of 120 +/- 4 mmHg 5 h after anesthetization in rats subjected to a sham traumatic shock protocol. Administration of R-68070 (1.5 mg/kg) significantly attenuated the plasma accumulation of the lysosomal protease, cathepsin D (p less than 0.05), as well as free amino-nitrogen concentration (p less than 0.05) and myocardial depressant factor activity (p less than 0.02). Additionally, R-68070 significantly prolonged survival time to 2.85 +/- 0.48 h (p less than 0.015) compared with traumatized rats given only the vehicle. These results suggest that TxA2 may be an important mediator in traumatic shock, and that R-68070 may prove to be a useful therapeutic agent in this situation if given early in the course of the shock state.

Animals↗
PubMed1989

Protective actions of a new potent thromboxane receptor antagonist in arachidonate induced sudden death.

Sodium arachidonate (NaAr) at a dose of 1.1 mg/kg injected i.v. is uniformly lethal in rabbits within 5 min. This sudden death is typified by a precipitous drop in mean arterial blood pressure, a dramatic decrease in the circulating platelet count, and by a marked rise in plasma thromboxane A2 (TxA2) concentration as measured by radioimmunoassay of its breakdown product, TxB2. Pretreatment with S-145, a new thromboxane receptor antagonist, at doses ranging from 50 to 500 micrograms/kg resulted in 100% survival of all the rabbits subjected to sodium arachidonate injection. However, at 20 micrograms/kg S-145 only 25% of the rabbits challenged with NaAr survived. S-145 pretreatment also inhibited the decreases in circulating platelet count and in blood pressure associated with the i.v. injection of sodium arachidonate (NaAr). S-145 blunted the rise in plasma TxB2 concentration at all doses. S-145 was also shown to be a potent and long-lasting antagonist of TxA2 receptors in isolated rabbit aortic rings. Our data show that S-145 is a very effective protective agent against NaAr-induced sudden death in rabbits.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1989

Induction of tissue injury and altered cardiovascular performance by platelet-activating factor: relevance to multiple systems organ failure.

PAF is a phospholipid formed from the action of phospholipase A2 upon cellular membranes in response to immunologic or hypoxic stimuli. PAF does not exist in its active form as a storage product within cells, but is synthesized rapidly after phospholipase A2 activation. A potent lipid released by multiple cell types in mammalian systems, the emerging perspective is that PAF is a major endogenous mediator influencing the pathogenesis and outcome of ischemia and conditions of circulatory shock. These effects appear to be especially relevant to the syndrome of MSOF during critical illness. All of the major criteria for validation of a shock factor have been fulfilled for PAF. First, PAF has been measured in biological fluid of animals during shock states, although this is not an easy task since PAF is formed in minute amounts and is rapidly metabolized. Nevertheless, combinations of high pressure liquid chromatography (HPLC) and bioassay methods employing washed rabbit platelets have been successfully utilized in this regard. Second, synthetic PAF has been injected into cell suspensions, isolated tissues, and live animals, where it produces most of the effects attributed to endogenous PAF released by immunologic or hypoxic stimuli. These studies have shown that PAF exerts a variety of pathophysiologic actions, including (1) cardiodepression (that is, a negative inotropic effect), (2) reductions in systemic blood pressure, (3) leakage of fluid from the microvasculature, (4) bronchoconstriction, and (5) platelet aggregation. All of these actions of PAF can initiate or exacerbate shock and ischemic injury in multiple organ systems. Third, specific PAF receptor antagonists have been found to markedly attenuate the severity of endotoxic, anaphylactic, hemorrhagic, and traumatic shock, as well as acute myocardial ischemia. In all these conditions, a variety of PAF receptor antagonists (including PAF analogues and structurally dissimilar substances) have improved survival and have retarded pathophysiologic processes believed to be important in causing tissue injury. These processes include lysosomal membrane damage and proteolysis. Moreover PAF receptor antagonists attenuate the release of secondary toxic factors in shock, such as myocardial depressant factor. Thus, administration of specific PAF receptor antagonists early in the course of circulatory shock and organ ischemia may prove to be useful therapeutic agents in a variety of life-threatening disorders. In addition to having direct actions, PAF appears to function as a pivotal agent in a chain of mediators producing tissue injury. Recent evidence suggests that tumor necrosis factors (i.e., cachectin) stim

Animals↗
PubMed1989

Platelet activating factor (PAF) and its role in cardiac injury.

PAF is a phospholipid formed from the action of phospholipase A2 triggered by immunologic or hypoxic stimuli. PAF does not exist in its active form but rather is present as a storage product within cells, and is synthesized rapidly upon appropriate activation. PAF is a potent lipid mediator which is released by a variety of cell types in mammalian systems. PAF appears to be a particularly important mediator of myocardial ischemia and circulatory shock states in mammalian species. Moreover, since PAF releases other lipid mediators, it may have an "amplifier" role in the propagation of circulatory disease states.

Animals↗
PubMed1988

Protective action of prostaglandin E1 (PGE1) against constrictor mediators in isolated rat heart and lung.

Prostaglandin (PG) E1 (2.8 to 280 nmol/L) dose-dependently inhibited the platelet-activating factor (PAF)-induced increase in coronary perfusion pressure (CPP) in isolated constant flow perfused rat hearts. The PAF-induced release of immunoreactive leukotrienes (iLT) and thromboxane B2 (iTxB2) in isolated rat hearts was also attenuated. PAF induced a significant decrease in left ventricular cAMP content, which was antagonized by PGE1. PGE1 also decreased the production of iLT, but not of iTxB2, in A23187-stimulated minced rat lung tissue. Furthermore, PGE1 inhibited the increase in CPP induced by LTD4 and arginine vasopressin (AVP) in the isolated perfused rat heart. The inhibitory effects of PGE1 on coronary vasoconstrictor substances were not due to a nonspecific vasodilator effect since sodium nitroprusside neither inhibited the increase in CPP nor the release of eicosanoids induced by PAF. Moreover, PGE1 did not inhibit the PAF-induced hypotension in vivo, indicating that PGE1 is not a PAF receptor antagonist. These results suggest that PGE1 may exert an important regulatory effect on coronary vascular homeostasis by stimulation of cyclic AMP and may be important in controlling eicosanoid metabolism in the rat heart. Furthermore, beneficial effects of PGE1 in circulatory shock and myocardial ischemia may be related to this inhibitory effect of PGE1.

Alprostadil↗
PubMed1988

Salutary consequences of blockade of platelet activating factor in hemorrhagic shock.

We studied the effects of a potent, specific platelet activating factor (PAF) antagonist, CV-6209, in a murine model of hemorrhagic shock. Hemorrhaged rats treated with CV-6209 (1 mg/kg) maintained post-reinfusion mean arterial blood pressure (MABP) at significantly higher values than rats receiving either 0.9% NaCl or a lower dose (0.2 mg/kg) of CV-6209 (final MABP 88 +/- 4 vs. 57 +/- 4, vs. 61 +/- 7 mm Hg, respectively). CV-6209 (1 mg/kg) also significantly attenuated the increase in plasma cathepsin D activity following hemorrhage compared with hemorrhaged rats receiving only its vehicle (i.e. 0.9% NaCl). CV-6209 (1 mg/kg) also significantly decreased the plasma accumulation of free amino-nitrogen compounds and the plasma activity of a myocardial depressant factor (MDF) compared to hemorrhaged rats receiving 0.9% NaCl. Rats receiving CV-6209 (1 mg/kg) exhibited a significantly increased survival rate and survival time post-reinfusion compared to rats receiving only the vehicle. These data indicate that PAF is an important mediator of hemorrhagic shock in the rat and that PAF receptor antagonists may be useful in hemorrhagic shock states.

Animals↗
PubMed1988

Novel mechanism of action of a prostacyclin enhancing agent in haemorrhagic shock.

Prostacyclin (PGI2) is a potent vasodilator, an inhibitor of platelet aggregation, and a membrane stabilizing agent with beneficial effects in ischemia and shock. We studied defibrotide, a new agent which enhances PGI2 release from vascular tissue, to determine its effects in a murine model of hemorrhagic shock. Hemorrhaged rats treated with defibrotide maintained post-reinfusion mean arterial blood pressure (MABP) at significantly higher values compared to rats receiving the vehicle (final MABP, 100 +/- 3 vs. 69 +/- 7 mm Hg, p less than 0.01). Defibrotide attenuated the release of the lysosomal hydrolase cathepsin D (p less than 0.02), and the plasma accumulation of free amino-nitrogen groups (p less than 0.02). The plasma activity of a myocardial depressant factor (MDF) was significantly lower in defibrotide treated shocked rats than in the vehicle group (29 +/- 4 vs. 61 +/- 8 U/ml, p less than 0.01). Moreover, plasma i6-keto-PGF1 alpha concentrations increased 3-fold above haemorrhaged rats receiving only the vehicle. This, as well as the improved MABP, was abolished by indomethacin. Additionally, defibrotide exerts an anti-proteolytic action in pancreatic homogenates, and a lysosomal stabilizing effect in large granule fractions of rat liver homogenates. Moreover, defibrotide enhanced the recovery from norepinephrine induced vasoconstriction in rat aortic rings having an intact endothelium (p less than 0.01 from vehicle), and augmented the release of i6-keto-PGF1 alpha, the stable metabolite of PGI2, from isolated rat aortae. Our results indicate that enhancement of endogenous vascular PGI2 release coupled with direct, or PGI2 mediated antiproteolytic and membrane stabilizing actions may be important physiological mechanisms counteracting the deleterious effects of hemorrhagic shock.

Adenosine Diphosphate↗