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Biomedical subjects

A M Lefer

Publications and source records attributed to A M Lefer.

At least 235 records · Page 13Linked to original sources
PubMed1987

Mechanisms of platelet-activating factor-induced cardiac depression in the isolated perfused rat heart.

A potent phospholipid (platelet-activating factor, PAF) has been implicated in a variety of inflammatory and ischemic responses (eg, myocardial ischemia and anaphylactic shock). In isolated rat hearts perfused at constant flow, PAF produced a dose-dependent increase in coronary perfusion pressure (CPP) and a decrease in contractile force (CF). At 20 nM, PAF increased CCP by 21 +/- 1 mm Hg and decreased CF by 31 +/- 3% in nine hearts. At the peak of the PAF response, coronary effluent contained LTC4, LTD4, and LTE4 (0.22 +/- 0.05 pmol/ml) and TxB2 (0.97 +/- 0.16 pmol/ml). Addition of specific PAF receptor antagonists (eg, BN-52021 and CV-3988) inhibited peptide leukotriene and TxB2 production and blocked the coronary vasoconstriction and decrease in contractile force. Cyclooxygenase inhibitors (eg, naproxen) or specific TxA2 receptor antagonists (eg, BM-13,505) failed to prevent the increase in CPP or the decrease in CF. Furthermore, a lipoxygenase inhibitor (ie, propyl gallate) or a specific LTD4 receptor antagonist (ie, LY-171,883) prevented the increase in CPP but did not antagonize the negative inotropic response. These data indicate that the coronary constriction in the isolated perfused rat heart is a result of the PAF-induced release of endogenous peptide leukotrienes but not TxA2 production. However, the negative inotropic response appears to be partly due to a direct negative inotropic action of PAF on cardiac muscle. Thus, PAF produces a variety of direct actions and indirect effects via release of eicosanoid mediators contributing to cardiac impairment in the rat heart.

Animals↗
PubMed1987

A pharmacological approach to thromboxane receptor antagonism.

Thromboxane A2 (TxA2) appears to be an important mediator of ischemia and hypoxia. Despite its short half-life and the fact that it may not circulate in the blood until its values become quite high, TxA2 contributes to the pathogenesis of cardiopulmonary diseases (e.g., sudden death, myocardial ischemia, circulatory shock). It does so because it propagates its own formation by activating platelets and constricting blood vessels, thus activating more TxA2 and trapping it locally within an ischemic or hypoxic region. TxA2 concentrations in the extracellular fluid of lymph of ischemic regions may be much higher than that occurring in nonischemic, normally perfused regions. Specific and potent Tx receptor antagonists (TxRA) have recently become available for study. The TxRA are useful tools in the study of the pathophysiology of Tx-dependent disease processes and have been found to be effective in a variety of ischemic disorders including circulatory shock, myocardial ischemia, and sudden cardiopulmonary death. Moreover, inasmuch as early work indicates that these agents are both safe and effective in humans, Tx receptor antagonists may be employed as therapeutic agents in several cardiovascular disease states. Further investigation is necessary to clarify the role of TxRA as therapeutic agents.

Animals↗
PubMed1987

Protective effects of a new specific thromboxane antagonist in arachidonate-induced sudden death.

Sodium arachidonate (NaAr), at a dose of 2.0 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 sharp rise in plasma thromboxane A2 (TxA2) concentration. Pretreatment with BM-13,505, a novel thromboxane receptor antagonist, at doses ranging from 0.25 mg/kg to 2.0 mg/kg resulted in 100% survival of rabbits subjected to sodium arachidonate injection. BM-13,505 pretreatment also inhibited the decreases in circulating platelet count and in blood pressure associated with arachidonic acid injection. BM-13,505 did not inhibit the sharp rise in plasma TxB2 concentrations at any dose. This evidence suggests that the mechanism of BM-13,505 protection is by means of thromboxane receptor antagonism and not via inhibition of thromboxane A2 synthesis.

Animals↗
PubMed1987

Beneficial actions of the thromboxane receptor antagonist, AH-23,848, in acute myocardial ischemia.

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 antagonists would be expected to be beneficial in acute myocardial ischemia. A new thromboxane A2 receptor antagonist, AH-23,848, was studied in a cat model of acute myocardial ischemia. Myocardial ischemia was induced by ligation of the left anterior descending (LAD) coronary artery. Thirty minutes later, AH-23,848 or vehicle was given as a bolus (1 mg.kg-1) followed by a continuous infusion (1 mg.kg-1.h-1). AH-23,848 effectively reduced the S-T segment elevation while vehicle treated cats showed an increase. From direct myocardial biopsies, it was also seen that AH-23,848 prevented the loss of creatine kinase (CK) activity from the ischemic myocardium. Furthermore, the loss of amino-nitrogen compounds was also significantly reduced (p less than 0.05) by treatment with the receptor antagonist. This protective effect was not due to an indirect reduction of myocardial oxygen demand since blood pressure, heart rate or their product was unaltered by AH-23,848 administration. Moreover, the specificity of AH-23,848 to thromboxane receptors was confirmed in isolated cat coronary arteries and in cat platelets. These experiments demonstrate that blockade of the thromboxane receptor by AH-23,848 is an effective means of preventing acute myocardial ischemic damage in the cat, and thus thromboxane A2 plays a role in propagating the extension of ischemic damage during acute myocardial ischemia.

Acute Disease↗
PubMed1987

Physiologic and pathophysiologic role of cyclo-oxygenase metabolites of arachidonic acid in circulatory disease states.

The overall assessment of eicosanoids in ischemia and shock is complex. Certain prostaglandins, notably PGI2, actually improved survival in shock and ischemic states; however, some, including TxA2, act as mediators, significantly contributing to the pathophysiology of vasospasm and ischemia. This makes the intelligent use of eicosanoid-related drugs very difficult. Broad-based inhibitors (for example, cyclo-oxygenase inhibitors) are not likely to exert significant protective effects because they inhibit beneficial as well as detrimental eicosanoids. More appropriately, the therapy of ischemic disorders should be designed to employ specific agents (for example, TxSI and TxRA) rather than broad-based agents. Preliminary studies already suggest the success of such an approach. Future investigations will focus on the application of potent synthetic modulators or analogues of specific eicosanoids in an attempt to prevent the deleterious effects of eicosanoid mediators of ischemic disorders and to potentiate and prolong the beneficial actions of therapeutic eicosanoids.

Animals↗
PubMed1987

Potentiation of the protective effects of a converting enzyme inhibitor and a thromboxane synthetase inhibitor in hemorrhagic shock.

The effect of a specific inhibitor of thromboxane (Tx) A2 synthesis, CGS-13080, a new angiotensin converting enzyme inhibitor, CGS-16617, and a combination of both drugs was studied in hemorrhagic shock in rats. Treatment with CGS-16617 (1 microgram/kg) or CGS-13080 (200 micrograms/kg) alone did not alter significantly postoligemic hypotension or the increase in plasma cathepsin D activity in shocked rats, compared with hemorrhaged rats receiving only their vehicle. Combined treatment with both drugs maintained postreinfusion mean arterial blood pressure and attenuated the increase in plasma cathepsin D activity in hemorrhaged rats. Treatment of shocked rats with each drug alone attenuated the accumulation of a myocardial depressant factor activity in the plasma, but the lowest myocardial depressant factor activities were observed in rats treated with the drug combination. Additionally, animals treated with the drug combination exhibited significantly longer postreinfusion survival times than rats receiving either the vehicle (P less than .01), CGS-16617 (P less than .05) or CGS-13080 (P less than .02). CGS-16617 (1 microgram/kg) attenuated significantly the pressor response to angiotensin I throughout the shock period. CGS-13080 attenuated the increase in TxB2 plasma concentrations in shock when compared with hemorrhaged rats receiving the vehicle (P less than .05). Greater attenuation of TxB2 was found after treatment with the drug combination (P less than .01 from vehicle, P less than .05 from CGS-13080 alone). CGS-16617, but not CGS-13080, was also found to have a direct antiproteolytic action in pancreatic homogenates. However, the drug combination (CGS-16617 and CGS-13080) decreased proteolytic activity even further (P less than .001) from CGS-16617 alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin I↗
PubMed1987

Beneficial actions of RO 15-1788, a benzodiazepine receptor antagonist, in hemorrhagic shock.

We studied RO 15-1788, a new benzodiazepine receptor antagonist, [ethyl 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo (1, 5a) (1, 4) benzodiazepine-3-carboxylate] to determine its effects in a murine model of hemorrhagic shock. Hemorrhaged rats treated with RO 15-1788 maintained post-reinfusion mean arterial blood pressure (MABP) at significantly higher values compared to rats receiving only the vehicle (final MABP 114 +/- 4 vs 82 +/- 4 mmHg, p less than 0.001). Moreover, RO 15-1788 decreased the release of the lysosomal hydrolase, cathepsin D (p less than 0.02) into the circulation and blunted the plasma accumulation of free amino-nitrogen groups (p less than 0.01). Furthermore, the plasma activity of a myocardial depressant factor (MDF) was significantly lower in RO 15-1788 treated rats subjected to hemorrhagic shock than in those given the vehicle (18 +/- 2 vs 42 +/- 4 U/ml, p less than 0.01). Additionally, in vitro analysis indicated that RO 15-1788 antagonizes PAF induced coronary vasoconstriction and cardiac depression observed in perfused rat hearts, as well as inhibiting PAF induced platelet aggregation in cat platelet rich plasma. Our results suggest that antagonism of PAF actions can contribute significantly to the beneficial effects of RO 15-1788 in hemorrhagic shock.

Animals↗
PubMed1987

Use of hypertonic saline in the treatment of hemorrhagic shock.

Hypertonic saline (ie, 7.5% NaCl) was injected intravenously (4 ml/kg bolus) to determine its effects in feline and murine models of hemorrhagic shock. Hypertonic NaCl transiently improved mean arterial blood pressure (MABP), superior mesenteric artery blood flow (SMAF), and cardiac output (CO) during the oligemic period. These effects lasted from 15 to 75 min. However, after reinfusion of blood, shocked cats which received 7.5% NaCl during the oligemic period, maintained MABP, SMAF, and CO at significantly higher values compared to cats receiving 0.9% NaCl. The postreinfusion values of these hemodynamic variables in cats given hypertonic NaCl were not statistically different from those of sham-shock cats. Hypertonic NaCl did not attentuate the increase in plasma cathepsin D activity or plasma proteolysis in either cats or rats. Nevertheless, the plasma activity of a myocardial depressant factor (MDF) was significantly lower in shock cats and rats given hypertonic saline compared with the 0.9% NaCl groups (31 +/- 4 vs 54 +/- 7 U/ml, p less than 0.02, in cats; and 27 +/- 2 vs 51 +/- 7 U/ml, p less than 0.02, in rats). The beneficial effects of small-volume resuscitation with 7.5% NaCl during hemorrhagic shock in cats and rats are likely due to the transient hemodynamic improvement during the oligemic period rather than sustained improvement in splanchnic perfusion or in prevention of cellular injury during shock. Our results in two species (eg, cat and rat) suggest that small-volume resuscitation with 7.5% NaCl may be a useful initial treatment of hemorrhagic shock when supplemented by subsequent blood transfusion or perhaps some other appropriate pharmacologic intervention.

Animals↗
PubMed1987

Efficacy of two leukotriene antagonists in rat traumatic shock.

The effects of CGP 33304 and CGP 35949 were studied in standardized model of traumatic shock. Both drugs are dual leukotriene receptor antagonists and phospholipase A2 inhibiting agents. Pentobarbital anesthetized rats (35 kg/mg) subjected to Noble-Collip drum trauma were characterized by a 128 +/- 16 min survival time and a 4-fold increase in plasma myocardial depressant factor (MDF) activity. CGP 33304 and CGP 35949 both significantly (p less than 0.01) attenuated the accumulation of MDF activity in the plasma (24 +/- 3 and 29 +/- 3 U/ml, respectively, vs. 57 +/- 5 U/ml in the trauma and vehicle group). A significant improval in survival time (p less than 0.05) was observed in the CGP 33304 treated group (182 +/- 23 min) and the CGP 35949 treated group (204 +/- 33 min). Both drugs exhibited significant anti-proteolytic activity in pancreatic homogenates. CGP 33304 and CGP 35949 appear to attenuate MDF production, probably secondary to their anti-proteolytic effect and the improved state of the splanchnic circulation. Both drugs also may prevent hypoxia secondary to leukotriene induced bronchoconstriction in shock states. CGP 33304 and CGP 35949 may, therefore, prove to be useful therapeutic agents in acute ischemic disorders including traumatic shock.

Animals↗
PubMed1987

Pharmacologic modulation of ATP release from isolated rat hearts in response to vasoconstrictor stimuli using a continuous flow technique.

A new method is described for continuously recording ATP release in isolated perfused hearts by a bioluminescence technique that makes possible the study of the dynamics of ATP release in terms of coronary vascular regulation. Infusion of exogenous ATP in isolated perfused rat hearts resulted in a clearance of 97.8 +/- 0.5% in one pass through the heart. Short-term infusion of either leukotriene (LT) D4 (0.02-0.5 nmol) or norepinephrine (NE; 0.06-0.6 mumol) released significant quantities of ATP from isolated rat hearts in a dose-dependent manner. In contrast, equipotent vasoconstrictor doses of arginine vasopressin (AVP; 20 and 60 microU) failed to release ATP. The amount of ATP released by LTD4 and NE declined by 50 to 60% with each consecutive challenge. LTD4-induced vasoconstriction and ATP release were totally abolished by the LT receptor antagonist FPL-55,712, whereas the NE-induced coronary vasoconstriction and ATP release were totally blocked by the alpha adrenergic blocking agent phentolamine. The coronary vasoconstriction induced by NE was followed by a slight coronary vasodilation, which was inhibited by the beta adrenergic blocking agent timolol without influencing ATP release. The LTD4- and NE-induced release of ATP appears to be receptor mediated and may play a role in the regulation of coronary vascular tone.

Adenosine Triphosphate↗
PubMed1986

Antagonism of thromboxane actions in the isolated perfused rat heart.

The effects of SQ-29,548, a novel thromboxane A2 (TxA2) receptor antagonist, were studied in the isolated perfused rat heart. SQ-29,548 at concentrations of 2.5 to 50 ng/ml antagonized the increase in coronary perfusion pressure (CPP) in response to the thromboxane agonist, 9,11-methanoepoxy PGH2. Increases in CPP induced by arginine vasopressin and leukotriene D4 were not altered by SQ-29,548. We conclude that SQ-29,548 is a very potent and specific TxA2 receptor antagonist in the coronary vasculature of the rat heart.

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

Role of platelet-activating factor-acether in mediating guinea pig anaphylaxis.

The pathophysiology of anaphylaxis is very complex, and the sequelae of events are not fully explained in terms of the effects of histamine and peptide leukotrienes alone. Platelet-activating factor (1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine, PAF-acether) has been detected in animals undergoing anaphylaxis. Injection of synthetic PAF-acether induces similar effects, including bronchoconstriction, respiratory arrest, systemic hypotension, neutropenia, and thrombocytopenia. The results reported here demonstrate that the histamine- and leukotriene-independent component of guinea pig anaphylaxis in vivo and in isolated lung parenchymal strips in vitro is mediated by PAF-acether. However, PAF-acether is not responsible for the anaphylaxis-induced thrombocytopenia.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1986

Anti-ischemic actions of a new thromboxane receptor antagonist, SQ-29,548, in acute myocardial ischemia.

Thromboxane A2 (TxA2) has been implicated as a mediator of ischemic damage to the myocardium. A new, selective thromboxane receptor antagonist, SQ-29,548 (2 mg/kg bolus + 2 mg/kg per h infusion) was studied for its effects on the extension of ischemic damage following acute myocardial ischemia (MI) in the rat. Administration of SQ-29,548 to sham MI rats had no significant effect on mean arterial blood pressure or heart rate over the 6 h experimental protocol. Ischemic damage was assessed by measurement of the depletion of creatine kinase (CK) activity and amino-nitrogen concentration from the myocardium. Six hours following ligation of the left main coronary artery, there was a significant loss of both CK (P less than 0.001) and amino-nitrogen (P less than 0.001) from the left ventricular free wall (LVFW). Administration of SQ-29,548 significantly blunted this loss of CK activity (P less than 0.01) and amino-nitrogen concentration (P less than 0.001) from the ischemic myocardium. Furthermore, the survival rate at 6 h following acute coronary artery ligation was 100% (7/7) for rats given SQ-29,548 and 58% (11/19) for rats given only the vehicle (P less than 0.05). These data indicate that SQ-29,548 significantly prevents the extension of ischemic damage in the myocardium and improves survival following acute coronary artery ligation, suggesting an important role for TxA2 in the pathophysiology of acute myocardial ischemia.

Animals↗
PubMed1986

Leukotrienes as mediators of ischemia and shock.

Leukotrienes have been implicated as mediators of ischemia and shock. Recent evidence has been obtained supporting the four major criteria of acceptance of leukotrienes as mediators of shock, namely (a) increased concentration in body fluids during shock states, (b) ability to exert significant pathophysiologic effects which aggravate ischemia and shock, (c) amelioration of the shock state by leukotriene synthesis inhibitors and leukotriene receptor antagonists, and (d) production of a shock-like state by exogenous administration of leukotrienes. In conclusion, both LTB4 and the peptide leukotrienes (e.g. LTC4, LTD4 and LTE4) also known as the slow reacting substance of anaphylaxis (SRS-A) can be considered as mediators of ischemia and shock. Although difficulties exist with measuring leukotrienes in circulating blood and in obtaining long lasting selective blockers of leukotriene synthesis, innovative experiments measuring leukotrienes in bile and other body fluids and in employing specific leukotriene receptor antagonists have helped in assessing the significance of the leukotrienes in shock states. Additional studies are necessary to evaluate these findings in perspective, and to compare and contrast the role of leukotrienes to that of other vascular mediators including prostaglandins and thromboxanes, as well as non-eicosanoids including serotonin, histamine, angiotensin II and vasopressin, all of which can play a mediator role in ischemia and shock states. Further clarification of these issues promises to open exciting new chapters in shock research.

Animals↗
PubMed1986

Synthesis and vascular actions of an arachidonic acid ethylene-diamino-triethyl-ester (AA-EDTA) derivative.

An ethylene-diamino-triethyl-ester derivative of arachidonic acid (AA-EDTA) was newly synthesized and tested for its coronary vasoactivity in isolated perfused cat coronary arteries. This arachidonic acid analog exerted a coronary vasodilator effect and significantly antagonized the coronary vasoconstrictor effect of LTD4. The constrictor response to the thromboxane analog carbocyclic thromboxane A2 was unaffected by AA-EDTA. These properties of AA-EDTA may be useful in counteracting the vasoconstrictor influence of leukotrienes in situations such as coronary artery vasospasm.

Animals↗