Biomedical subjects

A M Lefer

Publications and source records attributed to A M Lefer.

At least 217 records · Page 12Linked to original sources

PubMed1988

Detection of platelet-activating factor during traumatic shock.

The purpose of this study was to determine if platelet-activating factor (PAF) is formed in the peritoneal fluid of rats following traumatic shock. Anesthetized rats subjected to Noble-Collip drum trauma developed a lethal shock state characterized by a mean survival time of 80 +/- 16 min and a final mean arterial blood pressure of 54 +/- 7 mm Hg compared with 117 +/- 14 mm Hg in sham-shock control rats. Peritoneal fluid from traumatized and PAF-infused rats analyzed by high performance liquid chromatography (HPLC) contained a phospholipid which had a similar retention time as authentic PAF, but was absent in sham shock rats. Furthermore, aliquots of this chromatographic peak aggregated washed rabbit platelets, and the aggregation was blocked by a specific PAF receptor antagonist, CV-6209. Moreover, extraction of peritoneal fluid from traumatized rats aggregated washed rabbit platelets and this activity increased nearly four-fold in traumatized rats compared to sham shock rats. These findings are consistent with the formation of PAF in traumatic shock, and along with previous data of PAF antagonists ameliorating traumatic shock, support a role of platelet-activating factor in the pathogenesis of traumatic shock.

Animals↗

PubMed1988

Role of platelet activating factor in propagation of cardiac damage during myocardial ischemia.

The role of platelet activating factor (PAF) in acute myocardial ischemia (MI), produced by the ligation of the left main coronary artery, was studied in anesthetized rats. A significant loss of cardiac amino-nitrogen concentration and cathepsin D activity was observed 6 hr after permanent occlusion MI or 10 min of MI followed by 6 hr of reperfusion in rats. A novel, potent, PAF antagonist, CV-6209 (160 nmol/kg or 1.6 mumol/kg) injected after the ligation, significantly retarded the loss of amino-nitrogen and cathepsin D activity in a dose-related manner. In another group of rats, CV-6209 (1.6 mumol/kg) significantly blocked the hypotension induced by repetitive injections of PAF (570 pmol/kg) with an apparent half-life of approximately 180 min. In isolated rat hearts perfused with Krebs-Henseleit solution, PAF (25 nmol/l) significantly increased coronary perfusion pressure by 15 +/- 2 mmHg and induced an increase in cardiac permeability using fluorescein isothiocyanate bovine albumin as a marker. Furthermore, the increase in cardiac permeability induced in isolated perfused rat hearts undergoing 15 min global ischemia followed by reperfusion was significantly attenuated by CV-6209 (250 nmol/l). These data indicate that PAF is an important mediator of ischemic damage in rat MI. Moreover, the extension of ischemic damage may be enhanced by the increase in cardiac permeability induced by PAF.

Animals↗

PubMed1988

Beneficial actions of antagonism of peptide leukotrienes in hemorrhagic shock.

The peptide leukotrienes are biologically active eicosanoids which have recently been implicated as possible mediators of anaphylactic, endotoxic, traumatic, and splanchnic artery occlusion shock. We studied the effects of a novel selective peptide leukotriene antagonist, L-649,923, in a rat model of hemorrhagic shock. Hemorrhaged rats treated with L-649,923 (1 mg/kg/h) 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/h) of L-649,923 (final MABP 97 +/- 4 vs 60 +/- 5, p less than 0.01; vs 60 +/- 4 mm Hg, p less than 0.01, respectively). Both doses of L-649,923 attenuated the increase in plasma cathepsin D activity (p less than 0.01). L-649,923, at 1 mg/kg/h, also attenuated the plasma accumulation of free amino-nitrogen compounds (p less than 0.05). Furthermore, the plasma activity of a myocardial depressant factor (MDF) was significantly lower in rats treated with L-649,923 (1 mg/kg/h) than in rats receiving the lower dose of the drug or the vehicle (36 +/- 5 U/ml vs. 61 +/- 4 U/ml, p less than 0.01; and 60 +/- 3 U/ml, p less than 0.01, respectively). Furthermore, L-649,923 does not inhibit platelet aggregation in platelet rich plasma. Our data suggest that peptide leukotrienes are important mediators of hemorrhagic shock and that blockade of leukotriene-induced vasoconstriction may underlie the beneficial effects of L-649,923 in hemorrhagic shock.

Animals↗

PubMed1988

Protective effects of thromboxane receptor blockade in splanchnic artery occlusion shock.

Splanchnic artery occlusion (SAO) followed by release of the occlusive clamps produces circulatory shock characterized by an abrupt hypotension, cardiac depression and high lethality. We studied the effects of the thromboxane receptor antagonist, BM-13505, in rats during SAO shock. Anesthetized rats subjected to total occlusion of the celiac and superior mesenteric arteries for 40 minutes developed a severe shock state following reperfusion, usually resulting in death within 90-120 minutes of release of the occlusion. BM-13505 was started at reperfusion for 10 minutes. SAO shock rats treated with BM-13505 (1 mg/kg) maintained post-reperfusion mean arterial blood pressure (MABP) at significantly higher values compared to those receiving only the vehicle (0.9% NaCl). Treatment with BM-13505 attenuated the plasma activity of the lysosomal protease cathepsin D (p less than 0.05 from vehicle) and the plasma accumulation of free amino-nitrogen compounds (p less than 0.01 from vehicle). Furthermore, the plasma activity of a myocardial depressant factor was significantly lower in BM-13505 treated rats than in non-treated rats (p less than 0.01 from vehicle). SAO shock rats treated with BM-13505 also exhibited a higher survival rate than the vehicle group (75% vs. 20%). These results suggest an important role of thromboxane A2 in the pathophysiology of SAO shock.

Animals↗

PubMed1987

Mechanism of antagonism of thromboxane receptors in vascular smooth muscle.

The mechanism and profile of antagonism of thromboxane receptors were studied in isolated perfused cat coronary arteries and in rat aortic rings. In cat coronary arteries, the thromboxane receptor antagonist (TxRA) BM-13,505 at concentrations from 3 to 300 ng/ml, significantly attenuated the vasoconstrictor effects of both a thromboxane A2 analog (CTA2) and an endoperoxide analog (U-46,619) and did not alter the constrictor responses to leukotriene D4, arginine vasopressin, or angiotensin II. In rat aortic rings precontracted by CTA2 or U-46,619, the effective threshold concentration of BM-13,505 for relaxation was 5 ng/ml. Lower concentrations of BM-13,505 exerted no relaxation, and higher concentrations exhibited faster relaxation to the precontracted baseline levels. This relaxation was not observed in aortic rings precontracted by norepinephrine or angiotensin II. The action of TxRA was not influenced by the absence of the endothelium or by pretreatment with a selective guanylate cyclase inhibitor, methylene blue. Also, thromboxane receptor antagonists do not appear to block thromboxane induced constriction by action as free radical scavengers. It can be concluded that replacing thromboxane A2 on the vascular receptor by a TxRA is the main factor responsible for the antagonism of thromboxane induced vasoconstriction in vascular smooth muscle preparations, not, the presence of the endothelium, activation of guanylate cyclase, or scavenging of superoxide free radicals.

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

PubMed1987

PAF-acether induced cardiac dysfunction in the isolated perfused guinea pig heart.

PAF-acether (1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine) has been implicated in a variety of inflammatory and ischaemic disorders (e.g., myocardial ischemia, anaphylactic shock). Recently, the peptide leukotrienes (i.e., LTC4, LTD4) have been shown to mediate the increase in coronary vascular resistance induced by PAF-acether in the isolated perfused rat heart. In isolated perfused guinea pig hearts, PAF-acether produced a dose-dependent increase in coronary perfusion pressure (CPP) and a decrease in contractile force (CF). At 50 pmol/l, PAF increased CPP by 13 +/- 3 mm Hg and decreased CF by 47 +/- 12% in 8 hearts. Radioimmunoassay of the coronary effluent did not detect peptide leukotrienes or thromboxane B2 (TxB2) in response to PAF. Addition of a specific PAF-acether receptor antagonist, CV-6209 (25 nmol/l), blocked the increase in coronary perfusion pressure and decrease in contractile force. OKY-1581 (400 nmol/l), a thromboxane synthetase inhibitor or LY-171,883 (7.3 mumol/l) a leukotriene D4 receptor antagonist, failed to prevent the increase in CPP or the decrease in CF. These data indicate that the PAF-acether induced increase in CPP is not mediated by the peptide leukotrienes or thromboxane A2 (TxA2). Possible mechanisms for the increase in CPP induced by PAF-acether in the isolated perfused guinea pig heart include a direct receptor mediated constriction of coronary resistance vessels, release of a non-eicosanoid coronary constrictor as a mediator of the response, or via enhancement of coronary microvascular permeability.

Animals↗

PubMed1987

Increased severity of acute myocardial ischemia in experimental atherosclerosis.

We investigated the effects of acute myocardial ischemia (MI) in a rabbit model of atherosclerosis to determine whether atherosclerosis augments the severity of damage produced in the ischemic myocardium. Normal rabbits were fed a control rabbit chow diet or a diet enriched with either 2% cholesterol or 0.5% cholesterol for 10-12 weeks prior to induction of MI. Plasma cholesterol concentrations in the cholesterol-fed rabbits were 1697 +/- 70 mg/dl (2%) and 1056 +/- 51 mg/dl (0.5%) vs. 61 +/- 12 mg/dl for the non-cholesterol-fed rabbits. All rabbits were observed for 5 h following induction of MI or sham MI. At the conclusion of the experiment, tissue biopsies from the MI region and non-MI (NMI) regions were taken and analyzed for two indicators of the severity of MI--myocardial creatine kinase (CK) activity and free amino-nitrogen concentration. Atherosclerosis was confirmed histologically in coronary artery and aortic specimens. No difference was found among any group with respect to heart rate (HR), mean arterial blood pressure (MABP), or pressure-rate index (HR x MABP/1000, a measure of myocardial oxygen demand). Myocardial CK loss (NMI - MI) was significantly greater for the 2% and 0.5% cholesterol groups (7.3 +/- 1.3 and 4.9 +/- 0.7 IU/mg protein, respectively, P less than 0.05) than in the nonatherosclerotic group (2.5 +/- 0.4 IU/mg protein; P less than 0.001 for 2% and P less than 0.01 for 0.5%). Increased severity of MI was confirmed by a significantly greater myocardial loss of free amino-nitrogen (NMI - MI) in the two atherosclerotic groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

Influence of atherosclerosis on vascular responsiveness in isolated rabbit vascular smooth muscle.

Coronary arteries and aortic rings were isolated from rabbits fed either a control diet or a high cholesterol (1 to 2%) diet for 8 to 11 weeks and studied for their vasoactive properties to a variety of vasoconstrictor and vasodilator agents. Perfused coronary arteries without intact endothelium constrict markedly to a thromboxane A2 agonist (i.e., carbocyclic thromboxane A2, CTA2) and dilate markedly to iloprost, a prostacyclin analog. No differences occurred between the coronary arteries isolated from control or atherosclerotic rabbits. Additional studies were conducted on rabbit aortic vascular smooth muscle rings containing functionally intact endothelium and in rings denuded of their endothelium. Acetylcholine (20 to 2000 ng/ml) neither constricted nor dilated control aortic rings without endothelium, and markedly dilated aortic rings with intact endothelium in a concentration dependent manner. In atherosclerotic aortic rings, acetylcholine constricted preparations without endothelium, and dilated rings with endothelium to a much lesser extent than that observed in control rings. Similar reductions in responsiveness occurred with adenosine diphosphate (ADP), another endothelium-dependent vasodilator, but not with iloprost, a nonendothelium-dependent dilator. No differences were observed in constrictor responses to norepinephrine. Aortae from atherosclerotic rabbits produced less prostacyclin in response to arachidonic acid than control aortae. These data point to an important role of the endothelium in modulating the vascular response to vasodilators in atherosclerotic rabbit arterial vessels.

6-Ketoprostaglandin F1 alpha↗

PubMed1987

Constriction of cat coronary arteries by synthetic thromboxane A2 and its antagonism.

Synthetic thromboxane A2 (TxA2S) induced rapid, concentration-dependent constriction of isolated perfused cat coronary arteries. Its potency was approximately 30 times that of the prostaglandin endoperoxide, PGH2. Pinane thromboxane A2 (PTA2), BM-13.505 and SQ-29,548, compounds previously shown to antagonize the effects of stable prostaglandin endoperoxide analogs, inhibited the constriction induced by TxA2S in a concentration-dependent fashion. These experiments provide further evidence that the oxetane structure proposed for TxA2 is correct and show that compounds that inhibit the effects of prostaglandin endoperoxides also antagonize the effects of TxA2.

Animals↗

PubMed1987

Thromboxane induced red blood cell lysis.

The two thromboxane A2 mimetics, carbocyclic thromboxane A2 (CTA2) and U-46619 (9,11-methanoepoxy PGH2) at concentrations of 400 ng/ml significantly enhanced the release of hemoglobin from both feline and human erythrocyte suspensions. This effect was significantly attenuated by the thromboxane receptor antagonist BM-13,505 indicating that the membrane leakiness is in some way receptor mediated. The effects also appear to be concentration-dependent over the range of 100-400 ng/ml. The membrane labilizing effect of thromboxane analogs is not due to a non-specific eicosanoid effect since iloprost, the stable prostacyclin analog, actually stabilized erythrocyte membranes. Moreover, synthetic thromboxane A2 exerted similar effects to that of the two TxA2-mimetics. This membrane labilizing action of thromboxanes may be important in propagating the other pathophysiologic effects of thromboxane A2 in cardiovascular disease states.

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

PubMed1987

Protective actions of a stable prostacyclin analog in ischemia induced membrane damage in rat myocardium.

Myocardial ischemia leads to the damage of cellular membranes and release of intracellular enzymes. We studied the influence of the prostacyclin analog, iloprost, on alterations in membrane phospholipid content and composition in rat myocardium during ischemia. Infusion of iloprost (100 ng/kg/min) or its vehicle started 20 min after coronary artery ligation, and the hearts were analyzed after 6 h. Myocardial creatine kinase activity was significantly reduced by approximately 25% in the ischemic areas of hearts from rats receiving vehicle. This reduction in myocardial creatine kinase activity was totally abolished by infusion of iloprost. Total phospholipid content was significantly reduced by 10% in ischemic areas of hearts obtained from vehicle infused animals. Iloprost infusion also prevented the loss of total phospholipids in the ischemic areas. The data show that coronary artery ligation is associated with a significant loss of total membrane phospholipids in ischemic regions of rat myocardium, characterized by significant decreases in phosphatidylcholine, phosphatidylethanolamine and cardiolipin. The decrease in cardiac phosphatidylcholine and phosphatidylethanolamine content was prevented by iloprost, whereas the decrease in cardiolipin content was unaltered. Infusion of the prostacyclin analog iloprost almost totally inhibited the ischemia induced loss of phospholipids, suggesting that this may be an important component of its cytoprotective mechanism of action.

Animals↗

PubMed1987

Phenylephrine derivatives as leukotriene D4 antagonists.

Two series of phenylephrine derivatives were prepared and tested as inhibitors of leukotriene D4 (LTD4) induced and ovalbumin-induced bronchospasm in the guinea pig. The most potent compound of the urea series, (R)-N,N-diethyl-N-[2-hydroxy-2-[3-(2-quinolinylmethoxy)phenyl]ethyl]-N- methylurea (3, Wy-47,120), was orally active with ED50's of 56 mg/kg vs. LTD4 and 55 mg/kg vs. ovalbumin. When tested as an antagonist of LTD4-induced contraction of isolated guinea pig tracheal strips, 3 was a competitive inhibitor with a p kappa B value of 5.22. In the second series, (R)-3-methyl-5-[3-(2-quinolinylmethoxy)phenyl]-2-oxazolidinone (26, Wy-47,674) had oral ED50's of 36 mg/kg against LTD4 and 95 mg/kg against ovalbumin. Compound 26 selectively antagonized contractile responses of guinea pig trachea evoked by LTD4 (p kappa B = 6.09). In the cat coronary artery, 3 dilated the preparation and blocked the coronary constrictor effect of LTD4. Compound 3 (0.13 mg/kg, iv) also preserved myocardial integrity in rats 48 h after coronary artery ligation. When tested in the rat alcohol-induced gastric lesion model, 3 and 26 manifested a dose-dependent mucosal protection against ethanol.

Animals↗

PubMed1987

Beneficial effects of prostaglandin E1 infusion in experimental traumatic shock.

The effects of prostaglandin E1 (PGE1) were studied in a standardized model of traumatic shock in rats. Pentobarbital anesthetized rats were subjected to standardized drum trauma of 525 revolutions in a Noble-Collip drum. These traumatized rats were characterized by a survival time of 108 +/- 19 min, a 12-fold increase in plasma cathepsin D activity, and a three-fold increase in plasma myocardial depressant factor (MDF) activity. PGE1 (1.2 micrograms/kg X min) significantly improved survival time during traumatic shock (191 +/- 29 vs. 108 +/- 19 min), drug vs. vehicle, respectively (p less than .03). In addition, PGE1 significantly attenuated plasma MDF activity during traumatic shock (58 +/- 10 vs. 27 +/- 7 U/ml), vehicle vs. drug, respectively (p less than .02). Plasma cathepsin D activity was also significantly retarded (12.1 +/- 1.8 vs. 1.70 +/- 1.50 U/ml), vehicle vs. drug, respectively (p less than .01). PGE1 appears to exert a membrane stabilizing effect, decreasing plasma cathepsin D and attenuating MDF production. PGE1 thus appears to have significant antishock activity.

Alprostadil↗

PubMed1987

Coronary vascular actions of synthetic atrial natriuretic factor in isolated vascular preparations.

Administration of atrial natriuretic factor (ANF) in animals results in increases in renal blood flow, natriuresis, and a decrease in arterial blood pressure, supporting a role for the atrial peptide system in cardiovascular regulation. However, little is known about the vascular effects of synthetic ANF (26 amino acid) on coronary artery smooth muscle. We studied the coronary vascular effects of synthetic ANF in feline artery preparations in vitro. In isolated coronary arteries perfused at constant flow, ANF (3-300 nM) concentration dependently decreased perfusion pressure ranging from 2.6 +/- 0.7 mm Hg (p less than 0.02) at 3 nM to 28.6 +/- 3.7 mm Hg (p less than 0.001) at 300 nM. Perfusion with the prostacyclin analog, iloprost (20-100 nM), failed to alter the coronary vasodilator response to ANF. ANF also relaxed feline coronary helical strips when contracted by U-46,619 (an endoperoxide analog), serotonin, and leukotriene D4. This relaxant effect was independent of the presence of endothelial cells and occurred in the presence of a guanylate cyclase inhibitor, methylene blue. The ANF had no direct effect on electrically driven isolated feline papillary muscles, signifying a lack of direct inotropic activity of ANF in cat cardiac muscle. These results suggest that ANF may produce coronary vasodilation that therefore could contribute to coronary regulation, without directly altering myocardial performance.

Animals↗

PubMed1987

Interaction between myocardial depressant factor and vasoactive mediators with ischemia and shock.

A variety of endogenously formed vasoconstrictor substances circulate in the blood and act as mediators in ischemia and shock states. These humoral substances are chemically diverse and include peptides, lipids, and aromatic amines. One of the novel peptides, myocardial depressant factor (MDF) and several interesting lipids, including thromboxane A2 (TxA2), leukotriene D4 (LTD4), and platelet-activating factor (PAF) are very potent substances having a broad profile of pathophysiological actions. Some of the effects of MDF include myocardial depression, constriction of splanchnic vessels, and impairment of phagocytosis. TxA2 primarily constricts blood vessels, aggregates platelets, and increases membrane permeability. LTD4 is a potent vasoconstrictor and bronchoconstrictor and promotes leakage of fluid out of blood vessels. PAF activates platelets, depresses cardiac function, constricts airways, and enhances fluid leakage from the intravascular compartment. Thus vasoconstriction is common to all these mediators. Moreover, these vasoactive substances have common mechanisms of release and interact to exacerbate ischemia and contribute to the pathogenesis of a variety of shock states. New pharmacological approaches to blocking the formation and action of these mediators have provided interesting insights into the pathophysiology of shock.

Capillary Permeability↗

PubMed1987

Heterogeneity of vascular smooth muscle responsiveness to lipid vasoactive mediators.

Thromboxane A2 (TxA2), leukotriene C4 (LTC4), leukotriene D4 (LTD4), and platelet-activating factor (PAF) are novel lipids which exert a variety of biological actions. TxA2, LTC4 and LTD4 have been shown to induce direct vasoconstriction in several species, while PAF contracts isolated guinea pig ileum and lung parenchyma. We studied the direct vasoconstricting activities of these lipid mediators in isolated cat renal, superior mesenteric and coronary arteries. The TxA2 analog 9,11-methanoepoxy PGH2 (U-46619) constricted both perfused and helical strips, with the renal and mesenteric arteries being 4 times more responsive than the coronary arteries. LTC4 and LTD4 constricted coronary arteries to a significantly greater extent than renal and superior mesenteric arteries in both perfused arteries and helical strips. Furthermore, PAF failed to contract any of the perfused arteries or helical strips at concentrations from 1 ng to 20 micrograms. TxA2 was a potent vasoconstrictor in all the vessels studied, suggesting a role for this substance as a vasoactive mediator in ischemia and shock. The coronary arteries were more responsive to the leukotrienes than the mesenteric and renal arteries, suggesting that the leukotrienes may play an important role in myocardial ischemia. Moreover, both thromboxane and leukotriene effects were blocked in all preparations by specific receptor antagonists. While the biological effects of PAF are still poorly understood, PAF does not directly vasoconstrict large arteries of the feline renal, superior mesenteric or coronary vasculatures.

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

PubMed1987

Additive beneficial effects of two inhibitors of vasoconstrictor mediators in acute myocardial ischemia.

A specific inhibitor of thromboxane A2 (TxA2) synthesis, CGS-12970, a new angiotensin-converting enzyme (ACE) inhibitor, CGS-16617, and a combination of both agents were evaluated for their ability to reduce the extension of myocardial infarct size in rats. Myocardial creatine kinase (CK) loss from the left ventricular free wall (LVFW) 48 hr after left coronary artery ligation was used as an index of ischemic damage. Treatment with either CGS-12970 (4 mg/kg) or CGS-16617 (1 microgram/kg) alone did not attenuate the loss of CK from LVFW significantly, compared with animals receiving only the vehicles for these drugs. However, the combined use of both agents significantly reduced CK depletion from LFVW (P less than 0.01). These findings support the interrelated role of TxA2 and angiotensin II as mediators of myocardial ischemia and suggest that combined inhibition of their formation may be useful in the treatment of acute myocardial infarction.

Acute Disease↗

PubMed1987

Cardioprotective actions of specific thromboxane receptor antagonist in acute myocardial ischemia.

Thromboxane A2 (TxA2) has been implicated as a potential mediator of myocardial damage during acute ischemia. A potent and specific TxA2 receptor antagonist, SQ-29,548 (2 mg/kg bolus + 2 mg/kg/h) was tested in a cat acute coronary ligation model of myocardial ischemia over a 5-h observation period. Those cats given the TxA2 receptor antagonist had a significant reduction in elevated S-T segment from 0.32 to 0.17 mV (p less than 0.01) in contrast to cats given only vehicle which showed a progressive increase in S-T segment elevation over the 5-h course of the experiment. Furthermore, the rise in plasma creatine kinase (CK) activity during myocardial ischemia was significantly attenuated after SQ-29,548 administration (p less than 0.05). This was confirmed by direct myocardial biopsies which demonstrated a reduction in the loss of myocardial CK and nitrogenous compounds from the ischemic region. Because heart rate (HR), mean arterial blood pressure (MABP), and the pressure rate index (PRI) were unaffected by SQ-29,548 administration, its mechanism of protection probably does not occur through reduction of myocardial oxygen demand. Furthermore, specificity of SQ-29,548 for thromboxane/endoperoxide receptors was demonstrated in the isolated cat coronary arteries. These data suggest that SQ-29,548 reduces the damage associated with myocardial ischemia through direct TxA2 receptor antagonism. The data are also consistent with an important role of TxA2 in the pathophysiology of myocardial ischemia.

Animals↗