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Biomedical subjects

A M Lefer

Publications and source records attributed to A M Lefer.

At least 343 records · Page 19Linked to original sources
PubMed1981

Effects of arachidonic acid hydroperoxides on vascular and non-vascular smooth muscle.

The omega-6 and omega-9 hydroperoxides of arachidonic acid (AA) caused dose-dependent contraction of rabbit aortic strip (RAS) and guinea pig ileum (GPI) at concentrations between 5 and 200 microM. At these concentrations, arachidonic acid had no effect in these preparations. The contractions could not be blocked by indomethacin, methysergide, phenoxybenzamine, propranolol, diphenhydramine, scopolamine, or the SRS-A antagonist FPL-55712, but were abolished by the calcium channel blocker nimodipine. In both tissues, the hydroperoxides initiated a sustained contraction. The onset of GPI contraction however, was much faster than the response of RAS to these hydroperoxides. 15-HPETE produced a more sustained contraction than 12-HPETE in both RAS and GPI. These results suggest that hydroperoxides generated from AA by the action of lipoxygenase can directly induce smooth muscle contraction and this effect is probably mediated through altering calcium fluxes in these smooth muscle preparations.

Animals↗
PubMed1981

Delayed appearance of a circulating myocardial depressant factor in burn patients.

Fourteen burn patients and four normal controls were studied for the plasma activity of a myocardial depressant factor (MDF). The mean age of the burn patients was 40.4 years and the burn area was 61.9% of body surface. MDF activities were 28 +/- 3 units in the burn patients on day 1 and 56 +/- 4 units on days 4 and 5. This compares with 23 +/- 3 units for the control patients. Despite maintenance of high cardiac output by fluid therapy, only three of the 14 patients (21%) survived. Our data show the presence in burn patients of MDF, which may contribute to high mortality rates in these patients.

Adult↗
PubMed1981

Mechanism of coronary vasoconstriction induced by carbocyclic thromboxane A2.

The mechanism of carbocyclic thromboxane A2 (CTA2) vasoconstriction was studied in thoracic aortic strips and isolated perfused cat coronary arteries. CTA2, a stable thromboxane analog, produced coronary constriction at 50 pg/ml or greater. At constant flow, 5 ng/ml CTA2 increased perfusion pressure 40 +/- 4 mmHg. The calcium antagonist nifedipine reduced CTA2-induced vasoconstriction by 8% at 1 ng/ml (NS), 22% at 10 ng/ml (NS), 65% at 100 ng/ml (P less than 0.01), and 75% at 1,000 ng/ml (P less than 0.005). Other calcium antagonists also significantly reduced CTA2-induced coronary constriction. Inhibition of vasoconstriction by calcium antagonists was not due to direct thromboxane-receptor antagonism, inasmuch as nifedipine did not prevent CTA2-induced contraction in cat aortas, vessels that are not dependent on external calcium for contraction. Reducing external Ca2+ concentration to 0.63 mM significantly reduced coronary constriction over most of the CTA2 concentration-response range. Phentolamine (1-50 micrograms/ml), phenoxybenzamine (1-100 micrograms/ml), and saralasin (0.1-10 micrograms/ml) were all without significant effect on CTA2-induced coronary constriction. The results indicate that the mechanism of thromboxane coronary vasoconstriction is by a specific thromboxane receptor that is dependent on an inward calcium flux. The data also suggest that the efficacy of calcium antagonists in coronary vasospasm may be related to their ability to noncompetitively inhibit thromboxane-induced vasoconstriction.

Animals↗
PubMed1981

Biphasic actions of chlorpromazine and mepacrine on modulation of hepatic cell injury in the perfused cat liver.

The effect of chlorpromazine (CPZ) and mepacrine on hypoxic liver cell damage was studied using an isolated perfused cat liver preparation. High concentrations of CPZ (10(-4) M) significantly augmented the hypoxic leakage of the lysosomal enzyme, cathepsin D, and the cytoplasmic enzyme, lactate dehydrogenase (LDH) into the perfusate. The per cent free cathepsin D activity of hepatic tissue was significantly higher in the 10(-4) M CPZ treated groups (87%) than in the vehicle group (65%). CPZ at a concentration of 10(-6) M also possessed a detrimental effect on hypoxic liver integrity but to a lesser extent compared to 10(-4) M. In contrast, low concentrations of CPZ (10(-7) M) showed a protective effect during hypoxia (i.e., significantly lower perfusate cathepsin D activity and per cent free cathepsin D activity) compared to livers receiving only the vehicle. Mepacrine, another phospholipase A2 inhibitor, showed no significant effect on hypoxic liver damage at concentration of 10(-6) and 5 x 10(-5) M. CPZ has a biphasic action on liver integrity during hypoxia, low concentrations being protective and high concentrations are deleterious. Mepacrine had no significant effect in the hypoxic liver.

Amines↗
PubMed1981

Beneficial actions of a free radical scavenger in traumatic shock and myocardial ischemia.

The role of prostanoids in shock states is complex because beneficial as well as deleterious prostanoids are formed during circulatory shock. Recent attention has focused on free radicals formed in the arachidonic acid cascade. MK-447, a free radical scavenger, at 1-4 mg/kg, was found to prolong survival in traumatic shock and to prevent the plasma appearance of a myocardial depressant factor (MDF) in shock rats. In the isolated cat heart perfused under ischemic conditions (ie, coronary flow less than 0.7 ml/min for 2 hours), MK-447 partially restored contractile performance after reestablishment of normal flow and partially prevented cardiac edema. In combination with the cyclooxygenase inhibitor, meclofenamate, MK-447 dramatically restored mechanical performance, prevented leakage of myocardial creatine kinase activity, and cardiac edema. It appears that MK-447 protects in traumatic shock and in myocardial ischemia by a mechanism related to removal of free radicals formed in arachidonic acid metabolism.

Animals↗
PubMed1980

Beneficial actions of imidazole in endotoxin shock.

The effects of imidazole were studied in anesthetized cats during endotoxin shock. Imidazole (25 mg/hg/hr) was administered 30 minutes after intravenous injection of E. coli endotoxin (5 mg/kg). The degree of the severity of the shock state was assessed by mean arterial blood pressure (MABP), and by plasma cathepsin D and MDF activities. Analysis of thromboxane B2 concentrations during shock was also performed by radioimmunoassay. Administration of imidazole to cats given endotoxin partially prevented the decrease in MABP of endotoxin shock. Imidazole significantly prevented the increase in plasma cathepsin D and MDF activities. Thus, infusion of imidazole resulted in metabolic and hemodynamic improvement during endotoxin shock. The mechanism of imidazole protection appears to be via lysosomal membrane stabilization, stimulation of cardiac function and possibly by antagonizing the biochemical effects of endotoxin administration, rather than by inhibition of thromboxane synthesis. Data obtained using imidazole to block thromboxane synthesis in shock states must be interpreted with caution.

Animals↗
PubMed1980

Dietary modification of the vascular effect of prostacyclin in hypertensive rats.

Hypertension increased the responsiveness of spontaneously hypertensive rats (SHR) to exogenously infused prostacyclin (PGI2) at rates of 300 ng/kg/min and 1 microgram/kg/min. This did not occur for angiotensin infusion. Substitution of a diet containing alpha-linolenic acid for the control diet to SHR abolished this increased responsiveness to PGI2. Accompanying the abolition of the increased responsiveness to PGI2 was a significant increase in specific activity of two lysosomal hydrolases (N-acetylglucosaminadase and cathepsin D) within the aorta of SHR. These changes may reflect compensatory responses of the vasculature to protect the animal.

Acetylglucosaminidase↗
PubMed1980

Dissociation of vasoconstrictor and platelet aggregatory activities of thromboxane by carbocyclic thromboxane A2, a stable analog of thromboxane A2.

Carbocyclic thromboxane A2 [2 beta (Z),3 alpha- (1E,3R*)-3-(3-hydroxy(1-octenyl)-bicyclo[3.1.1]hept-2-yl-5-heptenoic acid], a stable analog of thromboxane A2, has been tested for its physiologic properties. Carbocyclic thromboxane A2 is a potent coronary vasoconstrictor, stimulating cornonary vascular smooth muscle at concentrations as low as 29 pM. At 1-5 micro M it is also an inhibitor of arachidonic-acid- and endoperoxide-induced aggregation of platelets. At 200 nM it stimulated the release of lysosomal hydrolases from large granule fractions of liver homogenate. It inhibited thromboxane synthesis in platelets, although it did not inhibit synthesis of prostacyclin in ram seminal vesicles. Thus, carbocyclic thromboxane A2, a molecule closely related to thromboxane A2, separates coronary vasoconstrictor from platelet-aggregating activity. The constrictor activity predominates in vivo; carbocyclic thromboxane A2 induces coronary vasoconstriction leading to myocardial ischemia and sudden death in rabbits in the absence of pulmonary or coronary thrombosis.

Animals↗
PubMed1980

Role of the splanchnic visceral organs in development of tolerance to traumatic shock.

Tumbling pentobarbital-anesthetized rats (25 mg/kg) in a Noble-Collip drum for 600 revolutions resulted in a severe form of circulatory shock, and all traumatized rats died within 5 hours. However, rats subjected to sublethal tumbling (i.e., conditioning) for 4 days before lethal tumbling developed tolerance to this usually lethal dose of trauma. After the tumbling, untreated nonconditioned rats showed a marked production of the cardiotoxic peptide, myocardial depressant factor (MDF), and depression of reticuloendothelial system (RES) function. Conditioned rats subjected to trauma did not show these changes. Nonconditioned tumbled rats developed severe twisting of the small intestine resulting in a vascular strangulation of the intestine: conditioned rats did not exhibit strangulation after tumbling. To eliminate mesenteric strangulation during tumbling, two methods were employed: 1) a four-baffle drum to prevent torsional twisting of rats in the drum; and 2) emptying the intestinal contents before tumbling in the ordinary two-baffle drum. Both of these procedures eliminated mesenteric strangulation in rats during tumbling, and all rats subjected to either of these procedures survived 5 hours post-trauma. Thus mesenteric strangulation may be a critical factor contributing to lethality in Noble-Collip drum trauma. Post-traumatic splanchnic lysosomal labilization, depression of RES function, and pancreatic MDF formation and its accumulation in the plasma may be direct consequences of the splanchnic ischemia leading to lethal shock. Since conditioned rats did not develop mesenteric ischemia during tumbling, no subsequent detrimental event occurred, and these rats did not develop lethal circulatory shock.

Animals↗
PubMed1980

Influence of thromboxane inhibition on the severity of myocardial ischemia in cats.

The effects of thromboxane (Tx) inhibition or arachidonic acid (AA) infusion were studied in anesthetized cats during acute myocardial ischemia (MI). AA (7.2 mg kg-1 h-1) or imidazole (25 mg kg-1 h-1) infusions were initiated 30 min after occlusion of the left anterior descending coronary artery. Assessment of the degree of protection of the ischemic myocardium was made by measurement of S-T segment elevation, plasma and myocardial creatine phosphokinase (CPK) activities, and myocardial amino-nitrogen content. Assessment of Tx inhibition was performed by radioimmunoassay. Administration of imidazole inhibited the sevenfold increase in plasma thromboxane B2 (TxB2) levels occurring in MI (p less than 0.001 at 2-5 h), markedly decreased S-T segment elevations at 2-k h (p less than 0.025), significantly prevented the elevation in plasma CPK (p less than 0.05, at 4 and 5 h), the increase in TxB2 post-MI, significantly decreased (p less than 0.025) S-T segment evaluations at 2-5 h, caused a decrease in plasmaCPK levels (p less than 0.05 at 5 h), but did not prevent loss of myocardial CPK or amino-nitrogen. In summary, the administration of imidazole resulted in significant protection of the myocardium in all indices of ischemic damage measured, while AA infusion resulted in only a partial protection. The mechanism of the imidazole protection of ischemic myocardial tissue appears to be via inhibition of Tx synthesis althoug we cannot exclude a hemodynamic or cytoprotective mechanism. These results suggest that specific inhibition of Tx formation is beneficial during acute MI.

Animals↗
PubMed1980

Preservation of ischemic myocardium by pinane thromboxane A2.

Pinane thromboxane A2 (PTA2), a thromboxane A2 analog has been shown to antagonize the vasoconstriction and platelet aggregation induced by thromboxane A2, in addition to specifically inhibiting thromboxane synthetase. Because thromboxane A2 generation would be detrimental in acute myocardial ischemia (MI) by both decreasing coronary blood flow and increasing platelet aggregation, inhibition of thromboxane production and action may be beneficial in myocardial ischemia. In pentobarbital-anesthetized cats, the left anterior descending coronary artery was ligated, and PTA2 (0.5 mumol . kg-1 . h-1) or a Na2CO3 vehicle was infused 30 min post-MI for 270 min. Compared to vehicle-treated MI cats, PTA2 prevented the increase in plasma thromboxane levels seen at 2 through 5 h (P less than 0.005 at 2 through 5 h) and prevented the large increase in plasma CK activities at 4 and 5 h (P less than 0.025). In addition, PTA2 treatment abolished the differences in myocardial CK activities between ischemic and nonischemic regions and prevented the decrease in percent-bound cathepsin D in the ischemic region. Moreover, ECG analysis revealed a decreased incidence of premature beats in PTA2-treated MI cats as compared to MI-vehicle cats. In summary, these data indicate that PTA2 protects the ischemic myocardium and provide further evidence that inhibition of thromboxane formation, in addition to antagonism of its activity, is beneficial during the early stages of acute myocardial ischemia.

Animals↗
PubMed1980

Cytoprotective actions of prostacyclin during hypoxia in the isolated perfused cat liver.

The cytoprotective effect of prostacyclin (PGI2) was examined using hypoxic cat livers perfused with Krebs-Henseleit buffer at constant flow. PGI2 infusion (10 ng . g-1 . min-1) showed no direct vasodilator effect on the hepatic circulation under conditions of normoxia or hypoxia, as studied by changes in perfusion pressure. Hypoxia induced a marked decline in hepatic oxygen consumption, an increase in perfusion pressure, and in perfusate cathepsin D and LDH activity in the hepatic effluent indicating lysosomal and cytoplasmic leakage. Tissue samples, obtained 150 min after hypoxic perfusion, showed higher percent-free cathepsin values (82 +/- 4%, mean +/- SE, 7 livers, P less than 0.025) compared to that of normoxia (58 +/- 4). Phagocytic activity, measured by the clearance rate of colloidal carbon particles, was also depressed by hypoxia. PGI2 infusion significantly inhibited the posthypoxia leakage of liver cathepsin D and LDH into the recirculating perfusate, restored the percent-free cathepsin D to 64 +/- 3%, and preserved the phagocytic activity during hypoxia, indicating preservation of lysosomal and cytoplasmic membrane integrity and Kupffer cell phagocytic function. The preservation of lysosomal integrity by PGI2 was further confirmed by electron microscopy. It is evident that PGI2 has a significant protective effect in hypoxic hepatocytes that may not be related to its vasodilation and inhibition of platelet aggregation.

Animals↗
PubMed1980

Protective actions of naloxone in hemorrhagic shock.

The opiate antagonist, naloxone, was infused at 8 mg x kg-1 x h-1 in cats to determine its effect in hemorrhagic shock. Hemorrhaged cats treated with naloxone maintained postreinfusion mean arterial blood pressure at a higher value compared to those receiving only the vehicle. Final pressures were 77 +/- 9 mmHg for cats receiving vehicle compared to 120 +/- 6 mmHg for cats receiving naloxone. These values represent 58 +/-7 and 98 +/- 6% of initial pressures for vehicle- and naloxone-treated cats, respectively (P < 0.001). Naloxone also moderated increases in circulating lysosomal hydrolase activity (4- vs. 23-fold increase) and total plasma proteolysis (33 vs. 100% increase). Plasma myocardial depressant factor activity was also significantly reduced in naloxone-treated hemorrhaged cats compared to shock cats given 0.9% NaCl (16 +/- 3 vs. 58 +/- 4 U, respectively; P < 0.001). Studies on cat papillary muscles demonstrated that naloxone at concentrations slightly higher than estimated plasma values during shock exerted a moderate positive inotropic effect. Our results show that naloxone improved the hemodynamic and biochemical state of cats in hemorrhagic shock. Inhibition of proteolysis and stabilization of lysosomal membranes appear to be ivolved in the protective action of naloxone, along with the well-known opiate-antagonistic action of this agent.

Animals↗
PubMed1980

Salutary effects of prostacyclin in endotoxic shock.

Endotoxin shock was induced in anesthetized cats with E. coli endotoxin (5 mg/kg, i.v.) This produced a severe decline in mean arterial blood pressure and a marked decrease in superior mesenteric artery flow (SMAF) within 1 h. The plasma activity of cathepsin D, a lysosomal protease, increased 6-fold by 2 h. At 5 h, myocardial depressant factor (MDF), a toxic of 0.75 nmol.kg-1.min-1 dilated the splanchnic circulation and significantly increased SMAF. In addition, PGI2 almost completely prevented the accumulation of cathepsin D and MDF in the circulating blood of cats given endotoxin. These findings suggest that PGI2 exerts a variety of beneficial actions in endotoxin shock including vasodilation and stabilization of lysosomal membranes. In addition, PGI2 is known to prevent platelet aggregation and suppress thromboxane formation, two additional effects that may be of positive survival value in endotoxin shock.

Animals↗
PubMed1980

Prostaglandin-mediated, angiotensin-induced vasoconstriction in isolated cat arteries.

The current study examines the prostaglandin contribution to angiotensin II-induced vasoconstriction in isolated perfused cat arteries. Superior mesenteric arteries were the most sensitive to angiotensin II. Superior mesenteric arteries responded to angiotensin II (25 nM) with a vasoconstriction which increased perfusion pressure 47 mm Hg. Sodium meclofenamate diminished this response to 2 mm Hg, but indomethacin did not significantly attenuate this effect. Angiotensin II (25 nM) produced a 31 mm Hg increase in perfusion pressure in coronary arteries but indomethacin (20 muM) or sodium meclofenamate (75 muM) reduced this response to 11 and 14 mm Hg, respectively (p < 0.05). Hepatic arteries were the least responsive to angiotensin. Also, neither cyclooxygenase inhibitor reduced the angiotensin II response in the common hepatic artery. Angiotensin II, therefore, may require prostaglandin synthesis for part of its vasoconstrictor activity in certain vascular beds, notably the coronary vasculature, but less so in splanchnic arteries.

Angiotensin II↗