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Biomedical subjects

A M Lefer

Publications and source records attributed to A M Lefer.

At least 379 records · Page 21Linked to original sources
PubMed1979

Synthesis and biological properties of pinane-thromboxane A2, a selective inhibitor of coronary artery constriction, platelet aggregation, and thromboxane formation.

Pinane-thromboxane A2 (PTA2, [1alpha,2 beta(Z),-3 alpha (1E,3R*),5 alpha]-7-(3-(3-hydroxy-1-octenyl)-6,6-dimethylbicyclo[3.1.1]hept-2-yl)-5-heptenoic acid) has been synthesized and tested for biological activity in systems responsive to thromboxane A2, stable prostaglandin endoperoxide (PGH2) analogs, and prostatacyclin (PGI2). At low concentrations, PTA2 inhibited cat coronary artery constriction induced by stable prostaglandin endoperoxide analogs, and it stabilized liver lysosomes. At slightly higher concentrations, it inhibited platelet aggregation. At still higher concentrations, PTA2 inhibited thromboxane synthetase, but it had no effect on prostacyclin synthetase. The analog also had no effect on the inhibition of platelet aggregation by PGI2 or prostaglandin D2. It is suggested that PTA2 has a suitable biochemical profile for use as an antithrombotic agent.

Animals↗
PubMed1979

Effect of angiotensin II receptor blockade by [Sar1-Ala8]angiotensin II in hemorrhagic shock.

An angiotensin II receptor antagonist, [Sar1-Ala8]angiotensin II (saralasin), was infused at 60 (microgram/kg)/h into cats to examine its effect in hemorrhagic shock. Aprotinin (1,000 (KIU/kg)/h) was also administered to cats to determine how kinin inhibition effects angiotensin receptor blockade in shock. Saralasin was infused into shocked and sham-shocked cats. Aprotinin was administered to additional cats receiving either saralasin or its vehicle. Hemorrhaged cats treated with saralasin revealed a postoligemic preservation of mean arterial bloood pressure and superior mesenteric artery blood flow (SMAF). Final pressures were 48 +/- 12 mmHg and 81 +/- 9 mmHg with vehicle and saralasin treatment, respectively, and final SMAF were 2.5 +/- 0.5 (ml/kg)/min in cats receiving vehicle and 5.5 +/- 0.6 (ml/kg)/min in those receiving saralasin. Total plasma proteolysis was diminished by both saralasin and aprotinin, exhibiting elevations of free amino-nitrogen groups of 2.5-fold and 2-fold over initial as compared to a 3.5-fold elevation in vehicle-treated shocked cats. Myocardial depressant factor (MDF) activities were also suppressed by saralasin compared to shocked cats receiving vehicle (24 +/- 4 units vs. 59 +/- 3 units). These results indicate that blockade of angiotensin II actions in hemorrhagic shock is beneficial.

Amino Acids↗
PubMed1979

Beneficial effects of ibuprofen in acute myocardial ischemia.

Ibuprofen, a nonsteriodal anti-inflammatory agent, was studied in the early stages of myocardial ischemia in order to determine whether it helps preserve myocardial integrity. Ibuprofen was administered intravenously at a dose of 12.5 mg/kg at the time of coronary artery occlusion and again 2.5 h later. Ibuprofen significantly prevented the loss of myocardial creatine phosphokinase (CPK) release in ischemic cardiac tissue. In addition, this drug significantly returned S-T segment elevation toward normal values, and significantly prevented the myocardial loss of compounds having free amino nitrogen groups, an index of proteolysis. Although ibuprofen moderated the increased plasma CPK activity, plasma CPK values 5 h after coronary occlusion were above control values. Thus, ibuprofen significantly prevented alterations in three of the four indices used to assess myocardial ischemic damage. The protective mechanism of ibuprofen may be via stabilization of cellular membranes (i.e., lysosomal membranes) and to a lesser extent on reduction in myocardial oxygen demand.

Acute Disease↗
PubMed1979

Lysosomal hypothesis in evolution of myocardial infarction. Subcellular fractionation and electron microscopic cytochemical study.

Twenty-two cat hearts were perfused according to Langendorff technique and myocardial regional ischemia was induced by occlusion of left anterior coronary artery. Separation of particulate (bound) from soluble (free) fraction, and subsequent fractionation into plasma membranes, lysosomes, sarcoplasmic reticulum, and mitochondria were performed by sucrose density gradient ultracentrifugation. By ischemia for 60 min, particle-bound activity of cathepsin D decreased from 4.2 +/- 0.24 U/mg protein to 3.2 +/- 0.31 U/mg protein (p less than 0.01). Likewise, the particle-bound activity of beta-glucuronidase decreased from 11.9 +/- 0.92 U/mg protein to 6.2 +/- 1.28 U/mg protein (p less than 0.01). Accordingly, free/bound activity ratios of cathepsin D increased from 0.8 to 1.9 and beta-glucuronidase from 0.9 to 2.8, respectively. Conspicuous fall from 12.8 +/- 0.6 U/mg protein to 8.0 +/- 0.97 U/mg protein (p less than 0.01) in absolute specific activity of cathepsin D bound to the lysosomal fraction, presents definitive evidence of lysosomal release of the acid hydrolases during the early phase of myocardial ischemia. Electron microscopic observation of the ischemic myocytes revealed ultrastructural alterations of the lysosomes suggestive of autophagic degradation of various subcellular organelles.

Acid Phosphatase↗
PubMed1979

Protective actions of aprotinin in acute traumatic shock.

The effect of the protease inhibitor, aprotinin, was examined in rats during traumatic shock. In sham-operated control rats, intravenous administration of aprotinin (20,000 or 40,000 KIU/kg) showed no immediate changes in the mean arterial blood pressure and heart rate. In rats subjected to Noble-Collip drum trauma, aprotinin at a dose of 20,000 KIU/kg prolonged survival time to 2.1 +/- 0.3 hr (p less than 0.05) and 40,000 KIU/kg prolonged the survival time of rats to a greater extent (3.1 +/- 0.4 hr, p less than 0.001) compared to rats given only its vehicle (1.1 +/- 0.2 hr, mean +/- SE). The improved survival was accompanied by inhibition of the plasma accumulation of the cardiotoxic peptide, myocardial depressant factor (MDF). However, aprotinin showed no inhibitory effect on the plasma accumulation of the lysosomal enzyme, cathepsin D. Aprotinin has a beneficial effect on traumatic shock in rats possibly by its potent inhibitory action on MDF formation.

Animals↗
PubMed1978

Prostacyclin: a potentially valuable agent for preserving myocardial tissue in acute myocardial ischemia.

Prostacyclin, a potent, naturally occurring prostaglandin exerts a variety of cardiovascular and cellular actions of potential value in acute myocardial ischemia. These properties include the reduction of systemic blood pressure without changing heart rate, the lowering of coronary vascular and total peripheral resistance, the inhibition of platelet aggregation and the concomitant formation of thromboxane B2, and the reduction of the release of lysosomal enzymes.

Animals↗
PubMed1978

Actions of prostaglandins on isolated perfused cat coronary arteries.

Effects of prostaglandins on coronary arterial smooth muscle were studied in isolated perfused cat coronary arteries. This preparation was shown to be responsive to known vasoactive agents, including angiotensin II, adenosine, and norepinephrine. Prostaglandins E2 and F2 alpha (PGE2 and PGF2 alpha) produced dose-dependent coronary arterial constriction at concentrations of 3 times 10(-9) M or greater. PGE1 produced a biphasic dose-response curve with constriction at low concentrations greater than 10(-7) M.PGI2 dilated coronary arteries at concentrations greater than 10(-8) M. Inhibition of endogenous prostaglandin synthesis with meclofenamate potentiated responses to prostaglandins. The endoperoxide, PGH2, slightly constricted cat coronary arteries. However, in the presence of human platelet microsomes, PGH2 was converted to thromboxane A2(TxA2), which was the most potent coronary artery constrictor among the naturally occurring compounds studied. Analysis of coronary artery perfusate for TxB2 confirmed the thromboxane generation, which was markedly lower in the presence of imidazole. Two synthetic endoperoxide analogs produced potent coronary arterial constriction. Induction of hypoxia to a PO2 of 50 mmHg or increasing basal tome with 30 mM KCl did not diminish coronary artery response to prostaglandins, suggesting that prostaglandins released from ischemic myocardial tissue may influence coronary arterial tone.

Animals↗