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Biomedical subjects

A M Lefer

Publications and source records attributed to A M Lefer.

At least 361 records · Page 20Linked to original sources
PubMed1980

Actions of non-cardiodepressant beta-adrenergic blocking agents in hemorrhagic shock.

Two new beta-adrenergic blocking agents, timolol and MK-761, were found to effectively antagonize the positive inotropic effects of isoproterenol on isolated cat papillary muscles without depressing contractile force. However, appropriate doses of these beta-adrenergic blockers (ie, 12.5--25 microgram/kg) did not significantly prolong survival in hemorrhagic shock in anesthetized cats. MK-761 prevented some of the plasma accumulations of myocardial depressant factor (MDF) during shock. Nevertheless both beta-blockers failed to prevent the accumulation of the lysosomal protease cathepsin D or peptide fragments (ie, amino-nitrogen groups) in the blood during shock. We conclude that neither agent is of significant benefit in severe hemorrhagic shock, and probably beta-adrenergic blockade is not a productive approach to pursue in the therapeutics of hemorrhagic shock.

Adrenergic beta-Antagonists↗
PubMed1980

Thromboxane A2, prostacyclin and aspirin: effects on vascular tone and platelet aggregation.

Novel compounds that induce or inhibit platelet aggregation and constrict or dilate blood vessels were recently discovered. These compounds are all derivatives of arachidonic acid and include prostaglandin endoperoxides, thromboxane A2, prostaglandin E2, prostaglandin D2 and prostacyclin. Thromboxane A2 (TxA2) could be one of the precipitating factors in coronary or cerebrovascular ischemia because it is a potent vasoconstrictor that is produced by platelets during their aggregation. On the other hand, prostacyclin (PGI2) is a potent vasodilator and inhibitor of platelet aggregation produced by vessel walls whose enhanced production should be beneficial. Aspirin inhibits prostaglandin endoperoxide synthetase and therefore prevents the subsequent production of TxA2, PGI2 and other prostaglandins. It has been suggested but not yet established that low doses of aspirin preferentially inhibit TxA2 biosynthesis. The roles of classic prostaglandins PGD2, PGE2 and PGF2 alpha in ischemia have not been determined.

Adenosine Diphosphate↗
PubMed1980

Mechanisms of the optimal protective effects of ibuprofen in acute myocardial ischemia.

Ibuprofen in doses from 3.12 to 12.5 mg/kg effectively preserve ischemic myocardial tissue in acute myocardial ischemia. The mechanisms for this protective effect do not appear to be primarily related to reducing afterload or rate (ie, curtailing myocardial oxygen demand) or to a profound antiarrhythmic effect. Rather, ibuprofen in doses that protect in acute MI, appears to 1) inhibit generation of thromboxanes, 2) stabilize lysosomal membranes, and 3) dilate the coronary vasculature. These actions may account for the ability of ibuprofen to protect in ischemia, in contrast to other nonsteroidal anti-inflammatory agents (eg, aspirin, indomethacin, meclofenamate), which fail to protect in this life-threatening disorder.

Animals↗
PubMed1980

Effects of flurbiprofen on myocardial cell damage in acute myocardial ischemia.

Fluribiprofen, a non steroidal anti-inflammatory agent, was studied in anesthetized cats subjected to acute myocardial ischemia. Flurbiprofen was given at 0.25, 1 or 4 mg/kg bolus intravenously at 0.5 hours and again at 2.5 hours. Assessment of ischemic myocardial preservation was appraised by measurement of S-T segment elevation, and plasma and cardiac tissue creatine phosphokinase (CK) specific activity. Plasma thromboxane B2 (TB2) concentrations measured by specific radioimmunoassay for TB2, and arachidonic-induced platelet aggregation were also assessed. All three doses of flurbiprofen prevented both the increase to plasma TB2 concentrations occuring in MI (p less than 0.05) at 2, 3 and 4 hours) and platelet aggregation induced by arachidonic acid. However, flurbiprofen at either 0.25 or 4 mg/kg failed to prevent the increase in the S-T segment, the increase in plasma CK activity and failed to maintain myocardial CK values in the ischemic region. At 1 mg/kg, flurbiprofen returned S-T segment to normal values and preserved myocardial CK activities but only slightly prevented the increase in plasma CK activity. These data suggest that the low and high dose of flurbiprofen showed no protection during acute myocardial ischemia, while the intermediate dose was effective. The reason for the narrow range of myocardial preservation is not clear.

Acute Disease↗
PubMed1980

Shock potentiating actions of angiotensin II infusion in cats.

Anesthetized cats were infused with angiotensin II or its vehicle (0.05 M phosphate buffer) to detect actions of angiotensin II which can contribute to shock. Mild hemorrhage, or saralasin-induced angiotensin II receptor blockade, were also employed in an attempt to enhance or reduce the angiotensin II effects. Angiotensin II produced a prolonged reduction in superior mesenteric artery blood flow (50% of initial) and an elevation in plasma lysosomal hydrolase (cathepsin D) activity. Additionally, angiotensin II disrupted the normal functioning of the coronary endothelium resulting in macroscopically visible hemorrhagic patches on the myocardium. Saralasin blockade of the angiotensin II receptor prevented the pressor, splanchnic vasoconstrictor, and lysosomal labilizing actions of angiotensin, and also decreased the incidence of cardiac hemorrhages. Angiotensin II infusion after bleeding to 80 mm Hg, however, increased lysosomal hydrolase release, indicating an exacerbation of angiotensin II effects. These data indicate that high levels of angiotensin II are capable of inducing alterations similar to those occurring in hemorrhagic shock. These deleterious effects of angiotensin II were abolished by saralasin and potentiated by a mild hemorrhage.

Angiotensin II↗
PubMed1979

Hepatic blood flow in acute myocardial ischemia.

Hepatic blood flow was monitored in cats during myocardial ischemia (MI). Increased plasma CPK activity, the S-T segment of the electrocardiogram, and hepatic flow was reduced by 5 h to 40% of control. The results suggest that MI can influence organs distant from the original ischemic episode.

Animals↗
PubMed1979

Studies on the protective effect of prostacyclin in acute myocardial ischemia.

The ability of prostacyclin (PGI2) to alter responses to acute myocardial ischemia was studied in open-chest, anesthetized cats. PGI2 was infused intravenously at 0.5 nmoles kg-1 min-1 in cats subjected to 5 h of myocardial ischemia by occlusion of the LAD coronary artery, and in sham-operated controls. GI2 infusion resulted in significantly decreased arterial blood pressure and inhibition of platelet aggregation. Coronary ligation resulted in significant S-T segment elevations lasting 5 h in vehicle-treated animals but only 1 h in cats with myocardial ischemia and receiving PGI2. At 5 h, cats with ischemia and given the vehicle showed S-T segment elevations significantly greater than the other two groups. Ischemic myocardium from vehicle-treated animals exhibited significantly less creatine phosphokinase (CPK) specific activity than normal tissue from the same hearts or myocardial tissue from the other two groups. This loss of CPK from ischemic myocardium of the cats given vehicle was reflected in plasma CPK specific activities which were significantly greater than those of sham-operated cats. The cats with ischemia and treated with PGI2 exhibited lower plasma CPK activities. These changes were moderated by PGI2 infusion during myocardial ischemia. PGI2 infusion may protect the ischemic myocardium by reducing oxygen demand, primarily through reductions in cardiac work, and by perhaps inhibiting platelet aggregation and preserving myocardial cell integrity.

Animals↗
PubMed1979

Potent constriction of cat coronary arteries by hydroperoxides of arachidonic acid and its blockade by anti-inflammatory agents.

The omega-6 and omega-9 hydroperoxides of arachidonic acid caused dose-dependent constriction of cat coronary arteries in concentrations of 10(-8) to 10(-5) M. Their potency was comparable to that of prostaglandin (PG) E2, and PGF2 alpha and 100 times greater than that of arachidonic acid. The cyclooxygenase inhibitor, meclofenamate markedly reduced constriction caused by the hydroperoxides but potentiated constriction caused by the prostaglandins. The effects of the hydroperoxides were also reduced by indomethacin and dexamethasone but were unaffected by the thromboxane synthetase inhibitor imidazole. Since the hydroperoxides are not substrates for cyclooxygenase, it is suggested that they have a direct effect on the arteries which can be antagonized by anti-inflammatory drugs.

Animals↗
PubMed1979

Protective action of 6-keto-prostaglandin E1 in traumatic shock.

Since prostaglandin E1 (PGE1) is known to have a beneficial effect in hemorrhagic shock, a biologically active derivative of PGE1, 6-keto-PGE1, was examined for its effect on traumatic shock in rats. In sham-operated rats, infusion of 6-keto-PGE1, at a rate of 250 ng/kg/min intravenously decreased arterial blood pressure by 23 mm Hg at 5 hr. In rats subjected to Noble-Collip drum trauma, infusion of 6-keto-PGE1, starting 15 min after the trauma, significantly improved the survival time from 1.0 +/- 0.1 to 2.6 +/- 0.3 hr compared to rats given only the vehicle (i.e., Tris buffer). The improved survival was accompanied by a diminished plasma accumulation of the cardiotoxic peptide, myocardial depressant factor (MDF), and the lysosomal protease cathepsin D. 6-keto-PGE1 also exerted a direct lysosomal stabilizing effect in isolated cat liver lysosomes, as well as reducing cardiac afterload in rats. It is concluded that 6-keto-PGE1 protects in traumatic shock by hemodynamic as well as cytoprotective actions.

Alprostadil↗
PubMed1979

Protective effects of a novel thromboxane analog in lethal traumatic shock.

Pinane thromboxane A2 (PTA2) an analog of thromboxane A2 that inhibits the formation of thromboxanes as well as antagonizes their biological actions, at an infusion rate of 1.0 mumole . kg-1 . h-1, prolonged survival in traumatic shock in rats. PTA2 also prevented the accumulation of thromboxane B2, the lysosomal protease, cathepsin D, and the cardiotoxic peptide MDF in the circulating blood.

Animals↗
PubMed1979

Beneficial actions of prostacyclin in traumatic shock.

Prostacyclin (PGI2) infused at a rate of 350 ng/kg/min significantly increased survival time in rats subjected to Noble-Collip drug trauma from 2.7 +/- 0.3 to 4.6 +/- 0.2 h (p less than 0.01) compared with traumatized rats given only the vehicle (Tris buffer). Moreover, PGI2 treated rats exhibited significantly lower circulating cathepsin D and myocardial depressant factor (MDF) activities, indicative of lower lysosomal disruption and lower toxic factor formation. PGI2 induced vasodilation in rats as well as these other protective effects.

Animals↗