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Biomedical subjects

A M Lefer

Publications and source records attributed to A M Lefer.

At least 415 records · Page 23Linked to original sources
PubMed1977

Early prostaglandin release from the ischemic myocardium in the dog.

Cellular consequences of myocardial ischemia were studied in anesthetized dogs. Confirmation of myocardial ischemia was provided by electrocardiographic and biochemical indexes. Prostaglandin F2alpha release into coronary venous blood was significantly elevated during myocardial ischemia, whereas indomethacin treatment prevented this increase in coronary venous prostaglandin F2alpha concentrations. No significant increase in prostaglandin E2 release was observed in response to myocardial ischemia, but indomethacin treatment significantly reduced coronary venous prostaglandin E2 concentrations below those of control values. Within one hour after occlusion of the coronary artery, the S-T segment was significantly altered, and coronary venous prostaglandin F2alpha had increased significantly above the control concentration. These changes persisted during four hours of myocardial ischemia. Plasma creatine phosphokinase activity increased significantly after two hours of myocardial ischemia and remained elevated for the subsequent two hours of ischemia. After four hours of myocardial ischemia, myocardial creatine phosphokinase activity of ischemic myocardium was significantly reduced, and labilization of myocardial treatment prevented increases in prostaglandin release but did not influence other biochemical changes or the electrocardiographic response to ischemia. Thus, prostaglandin release by ischemic myocardial tissue is an early response to the ischemic stimulus.

Animals↗
PubMed1977

Tissue uptake of 3H-methylprednisolone in acute myocardial ischemia.

The tissue uptake of 3H-methylprednisolone (3H-MP) was studied in anesthetized cats during acute myocardial ischemia 1 and 2 hours after injection of 3H-MP. There was a rapid uptake of 3H-MP by many tissues. Liver, kidney, and pancreas exhibited tissue/perfusion ratios of 3 to 7, heart, lungs, and intestine about 2, spleen, adrenal, and aorta 1 to 2, and skeletal muscle and omentum less than 1. Very similar tissue uptakes occurred in cats subjected to myocardial ischemia and sham myocardial ischemia at 1 and 2 hours. Plasma clearances of 3H-MP was not significantly altered either 1 or 2 hours after the onset of myocardial ischemia. Although ischemic myocardial tissue took up less than nonischemic myocardial tissue, this region accumulated significant amounts of 3H-MP. Myocardial tissue metabolized only about 15 to 20 per cent of the 3H-MP taken up after 2 hours. These data indicate that in acute myocardial ischemia, myocardial tissue takes up large amounts of exogenously administered glucocorticoid, most of which remains in the native form during the early phase of acute myocardial infarction.

Animals↗
PubMed1976

Lack of a significant protective effect of augmented circulating glucose on the ischemic myocardium.BJ.

Infusion of glucose alone or glucose with insulin in cats subjected to acute myocardial ischemia did not alter the hemodynamic response of the cats to coronary artery ligation. Furthermore, determination of myocardial creatine phosphokinase (CPK) (ATP:creatine N-phosphotransferase, EC 2.7.3.2) activities failed to reveal a protective effect of glucose and insulin upon the status of the developing infarct in the ischemic myocardium. However, glucose and insulin apparently promote clearance of CPK from the plasma and inhibit proteolysis during the early phase of myocardial ischemia. These actions may be of value in generalized adaptive response of the animal to the stress of ischemia, but does not per se appear to diminish the spread of the ischemic damage within the heart not to limit the extension of the evolving infarct.

Animals↗
PubMed1976

Release of prostaglandin F2alpha during splanchnic artery occlusion shock.

Prostaglandin F2alpha concentrations were determined in hepatic portal venous plasma of dogs during splanchnic artery occlusion (SAO) shock and in nonshock control dogs. Dogs subjected to SAO shock exhibited a dramatic decrease in mean arterial blood pressure and significant increases in portal venous PGF2alpha and amino-nitrogen concentrations, as well as in cathepsin D and MDF activities. Dogs treated with indomethacin prior to SAO shock did not exhibit a significant increase in portal venous PGF2alpha. Indomethacin had no effect on the increase of plasma amino-nitrogen and only slightly reduced portal venous cathepsin D activity during SAO shock. Nevertheless, indomethacin significantly attenuated the severity of the postrelease hypotension observed in SAO shock and diminished the plasma accumulation of MDF. These studies indicate that prostaglandins are released from the splanchnic region during SAO shock and that this release can be prevented by pretreatment with indomethacin. The role of endogenously released prostaglandins in SAO shock is not clear, but the magnitude of the increase warrants further study.

Animals↗
PubMed1976

Arachidonic acid in splanchnic artery occlusion shock.

Arachindonic acid infused into the mesenteric vascular bed of normal pentobarbital-anesthetized dogs at a concentrations of 150 mug/kg per min produced no significant changes in mean arterial blood pressure (MABP), portal vein pressure (PVP), screen filtration pressure (SFP), platelet count, circulating lysosomal enzyme or myocardial depressant factor (MCF) activities, nad only modestly increased superior mesenteric arter flow (SMAF)ans endogenous prostaglandin concentrations concentrations. It is concluded that arachidonic acid, at the infusion rate employed, dose not have any major effect on the circulatory status or on the lysosomal or platelet stability in normal dogs. In contrast, arachidonic acid administered to dogs in splanchnic artery occulusion (SAO) shock significantly exacerbated the decline in MABP seen after release of the occlusive clamps and also significantly reduced mesenteric blood flow. The hypothnsive of arachidonic acid appears to be partly due to the fatty acid itself and partly due to the metavolically formed prostaglandin endoct the platelet count or aggregability, lysosomal hydrolase activity, or MDF formation in the SAO shock dogs. These data suggest that increased endogenous prostaglandin concentrations in themselves are not a prime factor in the pathophysiology of circulatory shock, but that endogenous prostaglandin or related substances can significantly modulate the shock state.

Animals↗
PubMed1976

Hepatic cell integrity in hypodynamic states.

Changes in liver integrity were studied in isolated perfused cat livers during simulated shock conditions (i.e., combined hypoxia, acidosis, and ischemia) or under the influence of each hypodynamic state separately. The combined hypodynamic stimuli depressed carbon clearance 51% and significantly elevated lactic acid dehydrogenase (LDH) and cathepsin D activities in the perfusate. The perfused liver was more seriously affected by hypoxia than by acidosis or ischemia alone. Reticuloendothelial clearance was depressed 20% and 25% in acidosis and hypoxia, respectively. Hypoxia also induced a 3-fold increase in cathepsin D and a 13-fold increase in LDH activities in the perfusate. After 150 min of hypoxia or ischemia, free cathepsin D in liver tissue increased significantly. The impairment of liver cell integrity (i.e., of Kupffer and parenchymal cells) occurred between 60 and 90 min during simulated shock conditions, indicating that the liver is stable for 60 min when it is exposed to hypoperfusion. The perfused liver is sensitive to local stimuli that predominate in circulatory shock, particularly hypoxia. These stimuli promote the release of lysosomal and cytoplasmic enzymes as well as depress phagocytosis by the reticuloendothelial system, phenomena that exacerbate the shock state.

Acidosis↗
PubMed1976

Localization of glucocorticoid uptake in normal and ischemic myocardial tissue of isolated perfused cat hearts.

We studied the uptake of labeled dexamethasone (3H-Dex) or methylprednisolone (3H-MP) in isolated perfused cat hearts during the first hour of acute myocardial ischemia. Considerable amounts of 3H-Dex and 3H-MP were taken up by the plasma membrane (F1) fraction in control, border zone, and ischemic myocardial tissue. Lesser amounts were incorporated into the remaining cell fractions. A gradient of glucocorticoid uptake was observed that decreased from control tissue to ischemic tissue in all subcellular fractions (i.e., F1 to F5). Accordingly, supernatant fraction (S) to particulate (P) ratios of labeled glucocorticoid uptake increased from control to ischemic tissue, indicating that myocardial cell damage resulted in a decrease in glucocorticoid-binding capacity in subcellular fractions obtained from ischemic tissue. The activity of 5'-nucleotidase (5'ND), a plasma membrane marker in myocardial cells, also decreased from normal to ischemic tissue. Furthermore, we found that uptake of 3H-MP and 3H-Dex was associated with the retention of 5'ND activity in F1 fractions of both border zone and ischemic tissue. Similar protection of plasma membrane integritg occurred in the supernatant fraction as determined by changes in S/P ratios of 5'ND activity. These data provide support for the concepts that (1) plasma membrane changes occur soon after acute myocardial ischemia, and (2) the mechanism by which glucocorticoids exert a protective effect in myocardial ischemia may be related to membrane stabilization.

Animals↗
PubMed1976

Factors influencing nonspecific binding of glucocorticoids in myocardial tissue.

Myocardial slices from the left ventricle of cat hearts were incubated in Krebs-Henseleit buffer containing 10 mM glucose which were gassed with 95% O2 and 5% CO2. Tritiated dexamethasone (DEXA 0.171 MM) or methylprednisolone (MP 0.805 mM) was added under varying conditions of temperature, pH, and in the presence of various metabolic inhibitors. Glucocorticoid uptake by myocardial tissue was found to be temperature-dependent, plateauting after 60 min of incubation at 0.21 mumole of DEXA/g of tissue and 0.95 mumole of MP/g of tissue at 37 degrees. Steroid uptake was retarded about 50% at 0 degrees. Increasing the concentration of either steroid resulted in a linear increase in the uptake of that steroid. Incubation in the presence of metabolic or SH-inhibitors produced no significant changes in glucocorticoid uptake. Optimal glucocorticoid uptake occurred between pH 7.3-7.4. Thus, myocardial cells appear to be able to take up large quantities of glucocorticoids, but the uptake process does not appear to be energy-dependent.

Animals↗
PubMed1976

Plasma prostaglandin F2alpha and 15-keto-F2alpha concentrations during splanchnic artery occlusion shock.

Arterial plasma concentrations of PGF2alpha and 15-keto-PGF2alpha were determined in sham shock and splanchnic artery occlusion shock dogs. Arterial PGF2alpha concentrations (expressed as percentage of control) increased significantly in the SAO group when compared to the sham group during postrelease sampling periods. Similarly, 15-keto-PGF2alpha, a major metabolite of PGF2alpha also increased significantly in arterial blood in SAO shock. Comparison of 15-keto-PGF2alpha and PGF2alpha at each sampling period suggest that the efficiency of 15-hydroxyprostaglandin dehydrogenase is not impaired during SAO shock in the dog. However, the ability of the kidney and other organs to remove 15-keto-PGF2alpha from the circulation during SAO shock does appear to be significantly reduced. Although the changes in circulating concentrations of PGF2alpha are significant, the role of the increased prostaglandin is not clearly understood. We found no basis for any toxic effect of the PGF2alpha nor of any beneficial action. Others, however, have found exogenous PGF2alpha to improve survival in circulatory shock.

Animals↗
PubMed1976

Glucose and palmitate uptake in the myocardium of isolated hearts from adrenalectomized cats.

Hearts from chronically adrenalectomized (ADX) cats deprived of any steroid support for 9-12 days were isolated and perfused in a Langendorff apparatus at a constant pressure of 95 mm Hg. The perfusion medium was Krebs-Henseleit buffer with either 10 mM glucose or 0.4 mM palmitate complexed to 3 percent albumin. Labeled 14C substrate was used and the transient rate of glucose and palmitate uptake was measured. Oxygen consumption and [14C] palmitate incorporation into CO2, and heart lipids were also measured. ADX hearts showed an enhanced glucose uptake rate compared with controls, 65 +/- 11.3 mumoles/gm to 16.2 +/- 6. However, the qO2 was not significantly different from control hearts. Palmitate uptake, O2 consumption, and 14CO2 were significantly lower in ADX hearts perfused with fatty acid as the energy substrate. Fatty acid uptake decreased from 9.7 +/- 1.0 to 3.6 +/- 1.1 and lipid fractions in the heart showed significant decreases in [14C] palmitate incorporated into triglycerides (p less than 0.001) and monoglycerides (p less than 0.01). The ADX heart does not appear to have any impairment to glucose uptake but does show an impairment to fatty acid uptake. Because the heart uses lipid as the primary energy source, the impairment probably is not the primary factor responsible for cardiac failure in adrenal insufficiency because of its capability of using other available substrates for energy.

Adrenalectomy↗
PubMed1976

Influence of nonsteroidal anti-inflammatory agents on myocardial ischemia in the cat.

Indomethacin, meclofenamic acid and acetylsalicylic acid are prostaglandin synthetase-inhibiting, nonsteroidal anti-inflammatory drugs. Their effects on hemodynamic and enzymatic responses to coronary artery occlusion were evaluated in the cat. The direct effects of these drugs on isolated tissue preparations (i.e., cat papillary muscle, aortic strip and liver lysosomes) were also studied. None of the drugs tested exhibited any significant hemodynamic or biochemical effects which would indicate protection against damage due to myocardial ischemia during the 5-hour experimental period. Furthermore, only indomethacin produced significant effects on the isolated tissues studied. Indomethacin increased the tension of aortic strips confirming a pressor effect seen in the intact animal and exerted a modest stabilization of isolated liver lysosomes. All three anti-inflammatory drugs inhibited prostaglandin F2alpha, release in heart homogenates by 82 to 87%. It is concluded that nonsteroidal anti-inflammatory drugs do not significantly influence the early course of myocardial ischemia in the cat, in contrast to the previously reported preservation of myocardial integrity afforded by dexamethasone and methylprednisolone.

Animals↗
PubMed1975

Effects of dexamethasone on myocardial cells in the early phase of acute myocardial infarction.

Dexamethasone exerted no significant hemodynamic effect in sham-operated cats or in cats subjected to acute myocardial ischemia. However, the glucoccortcoid did normalize elevated S-T segments toward pre-ischemic values, and prevented much of the increase in plasma CPK activity following coronary artery ligation. Moreover, dexamethasone prevented loss of CPK activity and restricted the loss of lysosomal hydrolase within ischemic myocardial tissue. These data indicate that lysosomal disruption is an early consequence of myocardial ischemia and that treatment with dexamethasone prevents the loss of myocardial lysosomal and cellular enzymes as reflected in normalization of the ECG and plasma CPK activity of ischemic cats. In this way, dexamethasone may act to retard the spread of the developing infarct within the ischemic myocardium.

Animals↗