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Biomedical subjects

R E Shepherd

Publications and source records attributed to R E Shepherd.

At least 37 records · Page 2Linked to original sources
PubMed1986

Mechanism of cardiac dysfunction in hearts from endotoxin-treated rats.

Myocardial performance was assessed in isolated perfused working hearts 3 hr after in vivo endotoxin administration (LD50-6 hr) to rats. Hearts removed from endotoxin-treated rats developed approximately 70% of the peak systolic pressure and 50% of the cardiac output (45% of the aortic flow and 50% of the coronary flow) at 25 cm H2O left atrial filling pressure (LAFP) compared to hearts from vehicle-injected controls. Hearts from endotoxin-treated rats were also characterized by decreased mechanical responsiveness to isoproterenol challenge at a high LAFP. These data suggest that myocardial dysfunction associated with endotoxin shock persists in vitro under conditions in which flow returning to the heart is not a limiting factor. Cyclic AMP accumulation was reduced in myocytes from endotoxin rats in response to 1 microM isoproterenol (29% of control values) and 1 microM forskolin (35% of control values) in both the absence and presence of phosphodiesterase inhibition with 0.2 mM isobutylmethylxanthine. Adenylate cyclase activity in crude membrane preparations of ventricular tissue from endotoxin-treated rats was unresponsive to challenge by isoproterenol and was reduced to 65% of control values by 100 micron GppNHp and by 10 mM NaF. Maximal specific binding of (-)[3H]dihydroalprenolol was decreased in membranes from endotoxin (56 +/- 2 fmol/mg) compared to control (64 +/- 2 fmol/mg) rats (P less than 0.05) but with similar antagonist affinities. These results suggest a decreased adrenergic responsiveness in myocytes and ventricular membrane preparations from endotoxin rats that may be linked to the reduction in myocardial adrenergic responsiveness during endotoxemia.

Adenylyl Cyclases↗
PubMed1985

Lipoprotein and apolipoprotein distribution in Zucker rats following an endurance running program.

We examined the response to 12 weeks of endurance running of the obese Zucker rat and its lean littermate with regard to changes in serum lipids, lipoproteins and apoproteins. The obese Zucker rat is hyperlipoproteinemic, characterized by elevated serum triglyceride and cholesterol levels primarily associated with the very low density lipoprotein (VLDL) fraction. In lean Zucker rats, training did not affect the concentrations of serum lipids or apolipoproteins. In marked contrast, obese Zucker rats that were trained had significant decreases in serum concentrations of triglycerides, free and esterified cholesterol, and apolipoprotein B compared to their sedentary counterparts. Training obese rats caused an increase in the serum concentration of apolipoprotein E (HDL fraction). In contrast, training did not affect the concentration of Apo E in lean rats. The VLDL fraction was most affected by training obese rats showing marked 50-65% decreases in VLDL triglyceride and VLDL cholesterol. HDL cholesterol was unchanged in lean rats whereas training prompted a 29% increase in obese rats. These data show that exercise training altered the metabolic abnormalities of obese Zucker rats which are responsible for the accumulation in serum of VLDL, lipids and apolipoproteins.

Animals↗
PubMed1985

Serum lipoproteins of the Zucker rat in response to an endurance running program.

Previous studies have concluded that exercise training has resulted in increases in cholesterol associated with high-density lipoprotein (HDL). However, data regarding alterations in triglyceride, cholesterol, and the protein associated with the three major lipoproteins in a hyperlipoproteinemic state in response to exercise training are not available. Serum lipoprotein levels from normal and hyperlipoproteinemic Zucker rats were studied following 9 and 18 wk of treadmill running to determine the extent that the three major serum lipoprotein classes were affected. Nine weeks of treadmill running reduced serum triglyceride content in obese rats (sedentary, 294 +/- 19 [SE]; trained, 128 +/- 40 mg X dl-1) but did not affect total serum cholesterol (sedentary, 85 +/- 6; trained, 90 +/- 6 mg X dl-1). Serum very low-density lipoprotein from the trained obese rats contained lower levels of triglyceride (57%), cholesterol (46%), and protein (61%). HDL cholesterol (sedentary, 61 +/- 4; trained, 73 +/- 4 mg X dl-1) was increased by 14% in the obese rat. In the lean rat, HDL cholesterol was the only lipoprotein fraction altered following 9 wk of treadmill running. The data from this study indicate that hypertriglyceridemia can be reduced in the obese rat and that HDL cholesterol can be increased by physical activity requiring about 70% maximal aerobic capacity.

Animals↗
PubMed1984

Culture of the terminally differentiated ventricular cardiac muscle cell. Characterization of exogenous substrate oxidation and the adenylate cyclase system.

Oxidation of several exogenous substrates by cultured adult rat ventricular cardiac muscle cells has been assessed. Unlike freshly isolated cardiac muscle cells which oxidize glucose preferentially, the cultured cells more closely resemble metabolically the in situ heart and the isolated perfused heart, in that their preference for exogenous substrates is in the order of fatty acid greater than glucose. This switch in metabolic preference from glucose to fatty acid is complete within 12 h after placing freshly isolated cells in culture. Glucose oxidation is stimulated by insulin and isoproterenol and inhibited by beta-hydroxybutyrate and octanoate. The adenylate cyclase system has also been examined in these cultured cells. Isoproterenol, norepinephrine and epinephrine stimulate the accumulation of cyclic adenosine 3':5'-monophosphate (cyclic AMP) in a concentration-dependent manner. The order of potency is isoproterenol greater than norepinephrine approximately equal to epinephrine. This stimulation is potentiated by 1-isobutyl-3-methylxanthine and inhibited by 1-propranolol.

1-Methyl-3-isobutylxanthine↗
PubMed1982

Attenuation of blood pressure increases in Dahl salt-sensitive rats by exercise.

Systolic blood pressure was determined weekly to assess the development of hypertension in sedentary and active Dahl salt-sensitive (S) rats that were exercised by running at 20 m/min, 60 min/day, 5 days/wk. The marked rise in blood pressure that occurred with feeding 8% NaCl (wt/wt) diet in Dahl S rats could be attenuated by chronically practiced endurance running, but only if exercise at 20 m/min was started at the beginning of salt feeding. Under the same dietary feeding conditions, running at 27 m/min resulted in incomplete attenuation of hypertension. Further, running for 30 min/day was not as beneficial as running 60 min/day at 20 m/min. Delaying the start of exercise for 6 wk after the beginning of salt feeding did not result in reduction of hypertension in the S rat. These experiments indicate that increases in blood pressure can be prevented in Dahl S rats for 12 wk if running is initiated concomitantly with salt feeding. Blood pressure is not reduced if hypertension due to salt feeding has been continued for 6 wk. The results also indicate that there is an optimal exercise intensity, duration, or both, for controlling hypertension in Dahl rats.

Animals↗
PubMed1981

Lipolysis and cAMP accumulation in adipocytes in response to physical training.

Adenylate cyclase activity is lower in membrane preparations of fat cell homogenates from exercise-trained compared with sedentary rats (J. Appl. Physiol.: Respirat. Environ, Exercise Physiol. 42: 884-888, 1977). In the present investigations lipolysis and cyclic adenosine 3':5'-monophosphate (cAMP) accumulation were measured in isolated parametrial fat cells prepared from sedentary and trained rats. The purpose of these investigations was to determine whether the normal catecholamine-induced increases in cAMP accumulation is affected in isolated adipocytes from endurance-trained rats. The increases in cAMP accumulation in response to isoproterenol (0.01-10 microM) was reduced in fat cells isolated from trained rats. However, glycerol release in response to the same hormonal challenge was greater in these adipocytes. cAMP phosphodiesterase activity measured at 0.125 and 1.025 microM cAMP was greater in the particulate fraction of fat cell homogenates obtained from trained rats as compared with their sedentary counterparts. Hormone-sensitive lipase activity was reduced in crude fat pad homogenate preparations from trained rats if the animals were killed at rest. However, if the animals were run to exhaustion immediately prior to being killed, there were no differences in the hormone-sensitive lipase activity between preparations from trained and nontrained rats. These data indicate that, although cAMP accumulation by isolated fat cells in response to isoproterenol is markedly lower in trained rats, lipolysis and hormone-sensitive lipase activation is not reduced.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1979

Effects of bilirubin on fat cell metabolism and lipolysis.

Bilirubin (0.45 mM) inhibited lipolysis and stimulated [1-14C]glucose oxidation by rat fat cells in the presence of an equimolar concentration of bovine serum albumin. Bilirubin was an insulinlike agent with respect to inhibition of lipolysis and stimulation of glucose oxidation. There was a marked inhibition of adenylate cyclase activity of fat cell ghosts by 0.001--0.1 mM bilirubin in the absence of albumin, which was largely reversed by the addition of albumin. Although both bilirubin and free fatty acids bind to albumin, the primary binding sites appear to be separate. The effects of bilirubin at a molar ratio to albumin of 2 or less were not influenced by free fatty acid-to-albumin ratios up to 3. Triglyceride lipase activity of partially purified rat fat cell homogenates was inhibited by bilirubin in the presence of an equimolar concentration of bovine albumin. These data indicate that the antilipolytic action of bilirubin is probably due to direct inhibition of triglyceride lipase through a mechanism that does not involve competition with free fatty acids for binding to albumin.

Adenylyl Cyclase Inhibitors↗
PubMed1978

Electron spin resonance studies of the solution structure of vanadyl amino acid complexes and mixed ligand complexes of oxalate.

Esr and electronic spectra of complexes of the general composition VO(AA)2 and VO(ox)(AA) have been characterized; AA = gly, his, cys, pro, val, met, asp amino acids. Spectra of the formulation VO(ox)(LL) (with LL = imidazole plus monodentate oxalate, histamine plus monodentate oxalate, histidine, cysteine, 4-imidazolepropionic acid, mercaptopropionic acid, ethylenediamine and ethanolamine) have been used to deduce a self-consistent assignment of AL, a ligand donor additivity constant contribution to the observed hyperfine splitting, Aiso. Values of AL are sensitive to inductive effects in the ligand structure. The solution structures and likely coordination geometries of VO(his)2, and VO(cys)22-- are discussed. The role of the imidazole moiety as a sigma donor and sulfhydryl sulfur as a pi acceptor is observed in VO(AA)2 and VO(ox)(AA) complexes.

Amino Acids↗
PubMed1978

Protection against 7, 12-dimethylbenz[a]anthracene-induced rat mammary carcinoma by infection with mouse xenotropic type C virus.

A single ip inoculation of female, outbred Sprague-Dawley rats with a viable mouse xenotropic type C virus significantly reduced the incidence and/or retarded the development of mammary carcinoma induced by 7, 12-dimethylbenz[a]anthracene administered orally 7 days after virus. Although infectious virus could not be isolated from organs of infected rats, high titers of circulating and tumor-associated antibodies were detected against the viral internal core protein p30, and a low-grade antibody response to intact virus or envelope glycoprotein was found. Moreover, a cell-mediated immune response, measured by lymphocyte transformation, was detected with the use of intact virus but not with p30 antigen. No immunity developed after a single inoculation of UV-inactivated virus. These data indicated that inoculation of adult individuals of heterologous species with viable xenotropic mouse type C virus resulted in the rapid disappearance of infectious virus from the recipient, followed by the development of both humoral and cellular immunity to virion constituents. These events led, by unknown mechanisms, to the effective retardation of chemical carcinogenesis when infection preceded carcinogen administration.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1977

Effect of physical training on control mechanisms of lipolysis in rat fat cell ghosts.

Fat cell ghosts and homogenates of fat cells were used to study the influence of training on the regulatory system for lipolysis in adipose tissue of female rats. A training effect was identified from elevated succinate dehydrogenase activities in the soleus and plantaris muscles. Neither basal nor maximal (NaF-stimulated) adenylate cyclase activities per mg protein of fat cell ghosts were altered by training. Fluoride-stimulated adenylate cyclase activity per microgram DNA was lower in the trained than untrained group. Adenylate cyclase activities in response to norepinephrine expressed either on a per mg protein or per microgram DNA basis were lower (P less than 0.05) in fat cell ghosts from trained rats. Phosphodiesterase activity was higher (P less than 0.05) in fat cell ghosts from trained rats for cyclic AMP concentrations of 1--5.0 micrometer. The apparent Km's of phosphodiesterase were 1.19 and 2.0 micrometer of cyclic AMP for the untrained and trained groups, respectively (P less than 0.05). Protein kinase activity in the supernatant fraction of homogenates of fat cells was unchanged due to training. The overall effect of training was to blunt the system for cyclic AMP production in rat adipocytes. This may explain, at least partially, the lower plasma free fatty acid levels observed in trained compared to untrained persons during submaximal exercise.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1976

Oxygen uptake of rats at different work intensities.

An adaptation of a standard activity wheel has been used to determine oxygen uptake of rats prior to and during exercise at 7 different speeds (16-67 m/min). Pre-exercise oxygen uptake was 2.42 +/- 0.10 (S.E.) ml (100 g x min)-1. Oxygen uptake increased linearly with work intensity (running speed). At 16m/min oxygen uptake was 6.44 +/- 0.16 ml (100 g x min)-1 and it increased to a maximal value of 9.51 +/- 0.14 ml (100 g x min)-1 at a running speed of 53.6 m/min. Increasing running speed to 67 m/min did not produce any further increase in oxygen uptake. Some comparisons of exercise intensity between rats of various studies and rats and man can be made from these data.

Adaptation, Biological↗
PubMed1975

Free fatty acids as feedback regulators of adenylate cyclase and cyclic 3':5'-AMP accumulation in rat fat cells.

Rat fat cells incubated with lipolytic agents released substances to the medium which acted as feedback regulators of cyclic adenosine 3':5'-monophosphate (cyclic AMP) accumulation. The feedback regulators were not removed by adenosine deaminase. Dialyzed medium that had previously been incubated with fat cells in the presence of norepinephrine markedly inhibited cyclic AMP accumulation by fresh cells, whereas dialyzed medium from control cells did not inhibit cyclic AMP accumulation. The effects of lipolytic agents could be mimicked by adding dialyzed medium previously incubated with fat cells in the presence of oleic acid. This suggested that free fatty acids were the nondialyzable and adenosine deaminase-insensitive inhibitors of cyclic AMP accumulation released to the medium by fat cells incubated with lipolytic agents. The regulatory function of free fatty acids was related to the molar ratio of fatty acid to albumin. Profound inhibition of both lipolysis and cyclic AMP accumulation was seen as the free fatty acid/albumin ratio exceeded 3. The inhibition of cyclic AMP accumulation by oleate was seen as soon as there was a detectable increase in cyclic AMP due to lipolytic agents. Protein kinase activity (in the presence of cyclic AMP) of the infranatant obtained after centrifugation of fat cell homogenates at 48,000 x g was inhibited by medium from cells incubated with lipolytic agents or added oleate. Adenylate cyclase activity of rat fat cell ghosts was also inhibited by dialyzed or nondialyzed medium that previously had been incubated with lipolytic agents or added fatty acids. The direct addition of oleate markedly inhibited adenylate cyclase activity as the free fatty acid/albumin ratio exceeded 2. These data suggest that the prolonged drop in cyclic AMP accumulation seen during the incubation of rat fat cells with lipolytic agents is due to the inhibition of adenylate cyclase. This occurs when the free fatty acid/albumin ratio exceeds 3.

Adenylyl Cyclases↗