Biomedical subjects
Publications and source records attributed to S Hynie.
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In order to explain the differences in the hormone stimulated lipolysis during ontogenic development of rats, the activity of adenylate cyclase was determined in crude plasma membranes of subcutaneous adipocytes of 5, 14, 21 and 45 to 55-day-old animals. Stimulatory effects of nonhormonal and hormonal agents were expressed as the increment in percentage of basal values which were not significantly changed in the age groups studied. The highest stimulatory effect was observed after sodium fluoride in 14 and 21-day-old rats. Guanylylimidodiphosphate and GTP revealed the lowest stimulatory effects in adult animals (greater than 45-day-old). The beta-adrenergic agent isoproterenol revealed the highest stimulatory effect in the 5 and 45-day-old group while in the preparation from 14-day-old rats the adenylate cyclase activity was significantly lower. On the other hand, tetracosactide (beta 1-24-corticotropin) revealed the smallest stimulatory effect on the preparation from 5-day-old rats; its stimulatory effect steadily increased and reached the highest value in adenylate cyclase preparations from adult animals. It can be concluded that the adenylate cyclase system in subcutaneous adipocytes is already basically mature at early ontogenic stages of development in rats. Nevertheless, the explanation for the small variations of the enzyme activity in different age groups requires further study.
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In the heart the interaction of the thyroid hormones, the catecholamines and the effect of the beta-blocker was studied. The binding of the radioactive noradrenalin (3H-NA) was higher in the particles of the thyreotoxic myocardium of the dog got by centrifugation at 1,000 and 78,000 g. The 3H-NA-binding was inhibited with propranolol, isoprenalin and in lower concentrations with trimepranol in dogs and also in rats. In the myocardium of the thyreotoxic dogs 3H-NA was less superseded with isoprenalin, in the myocardium of thyreotoxic rats less with non-active norarenalin in comparison to euthyroid animals. The thyreotoxicosis caused an increase of the activities of phosphorylase, of the lipases, of the calcium-dependent ATPase, the protein kinase in presence of histone, further a decrease of the activity of adenyl cyclase, particularly in presence of sodium fluoride and a decrease of the concentration of the cyclic adenosine monophosphate in the myocardium of the rats and dogs, respectively. The pharmacological thyreotoxicosis decreased the concentration of the heart glycogen. This decrease was inhibited by the beta-blocker trimepranol, but not by the alpha-blocker phentolamine. Three possibilities of the explanation of the findings of this complex study are cited. The influence of the thyroid hormones and beta-blockers 1. on the transport and calcium metabolism, 2. on the synthesis of the heart proteins, 3. on the backbinding control of the hormonal effect at cellular level.
The actions of dimethyl sulfoxide (DMSO), acetone and two other aprotic solvents on the activity of rat hepatic adenylate cyclase were studied in order to detect their possible effects on both hormonal and nonhormonal enzyme stimulation. The glucagon- or guanylylimidodiphosphate [Gpp(NH)p]-stimulated activity was significantly increased by all DMSO concentrations (0.08--2.57 M) while the highest concentrations of this solvent decreased the enzyme activity stimulated by sodium fluoride. The effect of DMSO on adneylate cyclase activity is reversible and the stimulatory effect of this drug can be seen even on adenylate cyclase activity in the persistent active state induced by preincubation of the enzyme with Gpp(NH)p. An increase in adenylate cyclase activity stimulated by glucagon or Gpp(NH)p was also seen after the addition of other aprotic solvents (acetone, acetonitrile and dimethylformamide) to the assay system. These effects of aprotic solvents on the rat hepatic adenylate cyclase activity may be caused by an increase of membrane fluidity and facilitated movement of the adenylate cyclase subunits in the plane of the cell membrane.
The effects of ethanol, acetone and dimethylsulfoxide (DMSO) were tested on the accumulation of cyclic AMP in human peripheral blood lymphocytes in vitro. Isoproterenol (1.0X10(-8) - 1.0X10(-4)M), PGE2 (3X10(-8)-3X10(-6)M), adenosine (10(-7) - 10(-4)M) and phenylisopropyladenosine (10(-8) - 10(-4)M) caused a dose dependent increase in cyclic AMP accumulation. Over the entire range of concentration of stimulating drugs, ethanol caused an enhanced accumulation of cyclic AMP. At temperatures between 15 degrees and 30 degrees the effect of ethanol rose with increasing concentration from 0.2-6%. At 37 degrees and 40 degrees, 6% ethanol had less stimulatory effect than 2% ethanol. The effect of ethanol was shared by acetone and to a minor extent by DMSO, and was present also when phosphodiesterase was inhibited by isobutylmethylxanthine. It is suggested that ethanol enhances adenylate cyclase activity as a consequence of altered cell membrane fluidity. Since the effects on cyclic AMP accumulation can be observed already at rather low concentration of the solvents they may be of toxicological significance.
The mechanism of the nonspecific inhibitory effects of the prostaglandin antagonist polyphloretin phosphate (PPP) was studied on a partially purified adenylate cyclase preparation from rat livers, PPP in concentrations above 100 micrograms/ml reduced the enzyme activity below basal values regardless of the stimulator used. The activity of adenylate cyclase in a persistent active state due to enzyme preincubation with guanylylimidodiphosphate (Gpp(NH)p) was inhibited 5-10 times more weakly. Kinetic studies indicate that PPP does not influence directly the catalytic site for ATP. PPP seems to produce permanent enzyme inhibition which is not antagonized by repeated washing ot the enzyme preparation. The reduced catalytic activity of adenylate cyclase retains after treatment with PPP the character of its responsiveness to the stimulators, which depends on the state of the enzyme before exposure to the inhibitor.
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The enzyme activities of cyclic AMP system in the neuro- and adenohypophyses were studied, immediately after an irradiation by a single whole body exposure of 1600 R, in an attempt to find whether this intervention causes the changes in the responsiveness of the cyclic AMP regulatory system. In the irradiated rats the neurohypophyses revealed a reduced activity of adenylate cyclase, moderately increased activity of phosphodiesterase and slightly decreased activity of protein kinase, including the value stimulated by cyclic AMP. In the adenohypophyses the irradiation did not cause any significant changes in the enzyme activities of the cyclic AMP system, except of slightly decreased adenylate cyclase activity. The possible relationship of the plasma level of antidiuretic hormone immediately after irradiation and the enzyme activities of cyclic AMP system is discussed.
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Quantitative studies of the action of theophylline and papaverine were performed in rat epididymal fat pads, both on the lipolytic effect and on the activity of phosphodiesterase, adenylate cyclase and protein kinase. Papaverine, a stronger inhibitor of phosphodiesterase than theophylline, did not produce lipolysis. The maximum lipolytic effect (glycerol release) of theophylline was much higher than that of epinephrine and nearly approached the effect exerted by dibutyryl cyclic AMP. While theophylline potentiated or was without any effect on lipolysis produced by epinephrine and dibutyryl cyclic AMP, papaverine at concentration 10- minus 3 M reduced the effect of both drugs as well as of theophylline by 90 per cent. These concentrations of papaverine also strongly inhibited the activity of adenylate cyclase. Neither papaverine nor theophylline prevented the activation of protein kinase by cyclic AMP. The data suggest that the lack of a lipolytic effect of papaverine migth be caused by a combination of its inhibitory effect on adenylate cyclase and direct inhibition of activation of triglyceride lipase.
7-oxa-13-prostynoic acid (OPA) and polyphloretin phosphate (PPP) are believed to act as specific antagonists of prostaglandin action. In order to estimate their specificity, the inhibitory effects of these drugs were tested on the activity of adenylate cyclase from several tissues which were stimulated by prostaglandins and several other compounds. In adenylate cyclase preparation from L-fibroblasts both OPA (0.15-1.5 MM) and PPP (0.01-1.0 MG/ML) antagonized not only the stimulatory effects of PGE but also the stimulatory effects of sodium fluoride and increased enzyme activity due to the previous treatment of cell cultures by cholera toxin. Both OPA and PPP produced a dose dependent depression of adenylate cyclase activity to zero values both under basal conditions and after stimulation by sodium fluoride and various hormones in all preparations studied, including rat liver, heart, brain, epididymal adipose tissue, small intestine, renal cortex and renal medulla. The present results indicate that both prostaglandin antagonists may, in higher concentrations, act as nonspecific inhibitors of the catalytic unit of adenylate cyclase rather than specific antagonists of the prostaglandin effects on adenylate cyclase.
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