Adenosine In Regulation Research Articles

Regulation of cyclic adenosine 3′,5′-monophosphate in relation to growth of dimethylbenz[ a]anthracene-induced mammary tumors in rats

In this study, adenylate cyclase, phosphodiesterase and cyclic adenosine 3′,5′-monophosphate (cAMP) levels were measured in 7,12-dimethylbenz[ a]anthracene (DMBA)-induced mammary tumors with different growth characteristics in both intact and ovariectomized rats. Tumors were classified as growing, stable, or regressing over a 10–;14-day period before excision. Regressing or static tumors had a higher cAMP concentration relative to tumors that were growing actively. This was due to high adenylate cyclase activity and low phosphodiesterase (both high and low K m) activities. Although estrogen deprivation resulted in a much greater rate of tumor regression than would occur spontaneously under normal conditions, the levels of adenylate cyclase, phosphodiesterases and cAMP were the same in tumors obtained from either intact or ovariectomized rats, when comparisons were made within the same category of tumor. These observations suggest that cAMP metabolism is independent of estrogen, since it is related to enhancement or retardation of growth rather than to the presence of absence of estrogen.

Regulation of adenosine 5?-phosphosulfate sulfotransferase activity by H2S and cyst(e)ine in primary leaves of Phaseolus vulgaris L.

During chloroplast development in the primary leaves of Phaseolus vulgaris, the extractable activity of adenosine 5'-phosphosulfate sulfotransferase increased ten-fold. When chloroplast development took place in air enriched with 3.5 μl H2S·l(-1) there was a decrease in adenosine 5'-phosphosulfate sulfotransferase activity. Cyst(e)ine in concentrations up to 1 mM (in the external medium) did not affect the increase in adenosine 5'-phosphosulfate sulfotransferase activity in intact plants. In plants with excised roots, 0.75 mM cyst(e)ine inhibited this increase. In green primary leaves, H2S or cyst(e)ine treatment resulted in a decrease of extractable adenosine 5'-phosphosulfate sulfotransferase activity. In intact plants, this effect of cyst(e)ine was observed at a concentration of 1 mM, and in plants with excised roots, 0.25 mM had a comparable effect.In developing plants, the extractable activities of O-acetyl-L-serine sulfhydrylase (EC 4.2.99.9) and ribulosebisphosphate carboxylase (EC 4.1.1.39.) were not affected by H2S or cyst(e)ine.

Beta-Adrenergic regulation of adenosine 3',5'-monophosphate concentration in brain microvessels.

Norepinephrine increases the concentration of adenosine 3',5'-monophosphate (cyclic AMP) in an incubated suspension of brain microvessels. This response can be matched by other drugs that stimulate the beta receptors, but the alpha-adrenergic agonist phenylephrine is without effect; beta-adrenergic blockade abolishes the response while alpha-adrenergic blockade produces no change. The data support the contention that cerebral capillary function is subject to adrenergic neural control.

The regulation of adenosine 3′: 5′-cyclic monophosphate accumulation in glia by alpha-adrenergic agonists

This study examines the α-adrenergic modulation of cAMP accumulation in glia. This phenomenon occurs in three different glial culture systems: (a) primary surface cultures of glia, (b) reaggregate cultures containing neurons and glia, and (c) C6 glioma cells. The turn-on and turn-off times of α-adrenergic modulation appear to be in the same time frame as that of agents which normally increase cAMP accumulation. However, even after prolonged treatment periods, refractoriness does not develop to the modulating capacity of α-adrenergic agents. Clonidine, reported to act as both an α-adrenergic agonist and antagonist in the central nervous system, was found to interact with glia as an α-adrenergic agonist. Alpha- adrenergic modulation was not diminished by the addition of ethylene- glycol-bis-(β-amino-ethyl ether)N, N′-tetra-acetic acid (EGTA) to culture media, suggesting that external calcium is not required for this effect. These results illustrate the complexity of glial pharmacology and need for more defined systems which allow the examination of characterized populations of brain cells.

Regulation of adenosine 3‘:5‘-monophosphate efflux from animal cells

Cyclic AMP efflux was measured following hormonal stimulation of adenylate cyclase in a variety of animal cells including C-6 rat glioma cells, WI-38 human fibroblasts, and avian erythrocytes. Using a variety inhibitors of mitochondrial function and glycolysis, a correlation was noted between cellular ATP levels and the rate of cyclic AMP efflux in all cells examined. A relationship between the efflux rate and the magnitude of the membrane potential was not observed. Pharmacological agents which inhibited cyclic AMP egress in these cells without reducing ATP levels included several prostaglandins (A greater than B greater than E greater than F) and probenecid. The characteristics of the cyclic AMP efflux system resemble those of the organic anion transport system.

Adenosine 3′:5′-cyclic monophosphate-dependent protein kinase(s) of rat ovarian cells. Gonadotropin regulation of adenosine 3′:5′-cyclic monophosphate-receptor activity

Regulation of cyclic AMP-dependent protein kinase, cyclic AMP-receptor activity and intracellular cyclic AMP concentrations by choriogonadotropin was studied in ovarian cells prepared from 26-day-old rats. A close correlation was observed between phospho-transferase activity and cyclic AMP-receptor activity in 12000g supernatant fractions from rat ovarian homogenate. The apparent activation constant (K(a)) and I(50) (concentration required to produce 50% inhibition) of different cyclic nucleotides for phosphotransferase and cyclic AMP receptor activities respectively were also determined. Cyclic AMP and 8-bromo cyclic AMP were most effective, giving K(a) values of 0.08 and 0.09mum and I(50) of 0.12 and 0.16mum respectively. Other nucleotides were also effective, but required higher concentrations to give a comparable effect. An increased concentration of cyclic AMP produced by choriogonadotropin (1mug/ml) treatment was accompanied by decreased cyclic AMP binding as early as 5min after hormone addition. Choriogonadotropin also stimulated the protein kinase activity ratio (-cyclic AMP/+cyclic AMP) under identical experimental conditions. The phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine potentiated the action of choriogonadotropin on the three parameters measured in a dose- and time-dependent manner. The maximal cyclic AMP-binding capacity, as determined by cyclic AMP-exchange assay, remained unchanged before and after hormone addition. The endogenously bound cyclic AMP was determined from the difference between the maximal binding capacity and the exogenously bound cyclic AMP. With different choriogonadotropin concentrations, a quantitative correlation was established between maximal binding capacity, exogenous binding and endogenous binding activities. Approx. 60% of total binding sites were endogenously occupied in untreated cells, and choriogonadotropin (1mug/ml) treatment fully saturated available binding sites with a parallel 10-fold increase in cellular cyclic AMP. The present results provide evidence for a probable intracellular compartmentalization of cyclic AMP in the ovarian cell, and suggest that in the unstimulated state all cyclic AMP present in the ovarian cell may not be available for protein kinase activation.

Regulation of adenosine 3‘:5‘-monophosphate content of rous sarcoma virus-transformed human astrocytoma cells. Effects of cholera toxin on the responsiveness to catecholamines and prostaglandins.

Human astrocytoma cells (EH118MG) respond to catecholamines and prostaglandins with a marked increase in the rate of formation of cyclic AMP. Treatment of EH118MG cells with cholera toxin (10 to 100 ng/ml) for 45 to 60 min caused an increase in cellular cyclic AMP content (5- to 10-fold over basal). Cholera toxin also decreased the K0.5 for isoproterenol 10- to 50-fold and decreased the K0.5 for prostaglandin E1 (PGE1)30- to 100-fold, while increasing the maximal response to PGE1 by 1.5- to 3-fold. Treatment with cholera toxin did not change the K1 values for beta-adrenergic receptor antagonists such as propranolol, alprenolol, and sotalol. Direct binding studies using [125I]iodohydroxybenzylpindolol indicated no significant changes in the number of beta-receptors or in the kinetics of the interaction of the radioligand with receptors after treatment of cells with the toxin. Competition binding studies with propranolol and sotalol revealed no toxin-induced change in Kd values for these antagonists. Treatment with cholera toxin caused only small decreases (2- to 3-fold) in the Kd values for binding of isoproterenol and norepinephrine. It is concluded that cholera toxin has little direct effect on the binding of agonists or antagonists to beta-receptors, but instead increases the efficiency of coupling of receptor and catalytic moieties of adenylate cyclase.

Characterization and regulation of heart adenosine 3':5'-monophosphate-dependent protein kinase isozymes.

There is broad species variation in the type of cAMP-dependent protein kinase isozyme present in supernatant fractions of heart homogenates as determined by DEAE-cellulose chromatography, Isozyme I, which elutes at less than 0.1 M NaCl, is predominant in mouse and rat hearts; while isozyme II, which elutes at greater than 0.1 M NaCl, is the predominant type in beef and guinea pig. Human and rabbit hearts contain about equal amounts of the two types. The type I heart kinases are more easily dissociated into free regulatory and catalytic subunits by incubation with histone than are the type II kinases, and the separated regulatory and catalytic subunits of isozyme II of rat heart reassociate more rapidly than the subunits of isozyme I under the conditions used. The data from several experiments using rat heart indicate that the basal activity ratio of the protein kinase in crude extracts (approximately 0.15) is due mainly to basal endogenous cAMP and that cAMP elevation accounts entirely for the epinephrine effect on the enzyme. Addition of epinephrine and 1-methyl-3-isobutylxanthine to the perfusate causes a rapid (1 min) increase in cAMP, active supernatant protein kinase, and active phosphorylase in perfused hearts of both rat (mainly isozyme I) and guinea pig (mainly isozyme II). The elevation percentage in cAMP is about the same in the two species, but the increase in active protein kinase is greater in rat heart. If hearts from either animal are perfused continually (10 min) with epinephrine (0.8 muM) and 1-methyl-3-isobutylxanthine (10 muM), the cAMP level, active protein kinase, and active phosphorylase remain elevated. Likewise, all parameters return rapidly to the basal levels when epinephrine and 1-methyl-3-isobutylxanthin are removed. Most of the epinephrine effect on the rat heart supernatant kinase is retained at 0 degrees if cAMP is removed by Sephadex G-25 chromatography, although this procedure completely reverses the epinephrine effect in the guinea pig heart. The epinephrine effect on the rabbit heart kinase (approximately equal amounts of isozymes I and II) is partially reversed by Sephadex G-25. These species differences can be accounted for by differences in association-dissociation behavior of the isozymes in vitro. The data suggest that epinephrine causes activation of both isozymes. The activity present in the particulate fraction comprises nearly half of the total cAMP-dependent protein kinase activity in homogenates of rabbit heart. Triton X-100 extracts of low speed particulate fractions from hearts of each species tested, including rat heart, contain predominantly or entirely the type II isozyme, suggesting differences in intracellular distribution of the isozymes. The binding of the protein kinase to the particulate fraction is apparently due to the properties of the regulatory subunit component. Differences in topographical distribution of the isozymes could provide for differences in either physiological regulation or substrate specificity.

Studies on sex-organ development. The hormonal regulation of steroidogenesis and adenosine 3′:5′-cyclic monophosphate in embryonic-chick ovary

1. We investigated the production of steroid hormones by the ovaries of the developing embryonic chick under conditions of organ culture. Radioimmunoassay techniques were used to measure the amount of steroid hormone released into the culture medium. Stimulation of the production of steroid hormones by choriogonadotropin from the urine of pregnant human was dose-dependent. Oestradio and testosterone production was optimal when 20 i.u. of gonadotropic hormone was present in the culture medium 2. During development, both left and right ovaries responded to gonadotropic hormone stimulation with a 2.5-3-fold increase in oestrogen production. However, the right ovary was twice as efficient in testosterone production as the left one. The presence of dibutyryl cyclic AMP in the culture medium of the embryonic ovaries mimicked the effect of the gonadotropic hormone. 3. The human choriogonadotropic hormone stimulated cyclic AMP production in the embryonic ovarian tissue. Thyrotropin, growth hormone and insulin had no stimulating effect. 3-Isobutyl-1-methylxanthine potentiated the gonadotropic hormone effect by increasing the concentration of cyclic AMP in the ovarian tissue. 4. The amount of cyclic AMP synthesized in the embryonic ovary was gradually increased (from 1.2 to 6.5 pmol/mg of tissue) when incubated with increasing doses of human choriogonadotropic hormone in vitro. The newly synthesized cyclic AMP reached the maximum concnentration after 30 min of incubation, then decreased at 2 h of incubation. A portion of the newly synthesized cyclic AMP was released into the culture medium. 5. At various developmental stages, both left and right embryonic-chick ovaries responded to stimulation by gonadotropic hormone with an increase in cyclic AMP production. The cyclic AMP concentration in the right ovary was 80% higher than that in the corresponding left ovary.

Release of adenosine, inosine and hypoxanthine from the isolated guinea pig heart during hypoxia, flow-autoregulation and reactive hyperemia.

In an attempt to test the hypothesis whether adenosine is involved in the regulation of coronary flow adenosine, inosine and hypoxanthine were measured in the effluent perfusate and in the tissue of isolated guinea pig hearts under various experimental conditions. In addition, the release of 14C-adenosine, 14C-inosine and 14C-hypoxanthine was determined after prelabeling cardiac adenine nucleotides with 14C-adenine. The decrease in coronary resistance induced by hypoxic perfusion (30% and 20% in the gas phase) and during autoregulation was associated with a considerable increase in the release of adenosine and hypoxanthine. Under both conditions the concentrations of adenosine in the effluent perfusate were clearly within the coronary vasodilating range of exogenously administered adenosine. The tissue content of adenosine also increased significantly when the perfusion pressure was reduced. The release of 14C-adenosine closely paralleled the changes in coronary resistance during hypoxic perfusion, autoregulation and during reactive hyperemia. The specific activity of adenosine in the effluent perfusate, however, decreased substantially upon reduction of the oxygen supply to the heart, indicating that the release of 14C-adenosine does not provide an absolute measure of total adenosine release by the heart. Our data indicate that the greater part of the adaptive changes of vascular resistance during hypoxia and autoregulation can be attributed to adenosine which is formed at an enhanced rate under these conditions. However, other factors might be involved as well.

Neurotransmitter Regulation of Adenosine 3′,5′-Monophosphate in Clonal Nerve, Glia, and Muscle Cell Lines

Norepinephrine increases the intracellular level of adenosine 3',5'-monophosphate (cyclic AMP) in clonal cell lines of nerve, glia, smooth muscel, and skeletal muscle. The largest response is in skeletal muscle, where the cyclic nucleotide concentration is elevated more than 500-fold. Glia and muscle cells, but not nerve cells, respond to dopamine with increased cyclic AMP accumulation. This response appears to be mediated through a beta-adrenoreceptor.

Regulation of Cyclic Adenosine 3′,5′-Mono-Phosphate Dependent Protein Kinase of Rat Ovarian Cells by Luteinizing Hormone and Human Chorionic Gonadotropin

Regulation of cAMP dependent protein kinase activity from rat ovarian cells has been studied in response to luteinizing hormone and human chorionic gonadotropin. Treatment of cells with human chorionic gonadotropin in concentration range of 2.5ng-1000ng/ml resulted in increased accumulation of cAMP,activation of protein kinase followed by the stimulation of progesterone synthesis. A sixfold increase in the activity ratio, defined as the ratio of protein kinase stimulated in situ to that maximally stimulated in vitro by exogenous cAMP, was observed with 1ug/ml of hCG. This concentration of hormone also produced a ten-fold increase in cAMP and a thirty-to forty-fold increase in progesterone synthesis. Protein kinase activation was specific for LH and hCG, as other polypeptide hormones were without any appreciable effect. The stimulation of protein kinase persisted even after the elevated cAMP level began to fall. It appears that the activation of protein kinase is an obligatory early event that mediates an increase in gonadotropin stimulated progesterone synthesis.

Regulation of adenosine 3:5-monophosphate-dependent protein kinase.

The effects of epinephrine, glucagon, insulin and 1-methyl-3-isobutylxanthine on adenosine 3:5-monophosphate (cAMP)-dependent protein kinase activity were investigated in the perfused rat heart. The conditions for homogenization of heart tissue and assay of protein kinase are described. The activation state of the enzyme is expressed as the ratio of the rate of phosphorylation of histone in the absence to that in the presence of 2 mu-M cAMP. This activity ratio is stable in crude homogenates over 15 min of incubation; it is not affected by up to 30-fold dilution of the tissue volume. The ratio is elevated to a variable degree in hearts taken immediately from the animal but falls to a stable, basal level of 0.15 to 0.20 after 15 min of perfusion in vitro. An optimal concentration of epinephrine (10 mu-M) in the perfusate elevates cAMP from 0.5 to 1.3 nmol per g of tissue and increases the protein kinase activity ratio from 0.20 to 0.65. When hearts are perfused with a steady, submaximal concentration of epinephrine (0.4 mu-M), the level of cAMP and the protein kinase activity ratio rise in parallel within 15 s and remain elevated for at least 10 min. When epinephrine is removed from the perfusion medium, the level of cAMP and enzyme activity ratio decline rapidly to basal levels. Both glucagon and the phosphodiesterase inhibitor 1-methyl-3-isobutylxanthine also increase the cardiac cAMP levels and protein kinase activity ratio in a dose-dependent manner. Glucagon acts as rapidly as does epinephrine whereas 1-methyl-3-isobutylxanthine requires at least 30 s before any effect can be observed. Insulin by itself does not significantly affect the cyclic nucleotide level or enzyme activity. The hormone has not been observed to lower the cAMP level or protein kinase activity in the heart under any conditions tested. In concentrations of 10 microunits per ml or greater, it does, however, cause a slight rise in the tissue level of cAMP and the protein kinase activity when these have been elevated to intermediate levels by exposure to epinephrine. This effect could only be observed when hearts were treated with catecholamine and could not be detected with glucagon or 1-methyl-3-isobutylxanthine. In all cases tested, slight increases in the protein kinase activity ratio (from 0.2 to 0.3) were accompanied by much greater increases in the amount of phosphorylase in the a form (20% to 70%). It was observed that at perfusion times greater than 3 min, there was a significant reduction in phosphorylase activity even though both the cAMP level and protein kinase activity remained elevated. In these studies, changes in the protein kinase activity correlate well with the tissue cAMP levels under all conditions tested.

Regulation of adenosine 3' :5'-monophosphate efflux from rat glioma cells in culture*

Rat glioma cells grown in culture secrete cyclic adenosine 3':5'-monophosphate (cyclic AMP) into the culture medium following stimulation by beta-agonistic catecholamines. Agents which reduced cellular ATP levels such as valinomycin, oligomycin, and uncouplers of oxidative phosphorylation, inhibited cyclic AMP efflux. Secretion of cyclic AMP was also prevented by prostaglandin A-1 and pharmacological agents including probenecid and papaverine. Of the latter agents, only papaverine reduced ATP levels. These results suggest that the transport of cyclic AMP across animal cell membranes is energy-dependent and subject to regulation.

On the regulation of adenosine 3′,5′-monophosphate synthesis in bacteria I. Effect of carbon source variation on cyclic AMP synthesis in escherichia coli B/r

1. 1. The effect of carbon source variation in bacterial growth media on their growth rate, inducible enzymes and cyclic AMP synthesis was examined: an inverse relationship between the culture's growth rate and its differential rate of inducible enzyme (tryptophanase and β-galactosidase), and cyclic AMP synthesis was found. 2. 2. The effect of the culture's growth phase on its sensitivity or resistance to glucose catabolite repression was determined in the wild type and a catabolite insensitive mutant (ABDROI): the wild type's sensitivity to glucose repression was not affected, whereas the insensitivity of the mutant was found to be limited to its early logarithmic phase of growth. At late log, or stationary phase, the mutant was found to be sensitive to glucose repression. 3. 3. Examination of the kinetics of glucose uptake by the mutant, using α-[ 14C] methyl-glucoside showed evidence for two transport systems each with a different affinity to glucose. A low affinity transport system (apparent K m of 3.4 · 10 −5 M) which appears mostly at the early logarithmic phase of growth. A high affinity transport system (apparent K m of 1.2 · 10 −5 M) which appears mostly at the late log and stationary phases of growth. 4. 4. The effect of the culture density variation on its sensitivity to glucose repression showed that sensitivity to glucose catabolic repression is primarily a reflection of the formation of an allosteric effector molecule between glucose and its specific transport molecule which in turn regulates the activity of the adenylate cyclase.

Regulation of Adenosine 3′:5′-Monophosphate Content in Human Astrocytoma Cells by Adenosine and the Adenine Nucleotides

Abstract Adenosine and the adenine nucleotides AMP, ADP, and ATP (but not adenine) cause a rapid increase in the concentration of adenosine 3':5'-monophosphate (cAMP) in cultured human astrocytoma cells. Adenosine and AMP are equi-potent, causing a half-maximal rise in cAMP content at a concentration of about 10 µm. The time course of a rise in cAMP content to the maximal level effected by adenosine or AMP is the same (t1/2 ≃ 1 min). AMP is converted to adenosine in the incubation medium but not to an extent sufficient to account for its effect. The rate of uptake of adenosine into the cells is markedly faster than that of AMP, even though the t1/2 of their effects is the same. During a 10-min exposure of cells to 100 µm [3H]adenosine, the intracellular concentration of cAMP rises to 600 to 800 pmoles per mg of protein, of which only 30 to 40 pmoles per mg of protein are contributed by exogenous adenosine. The uptake of adenosine can be inhibited to greater than 95% by dipyridamole without any inhibition of the effect of adenosine on cAMP content. Such observations suggest that nucleotides act directly and need not be converted to adenosine to cause a rise in intracellular cAMP and that adenosine need not enter the cell to increase cAMP content. Theophylline is a rapidly acting, competitive inhibitor of the effect of adenosine. The inhibitory effect of theophylline is presumed to occur at the proposed extracellular site of action of adenosine and could not be related by our experiments to its well known action as an inhibitor of phosphodiesterase activity. On the other hand, papaverine potentiates the effect of adenosine, presumably as a result of the inhibition of phosphodiesterase. In contrast to theophylline, papaverine is a potent inhibitor (I50 = 17 µm) of the soluble, low Km phosphodiesterase from the astrocytoma cells. Catecholamines, which potentiate the effect of adenosine in brain slices, cause only additive increases in cAMP content in the astrocytoma cells when present with adenosine. Neither α- nor β-adrenergic receptor antagonists (phentolamine and propranolol) have any inhibitory action on the effect of adenosine. The results suggest that adenosine increases intracellular cAMP content as a result of its interaction with a specific plasma membrane surface receptor which results in the activation of adenylate cyclase.

Light regulation of adenosine 3′, 5′ cyclic monophosphate levels in vertebrate photoreceptors

The regulation of adenylyl cyclase activity (measured as the production of labeled cyclic-AMP (cAMP) from labeled ATP) in frog rod outer segment photoreceptor membranes has been studied. The activity was found to be more than 20 times higher in fully dark-adapted than in bleached material. A number of experimental parameters must be carefully regulated to obtain this large ratio of dark to light activities. The disrupted rod outer segments must not be washed, since a soluble factor is essential for inhibition of activity by light. The photoreceptor membranes should be assayed for adenylyl cyclase immediately after preparation since the specific activity and light-dark differences are substantially reduced on storage at 4°C. Mechanical trauma (homogenization or sonication) causes some decrease in dark activity and a lessening of sensitivity to illumination. Preparation and assay of the dark material must be carried out using infrared light since there is a marked disproportionality between photic bleaching of rhodopsin and loss of cyclase activity. This disproportionality was further studied by mixing dark and totally bleached material in various proportions. With as little as 2% of the material bleached the cyclase activity is the same as in fully bleached material. The inhibitory action of the bleached material is destroyed by heating but is not affected by dialysis or treatment with tryspin. If the photoreceptor material is fractionated by sedimentation at 60 000 × g and 200 000 × g, the rhodopsin and adenylyl cyclase are primarily in the 60 000 × g pellet. The inhibitor is present in both pellets but not in the high speed supernatant. However, the high speed supernatant is essential for action of the inhibitor on unbleached material. Bleached (but not dark) photoreceptor material was found to inhibit cyclase in brain, liver and melanoma. Recent work carried out after presentation of the above findings has indicated that although the activity of cAMP phosphodiesterase is not affected by light under the usual assay conditions, in the presence of ATP light produces a marked stimulation of this activity. This stimulation of phosphodiesterase exhibits many of the characteristics previously attributed to the inhibition of cyclase and accounts completely or in large part for the apparent light dark differences in cyclase activity. At present the evidence points to phosphodiesterase as the main locus of light regulation of cAMP concentrations in photoreceptors, though a role for the light regulation of cyclase activity is not excluded.

Enzymatic regulation of adenosine 3',5'-monophosphate (cyclic AMP) in the freezing epileptogenic lesion of rat brain and in homologous contralateral cortex.

AbstractFreezing epileptogenic lesions were made unilaterally in rat cerebral cortex. Such lesions were associated with an increase in adenyl cyclase activity and a decrease in the membrane‐associated phosphodiesterase activity, with a concomitant increase in the level of cyclic AMP. Similar, though less striking, changes occurred in homologous contralateral cortex (‘mirror focus’). The effects of cyclic AMP on brain membrane systems are discussed, with the suggestion that this substance may play an important role in the genesis of focal seizures.

The prostaglandins. Physiologic actions and clinical potential.

Prostaglandins (PGs) of which there are 6 primary compounds synthesize in a variety of human tissues where they can be identified in low concentrations. The mode of action of PGs is not yet clearly known but it appears that they can modify known metabolic functions by accelerating or slowing a variety of cellular reactions through regulation of the cyclic adenosine 3 5 monophosphate mechanism. In vitro investigations have shown very complicated actions of PGs. In the nonpregnant uterus PGE2 inhibits contractions while PGF2alpha stimulates them; in the pregnant uterus both compounds stimulate the smooth muscle. Intravenous infusion of both compounds have proven very useful in induction of labor perhaps more useful than oxytocin infusion although the question is still debated. PGE2 seems to be 40 times more potent than PGF2alpha which is 8 times more active than PGE1. Both PGs have been administered intravenously at rates between 25-100 mcg/min to induce therapeutic abortion with very good success. Intrauterine administration through a catheter has also been proven successful as has the intravaginal route; side effects are common. It is possible that PGs cause a sharp decline in progesterone production to the extent that the pregnancy cannot be maintained and the uterine contractions lead to expulsion of the conceptus. It has been indicated that PGEs may play an important role in fertility since semen samples from men in infertile marriages had PGE concentrations of 15 mcg/ml instead of the usual 55.2 mcg. PGA has been used to treat hypertension; it produces a marked but transient fall in blood pressure apparently producing its hypotensive effect by peripheral vasodilation with unchanged or increased cardiac output.

Regulation of adenosine 3′,5′-cyclic monophosphate phosphodiesterase activity in fibroblasts by intracellular concentrations of cyclic adenosine monophosphate: D'Armiento, M., G.S. Johnson, and I. Pastan, Proc. Nat. Acad. Sci. USA 69:459, 1972

Regulation of adenosine 3′,5′-cyclic monophosphate phosphodiesterase activity in fibroblasts by intracellular concentrations of cyclic adenosine monophosphate: D'Armiento, M., G.S. Johnson, and I. Pastan, Proc. Nat. Acad. Sci. USA 69:459, 1972