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PubMed1975

Cyclic AMP binding proteins in early embryos of Drosophila melanogaster.

A variety of effects of cyclic AMP on cellular and subcellular phenomena suggest that there may be other modes of action of cyclic AMP then activation of protein kinase. It is also known that developing embryos contain cyclic AMP and its related enzymes. In order to explore the role of cyclic AMP in embryogenesis, a survey of proteins capable of binding cyclic AMP in the embryonic supernatant of Drosophila melanogaster was carried out. As the result, two cyclic AMP-binding proteins were found and characterized. The one (L) is, as expected, associated with protein kinase and has a dissociation constant of about 10(-9) M. Its molecular weight of 21 000 daltons is extremely small when compared with similar proteins in other organisms. The other (H), whose function is yet to be found, has a molecular weight of about 200 000 daltons and has a dissociation constant of about 10-7 M. Some laxity in binding specificity of the latter protein among adenosine nucleotides was observed, but cyclic AMP is the strongest ligand among them.

Adenine Nucleotides↗
PubMed1988

Involvement of a plasma membrane phosphodiesterase in the negative control of cyclic AMP levels by vasopressin in rat hepatocytes.

Vasopressin has been shown previously to lower the glucagon-induced increase of cyclic AMP levels in isolated rat hepatocytes by way of an enhanced phosphodiesterase (EC 3.1.4.17) activity. Five phosphodiesterase inhibitors were tested for their ability to prevent vasopressin from lowering cyclic AMP levels in intact hepatocytes and for their inhibitory effect in vitro on soluble and particulate phosphodiesterase activities partially purified from hepatocytes. Three soluble activities have been separated by DEAE-cellulose chromatography: a phosphodiesterase hydrolyzing both cyclic AMP and cyclic GMP, a form stimulated by cyclic GMP and a cyclic AMP-specific activity. The absence of any statistically significant correlation between the in vivo (in intact cells) and the in vitro (on isolated phosphodiesterases) potencies of the inhibitors does not support a role for the cytosolic phosphodiesterases in mediating the vasopressin-induced decrease in cyclic AMP levels. No statistically significant correlation was observed between the inhibition of the vasopressin effect on cyclic AMP accumulation and the inhibition of phosphodiesterase activity either associated with the native plasma membranes or solubilized from these membranes with 0.4 M NaCl. In contrast, a statistically significant correlation was observed between the degree of inhibition of the vasopressin effect in the intact cells and the degree of inhibition of the intrinsic phosphodiesterase still associated with the plasma membranes after high-salt treatment. These data indicate that a phosphodiesterase activity integral to the plasma membrane is very likely involved in the negative control of cyclic AMP levels by vasopressin.

Animals↗
PubMed1990

Partial characterization of cyclic AMP-dependent protein kinases in guinea-pig lung employing the synthetic heptapeptide substrate, kemptide. In vitro sensitivity of the soluble enzyme to isoprenaline, forskolin, methacholine and leukotriene D4.

This paper describes the partial characterization of soluble cyclic AMP-dependent protein kinase (A-kinase) in guinea-pig lung using Kemptide, a synthetic serine-containing heptapeptide, and examines the sensitivity of this enzyme to drugs which are reported to increase and to decrease the intracellular concentration of cyclic AMP. Differential centrifugation of lung homogenates revealed that 78% of A-kinase was present in the 31,000 gmax x 15 min supernatant fraction. Both basal and cyclic AMP-stimulated phosphotransferase activity of this 'soluble' enzyme were abolished by the heat-stable inhibitor of A-kinase. Soluble A-kinase was Mg2(+)-dependent (apparent Km and and Kact 8.6 and 2.6 mM, respectively) and was stimulated nine-fold by saturating concentrations of both cyclic AMP (Kact: 131 nM) and cyclic GMP (Kact: 28.7 microM) at a protein (enzyme) concentration of 1.3 micrograms. Kinetic analysis of the effect of Kemptide and ATP revealed linear, Hanes plots with Michealis constants of ca. 12 and 13 microM, respectively. Chromatography of the soluble enzyme over DEAE-cellulose resolved three peaks of catalytic activity when fractions were assayed in the presence of cyclic AMP (10 microM): (i) free catalytic subunits (5%), (ii) Type I isoenzyme (5%) and (iii) Type II isoenzyme (90%). The A-kinase activity ratio was markedly increased in lung pre-treated with the smooth muscle relaxants isoprenaline and forskolin. This biochemical effect was both time- and concentration-dependent and was temporally associated with the ability of these drugs to reduce lung parenchymal tone. In contrast, the contractile agonists, methacholine (Mch) and leukotriene (LT) D4 exerted opposite effects on A-kinase activity. Thus, Mch significantly reduced cyclic AMP levels and lowered basal A-kinase activity whilst the converse was true for LTD4. For both drugs this biochemical effect accompanied contraction of the lung. Pre-treatment of lung tissue with flurbiprofen, an irreversible inhibitor of cyclo-oxygenase in vitro, abolished the ability of LTD4 to increase the A-kinase activity ratio suggesting that this biochemical response was mediated indirectly through the stimulated biosynthesis and release of a prostanoid(s) able to activate adenylyl cyclase; the increase in tension induced by LTD4, however, was not significantly affected by flurbiprofen pre-treatment. Collectively, these data support the concept that soluble A-kinase activity in guinea-pig lung can be regulated by changes in intracellular cyclic AMP and that activation and/or inhibition of this biochemical cascade may influence alterations in lung contractility.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Triphosphate↗
PubMed1978

Brain alpha-adrenergic receptors: comparison of [3H]WB 4101 binding with norepinephrine-stimulated cyclic AMP accumulation in rat cerebral cortex.

The ability of a series of adrenergic agents to displace the binding to brain membranes of [3H]WB 4101, a potent alpha-adrenergic antagonist (WB 4101 = 2-[2-(2,6-dimethoxyphenoxy)ethylaminomethyl]-1,4-benzodioxane hydrochloride), has been compared with the potency of these agents in stimulating or inhibiting the alpha-adrenergic component of cyclic AMP accumulation in rat cerebral cortex slices. [3H]WB 4101 rapidly bound to a high affinity site (KD = 2.7 nM) in membranes from cerebral cortex. Binding came to equilibrium by 2 min at 37 degrees C and was rapidly reversed in the presence of phentolamine. The potencies of adrenergic agents (WB 4101 greater than phentolamine greater than naphazoline) in displacing binding of [3H]WB 4101 were comparable to the potencies of these agents as inhibitors of the alpha-adrenergic component of norepinephrine-stimulated cyclic AMP accumulations. Phenoxybenzamine, clonidine, chlorpromazine and haloperidol were about 10--30 times more potent in inhibiting cyclic AMP accumulation than in displacing [3H]WB 4101 binding. The potency of classical alpha-adrenergic agonists in displacing WB 4101 (epinephrine greater than norepinephrine greater than methoxamine) correlated with the ability of these agonists to increase cyclic AMP levels. Overall a significant correlation (r = 0.87, P less than 0.005) was found between WB 4101 binding and alpha-adrenergically mediated cyclic AMP accumulation in brain. Several ligands bind to specific sites in brain membranes with alpha-adrenergic receptor properties. The identification of these binding sites as receptors depends on a correlation of binding with a known alpha-adrenergic receptor-mediated response in brain. These data demonstrating that WB 4101 correlates with norepinephrine-stimulated cyclic AMP accumulation suggest that WB 4101 may bind to the membrane receptor sites mediating the alpha-adrenergic accumulation of cyclic AMP in rat cerebral cortex.

Adrenergic alpha-Antagonists↗
PubMed1980

Catecholamine-stimulated cyclic AMP formation in phenylethanolamine N-methyltransferase containing brain stem nuclei of normal rats and of rats with spontaneous genetic hypertension.

Stimultaion of cyclic AMP formation by epinephrine and norepinephrine has been studied in discrete areas of rat brain that include the epinephrine-containing brain stem nuclei C-1 and C-2. In the C-1 area, epinephrine-stimulated cyclic AMP formation was partially reversed by 100 microM phentolamine and by 10--100 microM propranolol or alprenolol and hence appeared to involve activation of a mixture of both alpha- and beta-adrenergic receptors as has been reported for other rat brain areas such as the cerebral cortex. However, in the C-2-area, the epinephrine and norepinephrine stimulated cyclic AMP formation involved the activation of a single receptor type which was alpha-like in character. Stimulation of cyclic AMP formation by epinephrine in the C-2 area was antagonized by nanomolar concentrations of both phentolamine and yohimbine. The epinephrine-stimulated formation of cyclic AMP in the C-2 but not in the C-1 area was augmented in a strains of rats which exhibit spontaneous genetic hypertension (SHR) vs. Wistar-Kyoto controls. It is suggested that the enhanced epinephrine-stimulated cyclic AMP formation in the C-2 area of SHR rats could be a physiological compensatory response to some other hypertension-causing lesion which, for example, results in chronically reduced epinephrine release or in ruduced availability of epinephrine at its postsynaptic receptor thereby leading to receptor supersensitivity. Supporting this possibility was the finding that treatment of SHRs and control animals and reserpine resulted in enhancement of epinephrine-stimulated cyclic AMP formation in the C-2 area of control rats, essentially obliterating the difference between control and SHR. The findings are also interepreted as supporting the involvement of epinephrine neurons in central vaso-depressor mechanisms.

Adrenergic alpha-Antagonists↗
PubMed1991

Polarizing currents increase noradrenaline-elicited accumulation of cyclic AMP in rat cerebral cortex.

Cyclic AMP accumulation elicited by noradrenaline was determined in cerebral cortical slices of rats 24 h after an application of weak anodal direct current (anodal polarization) to the surface of the sensorimotor cortex. Noradrenaline-elicited accumulation of cyclic AMP was altered regionally by the anodal polarization in relation to the duration and intensity of the polarizing current. The cyclic AMP accumulation elicited by noradrenaline was highest in the left anterior cortical region including the polarized point under polarization conditions of 0.3 microA for 1.5 h and 3.0 microA for 30 min. Under these two polarization conditions, the cyclic AMP accumulation elicited by noradrenaline was higher than that in the non-polarized control in the same cortical region. Furthermore, the beta-adrenergic antagonist propranolol almost completely reduced the elicited accumulation of cyclic AMP by noradrenaline to the control level. These results suggest that anodal polarization enhances activity of noradrenaline-sensitive cyclic AMP generating systems through beta-adrenergic mechanisms as a function of both duration and intensity in the cerebral cortex and that one polarization event has a long-lasting aftereffect on noradrenaline-sensitive cyclic AMP generating systems in the cerebral cortex.

Animals↗
PubMed1991

A general role for adaptations in G-proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function.

Previous studies have shown that chronic morphine increases levels of the G-protein subunits Gia and Goa, adenylate cyclase, cyclic AMP-dependent protein kinase, and certain phosphoproteins in the rat locus coeruleus, but not in several other brain regions studied, and that chronic morphine decreases levels of Gia and increases levels of adenylate cyclase in dorsal root ganglion/spinal cord (DRG-SC) co-cultures. These findings led us to survey the effects of chronic morphine on the G-protein/cyclic AMP system in a large number of brain regions to determine how widespread such regulation might be. We found that while most regions showed no regulation in response to chronic morphine, nucleus accumbens (NAc) and amygdala did show increases in adenylate cyclase and cyclic AMP-dependent protein kinase activity, and thalamus showed an increase in cyclic AMP-dependent protein kinase activity only. An increase in cyclic AMP-dependent protein kinase activity was also observed in DRG-SC co-cultures. Morphine regulation of G-proteins was variable, with decreased levels of Gia seen in the NAc, increased levels of Gia and Goa in amygdala, and no change in thalamus or the other brain regions studied. Interestingly, chronic treatment of rats with cocaine, but not with several non-abused drugs, produced similar changes compared to morphine in G-proteins, adenylate cyclase, and cyclic AMP-dependent protein kinase in the NAc, but not in the other brain regions studied. These results indicate that regulation of the G-protein/cyclic AMP system represents a mechanism by which a number of opiate-sensitive neurons adapt to chronic morphine and thereby develop aspects of opiate tolerance and/or dependence. The findings that chronic morphine and cocaine produce similar adaptations in the NAc, a brain region important for the reinforcing actions of many types of abused substances, suggest further that common mechanisms may underlie psychological aspects of drug addiction mediated by this brain region.

Adenylyl Cyclases↗
PubMed1980

Mechanism of chlorpromazine action on plasma glucose and cyclic AMP levels.

The s.c. administration of chlorpromazine (CPZ) caused an elevation of plasma glucose and cyclic AMP levels in fed intact mice, but not in fed adrenalectomized mice. The pretreatment with reserpine partially blocked the elevation of plasma glucose and cyclic AMP. The pretreatment with 6-hydroxydopamine or alpha-methyl-p-tyrosine failed to inhibit the increase of plasma glucose and cyclic AMP induced by CPZ. These findings suggest that CPZ acts on the central nervous system and increases plasma glucose and cyclic AMP through epinephrine release from the adrenal medulla. The elevations of plasma glucose and cyclic AMP induced by epinephrine were enhanced by CPZ. CPZ increased plasma glucose and cyclic AMP significantly at high room temperatures (28 and 33 degrees C) at which CPZ did not decrease body temperature. The mechanism of CPZ action is discussed in relation to the increase in the plasma glucose and cyclic AMP levels.

Adrenal Glands↗
PubMed1984

Stimulation of P1-purinoceptors by ATP depends partly on its conversion to AMP and adenosine and partly on direct action.

The effects of degradative enzymes and enzyme inhibitors were examined on the inhibitory actions of adenosine, AMP and ATP on atrial muscle and on the cholinergic responses of the ileum to transmural stimulation of the guinea-pig, in order to determine whether ATP responses are mediated by its breakdown products, AMP and adenosine. In both the atria and the ileum, adenosine deaminase reduced responses to ATP, although when combined with 5'-nucleotidase it had no further effect. In the atrium, the 5'-nucleotidase inhibitor, alpha,beta-methylene ADP (APCP), had no effect on its own, but prevented the potentiating effect of the adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) on responses to ATP. In the ileum, EHNA had no effect, but APCP potentiated responses to ATP. The enzyme 5'-AMP deaminase was shown to have a non-specific inhibitory effect on purine responses in both preparations. It is concluded for both preparations, that (1) the inhibitory responses to ATP are partly mediated by AMP and adenosine following the ectoenzymatic breakdown of ATP, and partly mediated by ATP itself, and (2) that AMP as well as adenosine can act directly on P1-purinoceptors. It is suggested that of the two breakdown products of ATP, AMP and adenosine, a larger proportion of the response is mediated by AMP in the ileum, whereas adenosine is the major mediator in the atrium.

5'-Nucleotidase↗
PubMed1987

Chronic infusion of agents that increase cyclic AMP concentration enhances the regeneration of mammalian peripheral nerves in vivo.

Our previous investigation indicates that forskolin, a robust activator of adenylate cyclase, promotes sensory nerve regeneration in amphibians. The present study was designed to determine if forskolin had a similar effect in mammals. We also wished to test the hypothesis that cyclic AMP modulates nerve regeneration by comparing the effects of chronically infused forskolin with the effects of infused dibutyryl cyclic AMP, 8-bromo cyclic AMP, and the phosphodiesterase inhibitor, theophylline. Our results indicated that all agents promoted some aspect of regeneration. The two which presumably generated the largest increase in cyclic AMP concentration, forskolin and 8-bromo cyclic AMP, had the most profound effect on axonal elongation. All agents decreased the time to sprout initiation, but theophylline produced the largest decrease and its effect was mimicked by caffeine, a methylxanthine with limited ability to inhibit phosphodiesterase. This suggests that sprout formation may be triggered by an increase in intraaxonal free Ca2+, possibly modulated by cyclic AMP. The role of cyclic AMP in axonal elongation remains to be determined, but may be associated with stimulation of protein synthesis in the nerve cell body.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1985

An activator of protein kinase C (phorbol-12-myristate-13-acetate) augments 2-chloroadenosine-elicited accumulation of cyclic AMP in guinea pig cerebral cortical particulate preparations.

Norepinephrine and histamine markedly augment accumulations of cyclic AMP elicited by 2-chloroadenosine in a guinea pig cerebral cortical vesicular preparation. In addition, these biogenic amines stimulate phosphatidylinositol turnover. Phosphatidylinositol turnover is associated with mobilization of internal calcium and with stimulation of protein kinase C. Phorbol-12-myristate-13-acetate (PMA), a known activator of protein kinase C, has no effect on cyclic AMP levels alone, but in a concentration-dependent manner enhances accumulations of cyclic AMP elicited by 2-chloroadenosine. PMA, like norepinephrine, also enhances accumulations of cyclic AMP elicited by histamine. PMA has no effect on the synergistic accumulations of cyclic AMP elicited by combinations of amines and 2-chloroadenosine. PMA also augments accumulations of cyclic AMP elicited by forskolin. The results suggest that activation of phosphatidylinositol turnover by biogenic amines may lead via stimulation of protein kinase C to enhanced responsiveness of cyclic AMP-generating systems.

2-Chloroadenosine↗
PubMed1983

Urinary cyclic AMP excretion in birds: dependence on parathyroid hormone activity.

The cyclic AMP response of avian kidney to parathyroid activity has been evaluated both in vitro and in vivo. The production of cyclic AMP by dispersed avian kidney cells was stimulated by bovine parathyroid hormone or by an extract of avian parathyroid glands. Intravenous infusion of bovine parathyroid hormone resulted in increased urinary excretion and plasma concentration of cyclic AMP, as well as increased plasma calcium and urinary phosphorus excretion. The increases in plasma and urinary cyclic AMP preceded those of plasma calcium and of phosphorus excretion. EDTA infusion resulted in a decrease in plasma calcium and an increase in urinary cyclic AMP excretion. After 10 days on a low-calcium diet, chickens exhibited a 4.5-fold increase in urinary cyclic AMP excretion. The results suggest that urinary cyclic AMP in chickens reflects PTH activity similar to some mammalian species.

Animals↗
PubMed1991

Differential effect of pertussis toxin on adenosine and muscarinic inhibition of cyclic AMP accumulation in canine ventricular myocytes.

Cyclic AMP regulation by muscarinic and adenosine receptors was investigated in isolated canine ventricular myocytes. Both the muscarinic receptor agonist, carbachol, and the adenosine receptor agonist, phenylisopropyladenosine, decreased isoproterenol-stimulated cyclic AMP accumulation in a concentration-dependent manner. Carbachol was more potent than phenylisopropyladenosine and had a greater inhibitory effect. At 10(-6) M, carbachol reduced isoproterenol-stimulated cyclic AMP by 73 +/- 5% while 10(-3) M phenylisopropyladenosine was required to decrease cyclic AMP accumulation by 54 +/- 8%. Pretreatment of myocytes with pertussis toxin to inactivate the inhibitory guanine nucleotide binding protein, Gi, completely abolished the effect of phenylisopropyladenosine to reduce cyclic AMP stimulation. In comparison, pertussis toxin treatment blunted the response to carbachol and shifted the dose-effect curve to the right but did not eliminate the inhibitory action of carbachol. In toxin-treated myocytes, 10(-3) M carbachol produced a 26 +/- 6% reduction of isoproterenol-induced cyclic AMP accumulation. This pertussis toxin-insensitive action of carbachol was antagonized by atropine and pirenzepine and was prevented when either of two different phosphodiesterase inhibitors. RO-20-1724 or isobutylmethylxanthine, was included in the incubation medium. The results indicate that adenosine receptor-mediated inhibition of hormone-stimulated cyclic AMP accumulation in ventricular myocytes occurs by a single, Gi-dependent mechanism while muscarinic inhibition appears to involve both Gi-dependent and Gi-independent mechanisms. The Gi-independent mechanism may reflect enhanced phosphodiesterase activity which results from the activation of muscarinic receptors.

Animals↗
PubMed1991

Cyclic AMP in myocytes isolated from hypertrophied rat hearts.

Impaired inotropic responsiveness to isoproterenol stimulation has been reported in the hypertrophied hearts of spontaneously hypertensive rats and renal hypertensive rats. This study was carried out in order to investigate the possibility that a defect in cyclic AMP production by cardiac myocytes is responsible for the impaired inotropic responsiveness of these hearts. Basal and isoproterenol stimulated cyclic AMP levels were measured in ventricular myocytes isolated from hypertrophied rat hearts. Cyclic AMP accumulation was also measured in the presence of isobutyl-methyl-xanthine, a phosphodiesterase inhibitor, and the results were compared to the appropriate controls. In the spontaneously hypertensive rat, no changes were detected in the basal or isoproterenol stimulated cyclic AMP formation. This suggests that the biochemical alterations leading to a diminished inotropic response in this model of cardiac hypertrophy involve abnormalities in mechanisms other than cyclic AMP production. In the renal hypertensive rat, basal and isoproterenol stimulated cyclic AMP levels were significantly depressed as compared to controls. This suggests that abnormalities in the signal transduction mechanism and formation of cyclic AMP are, at least in part, responsible for the impaired inotropic responsiveness seen in this model. These results confirm that cardiac hypertrophy is a heterogeneous process. Reduced inotropic responsiveness to isoproterenol stimulation in the hypertrophied hearts of the SHR and the RHR, both models of pressure overload hypertrophy, involve different biochemical alterations. Results of this study suggest that the physiologic response of cardiac hypertrophy may not be as important as the underlying cause of hypertrophic stimuli in determining the pathophysiological consequences.

Animals↗
PubMed1976

In vivo reversal of thyroxine induction of DNA synthesis by dibutyrly cyclic AMP in developing rat cerebellum.

Thyroxine, dibutyryl cyclic AMP, and a combination of both drugs were administered daily from birth to 2, 2 and 3 pups, respectively from each of 5 litters of Sprague-Dawley rats. Body weight, brain weight, cerebellar weight, and cerebellar DNA were measured in each animal at age 5 days and compared with values from a pair of controls from each litter. Cerebellar weight and DNA content were affected more severely than body weight in cyclic AMP-treated animals, with cerebellar DNA reduced significantly to 88% of control values. Cerebellar DNA was significantly elevated to 117% of control values in thyroxine-treated animals. This augmentation of cerebellar DNA synthesis by thyroxine was negated by administration of dibutyryl cyclic AMP 10 min prior to the thyroxine injection. These results support an hypothesis that the enhancement of cerebellar cell division by thyroxine involves an increase in the ratio of intracellular cyclic guanosine monophosphate to cyclic adenosine monophosphate. The reversal of the thyroxine-induced increase in cerebellar DNA synthesis by a prior injection of dibutyryl cyclic AMP suggests that the early stimulation of cell division by thyroxine may be mediated by cyclic AMP, and that the intracellular balance between cerebellar cyclic AMP and cyclic GMP was distorted by in vivo elevation of intracellular cyclic AMP levels.

Animals↗
PubMed1982

Isoproterenol-stimulated renin secretion in the rat: second messenger roles of Ca and cyclic AMP.

These experiments were designed to elucidate which of two second messengers (cyclic 3',5' adenosine monophosphate [c-AMP]; intracellular calcium [Cai]) was more closely related to the renin secretory process. The rat renal cortical slice preparation was used. Agents which previously were shown to inhibit basal renin secretion by increasing Cai (ouabain, vanadate, angiotensin II, antidiuretic hormone, and 60 mM K) antagonized and/or blocked isoproterenol-stimulated secretion, which is thought to be mediated by adenylate cyclase activation and increased levels of c-AMP. The stimulatory effect of dibutyryl c-AMP was antagonized and/or blocked by the same agents which antagonized and/or blocked isoproterenol-stimulated secretion. Thus, the inhibitory effects of these agents on isoproterenol-stimulated secretion cannot be explained by a Ca-induced decrease in c-AMP production. Secretory rate was stimulated by a potent phosphodiesterase inhibitor (3-isobutyl-1-methylxanthine). A combination of this and dibutyryl c-AMP produced even greater stimulation. Ouabain blocked the stimulatory effect of this combination. These results are not consistent with an invariant direct relationship between c-AMP and renin secretory rate, but are consistent with an inverse relationship between Ca; and renin secretion. Further, they are consistent with the hypothesis that in isoproterenol-stimulated renin secretion. c-AMP is the second and Cai the third or the final messenger.

1-Methyl-3-isobutylxanthine↗
PubMed1988

Phorbol esters modulate cyclic AMP accumulation in porcine thyroid cells.

In cultured porcine thyroid cells, during 60 min incubation phorbol 12-myristate 13-acetate (PMA) had no effect on basal cyclic AMP accumulation and slightly stimulated cyclic AMP accumulation evoked by thyroid stimulating hormone (TSH) or forskolin. Cholera toxin-induced cyclic AMP accumulation was significantly stimulated by PMA. On the other hand, cyclic AMP accumulation evoked by prostaglandin E1 or E2 (PGE1 or PGE2) was markedly depressed by simultaneous addition of PMA. These opposing effects of PMA on cyclic AMP accumulation evoked by PGE and cholera toxin were observed in a dose-related fashion, with half-maximal effect of around 10(-9) M in either case. The almost same effects of PMA on cyclic AMP accumulation in basal and stimulated conditions were also observed in freshly prepared thyroid cells. The present study was performed in the presence of phosphodiesterase inhibitor, 3-iso-butyl-1-methylxanthine (IBMX), indicating that PMA affected adenylate cyclase activity. Therefore, it is suggested that PMA may modulate the production of cyclic AMP in response to different stimuli, possibly by affecting several sites in the adenylate cyclase complex in thyroid cells.

1-Methyl-3-isobutylxanthine↗
PubMed1993

Relationship between cyclic-AMP content, regional myocardial function and O2 consumption in experimental left ventricular hypertrophy: effect of negative inotropes.

The aim of this study was to examine the hypothesis that negative inotropic agents that lower myocyte cyclic-AMP by different means would have similar effects on local myocardial segment work and O2 consumption in control hearts, but that this response would differ in left ventricular hypertrophy (LVH) induced by aortic valve stenosis. Open chest anesthesized LVH and control dogs were studied before and during esmolol (100 micrograms/kg/min) and acetylcholine (100 micrograms/kg/min) infusion. Regional work was calculated as the integrated product of instantaneous force (miniature transducer) and shortening (sonomicrometry) per min. Regional O2 consumption was calculated from blood flow (radioactive microspheres) and O2 saturation of small frozen vessels (microspectrophotometry). Cyclic-AMP level was determined with a competitive binding assay using 3H-cyclic-AMP and was found to be 731 +/- 90 (mean +/- S.D.) pmol/g in control and 711 +/- 163 in LVH. There were similar decreases in cyclic-AMP levels in control hearts with acetylcholine (365 +/- 135) and the beta adrenergic blocker (430 +/- 95). In LVH, esmolol lowered cyclic-AMP (383 +/- 39), but acetylcholine did not (689 +/- 105). In control animals, regional O2 consumption (7.7 +/- 0.6, 5.6 +/- 0.4 and 5.6 +/- 0.5 ml O2/min/100 g, control, acetylcholine, esmolol, respectively) and segment work (878 +/- 82, 546 +/- 80, 627 +/- 66 g*mm/min) fell to similar levels with these agents. Similar decreases were found in LVH with esmolol for O2 consumption (7.1 +/- 1.2, 5.1 +/- 1.0, baseline, esmolol) and segment work (895 +/- 140, 427 +/- 65). Acetylcholine had no significant effect on segment work (800 +/- 201), but did lower regional O2 consumption (4.0 +/- 0.7) in LVH dogs. It is concluded that there is a strong relationship between the level of cyclic-AMP and myocardial function and O2 consumption in control hearts. The action of acetylcholine is altered in LVH leading to an uncoupling between regional cyclic-AMP, function and metabolism.

Analysis of Variance↗