The response of cyclic 3′,5′-AMP and cyclic 3′,5′-GMP phosphodiesterases to experimental diabetes

Summary Alloxan diabetes caused a decrease in cyclic AMP phosphodiesterase in all affected rat tissues. Cyclic GMP phosphodiesterase activity was, however, decreased in adipose and liver, but increased in heart and uterus.This research was supported by U.S. Public Health Service grant RO1-AM19364-O1 and MARC training grant No. 1-TO2-GMO50000.     

Interconvertibility of molecular forms of 3'5' cyclic AMP phosphodiesterase of human platelets]

Three forms of cyclic AMP phosphodiesterase from human platelets are resolved upon sucrose gradient centrifugation : 2.5S (monomer), 4.8S (dimer) and 7S (tetramer). They are interconvertible and form an association-dissociation equilibrium depending on the concentration of enzyme. The dissociated form has a high Km for cyclic AMP (Km : 3-5.10(-4) M) whereas the associated form has a low Km (Km : 3-5.10(-5) M).     

Plasma cyclic 3',5'-guanosine monophosphate and cyclic 3',5'-adenosine monophosphate response to methacholine in man

Cholinergic agents are known to induce increases in tissue and plasma levels of cyclic GMP in experimental animals. We observed that i.m. injection of methacholine, a cholinergic agent, caused significant increases in plasma cyclic GMP and cyclic AMP in man.     

Effects of morphine administration on cerebellar guanosine 3',5'-monophosphate.

An increase in mouse cerebellar C-GMP levels during acute morphine treatment was observed, which was possibly related to the decrease in C-GMP phosphodiesterase levels also observed in acute treatment. Chronic treatment lowered C-GMP levels as did abrupt withdrawal without naloxone.     

Effects of several preoperative medications on fat cell lipolysis, and activity of adipose tissue cyclic AMP phosphodiesterase.

Effects were examined of atropine, diazepam, pethidene, promethazine, scopolamine, omnopon and papaverine on basal and noradrenaline-stimulated lipolysis in rat isolated fat cells and on rat adipose tissue cyclic AMP phosphodiesterase activity. Papaverine at high concentration (1 mM) inhibited both basal and hormone-stimulated lipolysis, whereas diazepam enhanced basal lipolysis. At a 'clinical dose', omnopon increased both basal and noradrenaline-stimulated lipolysis. Adipose tissue cAMP phosphodiesterase activity was strongly inhibited by 1 mM diazepam, papaverine, promethazine and omnopon (280 microgram ml-1). Lack of enhancement of lipolysis by the established cAMP phosphodiesterase antagonist papaverine, is compatible with simultaneous inhibition also of adipose adenyl cyclase. Diazepam-stimulated lipolysis is compatible with its phosphodiesterase inhibitory activity. It is proposed that papaverine-containing omnopon may offer some survival advantages during surgical stress by facilitating a caloric supply.     

Effect of AD6 (8-monochloro-3-beta-diethylamino-ethyl-4-methyl-7-ethoxycarbonylmethoxy coumarin) on cyclic nucleotide phosphodiesterases in human platelets

Summary The effect of AD6 (8-monochloro-3-beta-diethylamino-ethyl-4-methyl-7-ethoxycarbonylmethoxy coumarin), an inhibitor of platelet aggregation, on cyclic nucleotide metabolism was investigated. AD6 inhibited selectively human platelet cyclic GMP phosphodiesterase, which was separated from cyclic AMP phosphodiesterase by DEAE-cellulose chromatography. Addition of AD6 to washed platelets increased cyclic GMP levels significantly in two minutes. These results could be useful in elucidating the action of AD6 on intact platelets.     

The reversal of glucose repressed prodigiosin production inSerratia marcescens by the cyclic 3′5′-adenosine monophosphate inhibitor theophylline

Summary Glucose was found to cause severe repression of prodigiosin production inSerratia marcescens and a dose related partial reversal was demonstrated by theophylline. It is suggested that this reversal is due to the inhibition of cAMP phosphodiesterase and the concomitant increase in cellular cAMP concentration.     

Effect of AD6 (8-monochloro-3-beta-diethylamino-ethyl-4-methyl-7-ethoxycarbonylme tho xy coumarin) on cyclic nucleotide phosphodiesterases in human platelets

The effect of AD6 (8-monochloro-3-beta-diethylamino-ethyl-4-methyl-7-ethoxycarbonylmeth oxy coumarin), an inhibitor of platelet aggregation, on cyclic nucleotide metabolism was investigated. AD6 inhibited selectively human platelet cyclic GMP phosphodiesterase, which was separated from cyclic AMP phosphodiesterase by DEAE-cellulose chromatography. Addition of AD6 to washed platelets increased cyclic GMP levels significantly in two minutes. These results could be useful in elucidating the action of AD6 on intact platelets.     

Regional and strain variation in brain 3':5' cyclic adenosine monophosphate of inbred mice.

Regional variations were found in cAMP levels in flash frozen mouse brains with the pons and cerebellum having higher levels than the cerebrum. There were also strain variations with CBA/J and BALB/cJ having higher levels than C57B1/6J in the pons and cerebellum.     

Correlation between 3',5', c-AMP levels and thyrotropin in separated rat pituitary thyrotropic cells.

The correlation between 3',5', c-AMP levels, TSH content and secretion of separated thyrotropic cells was studied. Incubation of the separated cells with 1, 10 and 100 ng of TRH does not change the 3',5',c-AMP levels, despite the significant rises of the TSH level. Dibutyryl c-AMP causes rise in TSH content, with no indication of its secretion. PGE2 10(-5) increased 3'5',c-AMP levels with no change in the content or secretion of TSH in separated thyrotropic cells.     

Effects of several preoperative medications on fat cell lipolysis,and activity of adipose tissue cyclic AMP phosphodiesterase

Summary Effects were examined of atropine, diazepam, pethidene, promethazine, scopolamine, omnopon and papaverine on basal and noradrenaline-stimulated lipolysis in rat isolated fat cells and on rat adipose tissue cyclic AMP phosphodiesterase activity. Papaverine at high concentration (1 mM) inhibited both basal and hormone-stimulated lipolysis, whereas diazepam enhanced basal lipolysis. At a clinical dose, omnopon increased both basal and noradrenaline-stimulated lipolysis. Adipose tissue cAMP phosphodiesterase activity was strongly inhibited by 1 mM diazepam, papaverine, promethazine and omnopon (280 g ml^–1). Lack of enhancement of lipolysis by the established cAMP phosphodiesterase antagonist papaverine, is compartible with simultaneous inhibition also of adipose adenyl cyclase. Diazepam-stimulated lipolysis is compatible with its phosphodiesterase inhibitory activity. It is proposed that papaverine-containing omnopon may offer some survival advantages during surgical stress by facilitating a caloric supply.The authours are grateful to Dr D. C. Williams for his continued support and encouragement.     

Fetal calf serum alters cyclic adenosine 3',5'-monophosphate's effect on heme synthesis in vitro.

An investigation of the effect of cAMP on heme synthesis of rat bone marrow cells revealed that at 10(-2) M this cyclic nucleotide inhibits heme synthesis and that optimum stimulation occurs at 10(-4) M. Some unidentified constituent of fetal calf serum in the culture medium modifies the direction and degree of cAMP's effect.     

The brachymorphic mutation of mice and altered developmental patterns of limb bud 3':5' cyclic adenosine monophosphate

Concentrations of cyclic AMP (cAMP) were determined in paired fore and hind limbs from day 12-16 of development in murine fetuses homozygous for the brachymorphic (bm) mutation and normal controls. A developmental rise in cAMP occurred 1 day earlier in bm/bm than in +/+ hind limbs and cAMP was higher in day-13 bm/bm than in +/+ fore limbs. Since cAMP is well documented to stimulate chondrogenic differentiation, premature cartilage determination secondary to altered levels of cAMP could play a role in bm/bm short-limbed dwarfism.     

Free and sulfoconjugated dehydroepiandrosterone, cyclic adenosime-3',5'-monophosphate, and free estriol in maternal and cord blood.

When free DHEA, its sulfatide, and sulfate were assayed in maternal plasma as well as in umbilical cord arterial and venous plasma, rather high concentrations were found in either fraction from cord arterial plasma, reflecting the fetal contribution not only of free DHEA and DHEA sulfate, but also of the lipophile steroid sulfatide. Since high DHEA levels were associated with elevated c-AMP concentrations, a certain interrelationship of both parameters is indicated. In the course of delivery, a rapid decrease of free estriol in maternal plasma was observed. Higher concentration of free estriol in umbilical venous plasma pointed at its placental biosynthesis from fetal precursors.