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PubMed1993

Alterations in [3H]MK-801, [3H]muscimol, [3H]cyclic AMP, and [3H]rolipram binding in the gerbil hippocampus following repeated ischemic insults.

Using [3H]MK-801, [3H]muscimol, [3H]cyclic AMP, and [3H]rolipram, we performed quantitative in vitro autoradiography to determine sequential alterations in the binding of N-methyl-D-aspartate and GABAA receptors, particulate cyclic AMP-dependent protein kinase, and cyclic AMP-selective phosphodiesterase, respectively, in the gerbil hippocampus following repeated brief ischemic insults. Changes from 1 h to 28 days after three 2-min ischemic insults at 1-h intervals were compared with those after 2 and 6 min of ischemia. We observed no alterations in the binding of all the four ligands throughout the observation period following 2 min of ischemia which produced no histological neuronal damage except for transient reductions in [3H]cyclic AMP binding during the early reperfusion period. [3H]Cyclic AMP binding in the CA1 subfield decreased one day after 6 min of ischemia and four days after three 2-min ischemic insults, and 62-65% of the binding was lost after 28 days. [3H]Rolipram binding in the CA1 subfield decreased one day after 6 min of ischemia and the binding was reduced by 45-50% after four and 28 days. Following three 2-min ischemic insults, [3H]rolipram binding decreased in the CA1 at one day, and decreased by 25-33% after 28 days. Both [3H]MK-801 and [3H]muscimol binding was preserved during the early reperfusion period after 6 min of ischemia and three 2-min ischemic insults. Reductions in [3H]MK-801 binding in CA1 were observed four days after ischemic insults when CA1 neuronal destruction was seen. After one month, approximately 50% of [3H]MK-801 binding was lost in CA1 in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2006

Lack of cyclic AMP-specific phosphodiesterase 4 activation during naloxone-precipitated morphine withdrawal in rats.

Intracellular cyclic AMP regulation systems play an important role in the mechanisms of morphine dependence and withdrawal. In the present study, to clarify the involvement of phosphodiesterase (PDE) 4, degradation enzyme of cyclic AMP in morphine dependence and withdrawal we investigated the activities of PDE4 after naloxone-precipitation in single morphine treatment and repeated morphine treatment (morphine-dependence) rats. Naloxone (5 mg/kg, s.c.) challenge caused a significant withdrawal signs such as jumping in morphine-dependent rats following repeated treatment with morphine (4, 8, 12, and 16 mg/kg, twice a day for 4 days), but not in single morphine-treated rats (16 mg/kg, single). Naloxone challenge caused an increase in PDE4 activities in the brain of rats treated with single morphine in connection with the elevation of brain cyclic AMP. In contrast, increase in the PDE4 activities was not caused by naloxone challenge in all brain regions of morphine-dependent rats, although brain cyclic AMP was significantly increased. These results suggest that the lack of PDE4 activation leading to remarkable elevation of cyclic AMP is involved in naloxone-precipitated morphine withdrawal symptoms.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2001

Diazepam and rolipram differentially inhibit cyclic AMP-specific phosphodiesterases PDE4A1 and PDE4B3 in the mouse.

Cyclic AMP is hydrolyzed by members of at least eight classes of cyclic nucleotide phosphodiesterases (PDEs). Although it has been reported that cyclic AMP PDE activity in mammalian tissues can be inhibited by benzodiazepines, it has not been conclusively demonstrated that members of the class of cyclic AMP-specific, rolipram-inhibitable PDEs (PDE4s) are targets for these drugs. Moreover, no PDE4s expressed in mice have been characterized. To address these issues, we isolated two cDNAs representing homologues of PDE4A1 and PDE4B3 from a mouse brain library. After transient transfection in human embryonic kidney (HEK) 293 cells, the mouse PDEs hydrolyzed cyclic AMP with a low K(m) and were inhibited by rolipram; both are properties typical of other mammalian PDE4 enzymes. In addition, we found that diazepam inhibited cyclic AMP hydrolysis by the mouse PDE4 subtypes. Interestingly, PDE4B was significantly more sensitive to inhibition by both rolipram and diazepam than the PDE4A subtype. This is the first demonstration that recombinantly expressed PDE4s are inhibited by diazepam, and should facilitate future studies with mouse models of depression and anxiety.

1-Methyl-3-isobutylxanthine↗
PubMed1998

Release of lipoprotein lipase from Ehrlich ascites tumor produced by an association with a rapid increase in cyclic AMP content.

Although it is considered that the lipoprotein metabolism in tumor plays an important role in growth and multiplication, it is not clear as to the details. Lipoprotein lipase (LPL) is a key enzyme responsible for the hydrolysis of lipoprotein-triacylglyceride. In this study, we examined the regulatory step of LPL in lipoprotein metabolism of Ehrlich ascites tumor and especially the enzyme-release from the tumor cells. When LPL was stimulated to release from the tumor cells by the low molecular weight dextran sulfate (3.2 kDa), cyclic AMP content in the tumor cells was observed to increase rapidly in a time-dependent manner up to 30 s; its maximal effect was 1.5-fold higher than the basal level of cyclic AMP. The increase in cyclic AMP content was more enhanced in the presence of isobutylmethylxanthine and was never suppressed by propranolol. Moreover, cyclic AMP-dependent protein kinase (PKA) activity in the tumor cells was also recognized to elevate in a time- and dose-dependent manner. In addition, the release of LPL activity from the tumor cells was inhibited by 2',5'-dideoxyadenosine. These results suggest that LPL in the tumor cells is released through a pathway involving an activation of PKA associated with the rapid increase in cyclic AMP content.

1-Methyl-3-isobutylxanthine↗
PubMed1997

Induction of cyclic AMP and cyclic GMP 3':5'-cyclic nucleotide phosphodiesterase activities in neuroblastoma lines under differentiating conditions.

It is now widely accepted that cyclic nucleotide phosphodiesterases (PDEs) play fundamental roles in signal transduction pathways; they show a remarkable molecular complexity, different tissue distribution and complex regulatory mechanisms. Here we report PDE isoforms expression in two dibutyryl cyclic AMP differentiated murine cell lines: the hybrid neuroblastoma-glioma 108CC15 and the parental neuroblastoma N18TG2. They differ in the ability to establish functional synapses, a feature present only in the former. Ionic exchange chromatography elution profiles of N18TG2 and 108CC15 undifferentiated cell extracts show two main peaks of activity. The first one hydrolyzes cyclic GMP and is specifically inhibited by Zaprinast, thus representing a member of the PDE5 family. The second peak hydrolyzes cyclic AMP and is significantly inhibited by rolipram, as all the PDE4 family members. The induction of differentiation by dibutyryl cyclic AMP in both clonal lines results in an increase of PDE activities only after 3 hr of treatment, suggesting that protein neosynthesis is involved. Interestingly in both clones, besides the increase in cyclic AMP hydrolyzing specific activity (3.1-fold in 108CC15 and 2.5-fold in N18TG2), we also observed an increase in cyclic GMP hydrolyzing activity (1.7-fold in 108CC15 and 4.3-fold in N18TG2). While the induction of PDE4, previously reported also in other cellular systems, could be considered as a feedback response to the higher cyclic AMP levels, this is not true for the isoform that hydrolyzes cyclic GMP. These data suggest that the induction of PDE isoforms in neuroblastoma cells could be related to the activation of neuronal differentiative pathway.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2006

Phosphodiesterase PDE3 blunts the positive inotropic and cyclic AMP enhancing effects of CGP12177 but not of noradrenaline in rat ventricle.

1.--The cardiostimulant effects of CGP12177, mediated through a beta(1)-adrenoceptor site with low affinity for (-)-propranolol, are potentiated by the nonselective PDE inhibitor IBMX but the role of PDE isoenzymes is unknown. We studied the effects of the PDE3-selective inhibitor cilostamide (300 nM) and PDE4-selective inhibitor rolipram (1 microM) on the positive inotropic and cyclic AMP-enhancing effects of CGP12177 and noradrenaline in right ventricular strips of rat. 2.--CGP12177 (under (-)-propranolol 200 nM) only increased contractile force in the presence of either cilostamide or rolipram with -logEC(50)M 6.7 (E(max)=23% over basal) and 7.1 (E(max)=50%) respectively. The combination of cilostamide and rolipram caused CGP12177 to enhance contractile force with -logEC(50)M=7.7 and E(max)=178%. 3.--The positive inotropic effects of noradrenaline (-logEC(50)M=6.9) were potentiated by rolipram (-logEC(50)M=7.4) but not by cilostamide (-logEC(50)M=7.0). 4.--In the presence of rolipram and (-)-propranolol, noradrenaline (2 microM) and CGP12177 (10 microM) produced matching inotropic effects but failed to increase cyclic AMP levels. 20 microM (-)-noradrenaline increased cyclic AMP levels, a response further enhanced by rolipram. 5.--Both PDE3 and PDE4 of rat ventricle appear to hydrolyse cyclic AMP generated through the low-affinity beta(1)-adrenoceptor site, thereby preventing inotropic responses of CGP12177. When (-)-noradrenaline interacts with the beta(1)-adrenoceptor, the generated cyclic AMP is hydrolysed only by PDE4, thereby reducing cardiostimulation.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1994

Inhibition of dopamine agonist-induced phosphoinositide hydrolysis by concomitant stimulation of cyclic AMP formation in brain slices.

We examined the effects of cyclic AMP on dopamine receptor-coupled activation of phosphoinositide hydrolysis in rat striatal slices. Forskolin, dibutyryl cyclic AMP, and the protein kinase A activator Sp-cyclic adenosine monophosphothioate (Sp-cAMPS) significantly inhibited inositol phosphate formation stimulated by the dopamine D1 receptor agonist SKF 38393. Conversely, the protein kinase A antagonist Rp-cyclic adenosine monophosphothioate (Rp-cAMPS) dose-dependently potentiated the SKF 38393 effect. In the presence of 200 microM Rp-cAMPS, the dose-response curves of the dopamine D1 receptor agonists SKF 38393 and fenoldopam were shifted to the left and maximal agonist responses were markedly increased. The agonist EC50 values, however, were not significantly altered by protein kinase A inhibition. Neither Sp-cAMPS nor Rp-cAMPS significantly affected basal inositol phosphate accumulation. These findings demonstrate that dopaminergic stimulation of phosphoinositide hydrolysis is inhibited by elevations in intracellular cyclic AMP. Dopamine receptor agonists that stimulate adenylyl cyclase could suppress their activation of phosphoinositide hydrolysis by concomitantly stimulating the formation of cyclic AMP in striatal tissue. The interaction between dopamine D1 receptor-stimulated elevations in cyclic AMP and dopaminergic stimulation of inositol phosphate formation suggests a cellular colocalization of these dopamine-coupled transduction pathways in at least some cells of the rat striatum.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1980

Modulation of cyclic AMP metabolism by S-adenosylhomocysteine and S-3-deazaadenosylhomocysteine in mouse lymphocytes.

Mouse lymphocytes incubated with micromolar concentrations of adenosine or 3-deazaadenosine, in medium supplemented with L-homocysteine, rapidly accumulated supramillimolar concentrations of S-adenosylhomocysteine (AdoHcy) or S-3-deazaadenosylhomocysteine (c3AdoHcy), respectively. Lymphocytes thus preloaded with high levels of AdoHcy or c3AdoHcy exhibited markedly enhanced (5- to 40-fold) cyclic AMP responses to prostaglandin E1, adenosine, 2-chloroadenosine, isoproterenol, and cholera toxin. This enhancement of cyclic AMP response by intracellular AdoHcy or c3AdoHcy was attributable both to amplification of the activity of adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] and to inhibition of cyclic AMP phosphodiesterase (3',5'-cyclic-nucleotide 5'-nucleotidohydrolase, EC 3.1.4.17). Basal and prostaglandin E1- and isoproterenol-stimulated activities of adenylate cyclase, assayed in lymphocyte homogenates, were increased 1.3- to 2.0-fold after treatment of the cells with homocysteine plus either adenosine or 3-deazaadenosine. AdoHcy and c3AdoHcy were found to be competitive inhibitors (with Ki values of 1.7 and 4.8 mM, respectively) of the high-affinity cyclic AMP phosphodiesterase present in lymphocyte homogenates. It is evident, therefore, that increased cellular levels of AdoHcy or c3AdoHcy can affect cellular physiology via perturbation of cyclic AMP metabolism as well as via inhibition of S-adenosylmethionine-dependent methylation reactions.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1995

Adenosine receptor-induced cyclic AMP generation and inhibition of 5-hydroxytryptamine release in human platelets.

1. We have assessed the effects of adenosine receptor agonists and antagonists on collagen-induced 5-hydroxytryptamine (5-HT) release and cyclic AMP generation in human platelets. 2. 5'-N-ethylcarboxamidoadenosine (NECA) and CGS 21680 elicited accumulations of cyclic AMP with mean EC50 values of 2678 and 980 nM, respectively. The maximal response to CGS 21680 was approximately half that of the response to 10 microM NECA. 3. NECA and CGS 21680 inhibited collagen-induced 5-hydroxytryptamine release with mean EC50 values of 960 and 210 nM, respectively. The maximal response to CGS 21680 was approximately 25% of the response to 10 microM NECA. 4. The A1/A2a-selective adenosine receptor antagonist PD 115,199 was more potent as an inhibitor of NECA-elicited responses than the A1-selective antagonist DPCPX with calculated Ki values of 22-32 nM and > 10 microM, respectively. 5. In the presence of a cyclic AMP phosphodiesterase inhibitor, the effects of CGS 21680 on cyclic AMP accumulation and 5-HT release were enhanced to levels similar to those elicited by 10 microM NECA. In the absence of phosphodiesterase inhibition, CGS 21680 did not antagonise the effects of NECA. Furthermore, endogenous adenosine did not contribute to the effects of CGS 21680 when phosphodiesterase was inhibited. 6. We conclude that an A2a adenosine receptor appears to be involved in the NECA-elicited increases in cyclic AMP levels and inhibition of 5-HT release in human platelets.(ABSTRACT TRUNCATED AT 250 WORDS)

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1978

Modulation of adenylate cyclase/cyclic AMP response by thyrotropin and prostaglandin E2 in cultured thyroid cells. 1. Negative regulation.

Isolated porcine thyroid cells, cultured in the presence of thyrotropin (greater than or equal to 0.25 mU/ml) or prostaglandin E2 (greater than or equal to 0.1 micron), showed decreased adenosine 3':5'-monophosphate (cyclic AMP) response to further thyrotropin or prostaglandin E2 stimulation, respectively. Kinetics of the refractory process to thyrotropin and prostaglandin E2 are different: (a) maximal refractoriness to prostaglandin E2 was attained after 2--6 h exposure to prostaglandin E2 while refractoriness to thyrotropin was maximal only after 12--24 h; (b) the degree of refractoriness to prostaglandin E2 was much greater than that to thyrotropin. Refractoriness to thyrotropin or prostaglandin E2 is characterized: by specificity for each thyroid stimulator; by dependence upon the dose of thyrotropin or prostaglandin E2 in culture, e.g. induction of high degree of refractoriness with 0.5 mU/ml thyrotropin (or 1 micron prostaglandin E2), which elicits only a small cyclic AMP increase; by time requirement for induction; by partial effect; by changes of maximum activation of cyclic AMP response; by reversibility. This refractoriness of the cyclic AMP response was not induced by dibutyryl adenosine 3':5'-monophosphate. It was not attributed to increased cyclic AMP-phosphodiesterase activity, but to alterations in the receptor-adenylate cyclase system. Prevention of refractoriness to thyrotropin or prostaglandin E2 by incubation of cells in the presence of actinomycin D, puromycin and cycloheximide suggests that new RNA and protein syntheses are required for the development of the refractory state.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1980

Effect of the antitumour agent 5-(3,3-dimethyl-1-triazeno imidazole-4-carboxamide (DTIC) on cyclic AMP levels in intact MH1C1 hepatoma cells.

Addition of the cytostatic agent 5-(3,3-dimethyl-1-triazeno)-imidazole-carboxamide (DTIC, dacarbazin) to MH1C1 hepatoma cells, alone or in combination with adrenaline, was shown to elevate intracellular cyclic AMP. The cyclic AMP level was increased from basal values of about 0.40 to about 0.75 pmol/mg protein 10 min. after DTIC addition. Accumulation of cyclic AMP in response to a supramaximal concentration of adrenaline is amplified in a dose-dependent way by 0.1-2 mM DTIC. The effect is apparently due to inhibition of cyclic AMP breakdown, since DTIC inhibits the low-Km form of the cyclic AMP phosphodiesterase without significantly affecting the adenylate cyclase activity of MH1C1 homogenates.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1987

Effects of calmodulin antagonists on hormone release and cyclic AMP levels in GH3 pituitary cells.

In GH3 cells the calmodulin antagonists trifluoperazine and N-(6-aminohexyl)-5-chloro-1-napthalene sulphonamide hydrochloride (W-7) showed a dose-dependent, biphasic effect on the release of growth hormone (GH) and prolactin (PRL). Hormone release was inhibited with 15-30 microM trifluoperazine and with 30-80 microM W-7, while stimulation was observed with 50-100 microM trifluoperazine and with 150 microM W-7. Trifluoperazine (greater than or equal to 30 microM) and W-7 (greater than or equal to 80 microM) increased the concentration of cellular cyclic AMP. Sulphoxides of trifluoperazine and chlorpromazine (less than or equal to 150 microM were without effect on hormone release and cellular cyclic AMP. Hydrolysis of cyclic AMP by GH3 cytosol was reduced after incubation of intact GH3 cells with trifluoperazine (15-60 microM). When trifluoperazine was incubated with cytosol, both the high and low affinity forms of cyclic AMP phosphodiesterase were inhibited competitively with calculated Ki of 4.5 and 56 microM, respectively. Stimulation of cyclic AMP phosphodiesterase caused by endogenous calmodulin was blocked by trifluoperazine. Particulate bound adenylyl cyclase activity was inhibited by trifluoperazine, and this effect was counteracted by endogenous calmodulin.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2002

The role of cyclic AMP and its effect on protein kinase A in the mitogenic action of thyrotropin on the thyroid cell.

Cyclic AMP has been shown to inhibit cell proliferation in many cell types and to activate it in some. The latter has been recognized only lately, thanks in large part to studies on the regulation of thyroid cell proliferation in dog thyroid cells. The steps that led to this conclusion are outlined. Thyrotropin activates cyclic accumulation in thyroid cells of all the studied species and also phospholipase C in human cells. It activates directly cell proliferation in rat cell lines, dog, and human thyroid cells but not in bovine or pig cells. The action of cyclic AMP is responsible for the proliferative effect of TSH. It accounts for several human diseases: congenital hyperthyroidism, autonomous adenomas, and Graves' disease; and, by default, for hypothyroidism by TSH receptor defect. Cyclic AMP proliferative action requires the activation of protein kinase A, but this effect is not sufficient to explain it. Cyclic AMP action also requires the permissive effect of IGF-1 or insulin through their receptors, mostly as a consequence of PI3 kinase activation. The mechanism of these effects at the level of cyclin and cyclin-dependent protein kinases involves an induction of cyclin D3 by IGF-1 and the cyclic AMP-elicited generation and activation of the cyclin D3-CDK4 complex.

Animals↗
PubMed1975

Cyclic AMP-dependent protein kinase: pivotal role in regulation of enzyme induction and growth.

Dibutyryl cyclic adenosine 3',5'-monophosphate (cyclic AMP) produces phosphodiesterase induction, growth arrest, and cytolysis in S49 lymphoma cells. The striking parallelism between protein kinase activity that is dependent on cytosol cyclic AMP and cellular responses to dibutyryl cyclic AMP in wild-type cells and three classes of clones resistant to cyclic AMP indicates that protein kinase mediates cyclic AMP regulation of growth and enzyme induction in S49 cells.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1987

Generation of deletions in the 3'-flanking sequences of the Escherichia coli crp gene that induce cyclic AMP suppressor functions.

The crp structural gene and its 3'-flanking sequences were subcloned into M13mp8, and in vitro deletions were constructed in both the 5' and 3' ends of the gene by using Bal 31 nuclease. Deletions ranged in size from 24 to 250 base pairs at the 5' end of crp. Sixteen deletions generated at the 3' end of the gene ranged in size from 133 to 675 base pairs. The majority of deletions extended into the crp structural gene. Another class of deletions, i.e., delta crp-4, delta crp-17, and delta crp-2, had endpoints extending in the 3'-flanking sequences external to the crp structural gene. Deletions were subcloned into pBR322 and transformed into the Escherichia coli cya crp deletion strain NCR438. Transformants containing plasmid pBM4 with the delta crp4 mutation, a deletion of 133 base pairs, were cyclic AMP independent. Strain NCR440 harboring this plasmid expressed beta-galactosidase and threonine dehydratase activities and fermented lactose, ribose, arabinose, and xylose in the absence of exogenous cyclic AMP. The delta crp-4 mutation also caused strain NCR440 to be hypersensitive to exogenous cyclic AMP. The cylic AMP receptor protein expressed in maxicells from pBM4 carrying the delta crp-4 mutation comigrated with the wild-type protein on electrophoretic gels. The delta crp-4 mutation demonstrates that sequences distal to the crp structural gene can mediate cyclic AMP suppressor functions.

Bacterial Proteins↗
PubMed1999

AMP deaminase in piglet cardiac myocytes: effect on nucleotide metabolism during ischemia.

The purpose of this study was to examine in situ regulation of AMP deaminase in newborn piglet cardiac myocytes and to determine its role in nucleotide metabolism during ischemia. When a rapid deenergization paradigm was used to assay AMP deaminase, enzyme activity depended on the hormonal and metabolic status of cells just before deenergization. Inosine 5'-monophosphate (IMP) formation was increased 150% in deenergized myocytes pretreated with phorbol 12-myristate 13-acetate (PMA; EC50 = 4.7 x 10(-8) M). This effect was 90% blocked with the protein kinase C (PKC) inhibitor staurosporine. In addition, the beta-adrenergic agonist isoproterenol stimulated AMP deaminase activity (EC50 = 1.5 x 10(-8) M), and IMP formation was directly correlated to intracellular cAMP levels (r2 = 0.9). Furthermore, adenosine increased IMP formation, whereas nonrespiring, glycolyzing piglet myocytes had reduced AMP deaminase activity. Pretreatment of perfused piglet hearts with adenosine, but not PMA, before exposure to global ischemia resulted in enhanced conversion of AMP to IMP during the ischemic period. Similar results were obtained in piglet myocytes preincubated with adenosine or PMA before exposure to simulated ischemia. These results may be relevant to the preconditioning phenomenon.

1-Methyl-3-isobutylxanthine↗
PubMed1980

The tissue content of cyclic AMP in rats after microwave irradiation in vivo.

When anesthetized rats were exposed to microwave (power output 1.3 kw, frequency 2,450 MHz), the cyclic AMP phosphodiesterase activity showed a rapid decline in the skeletal muscle, heart, trachea and lung; no activity essentially could be detected after a 30 sec irradiation. Cyclic AMP levels in these tissues also decreased rapidly to constant values within 30 sec. Concentrations of cyclic AMP in the heart, skeletal muscle, trachea and lung measured by the tissue fixation with liquid nitrogen were approximately 3, 3, 4 and 4 times higher than those after microwave irradiation, respectively. The intravenous injection of procaterol (1 mu mol/kg), a beta 2-adrenoceptor agonist, caused a 6-fold increase in the trachea cyclic AMP level when measured after microwave fixation but only a 2-fold increase when measured after liquid nitrogen fixation. It is concluded that rapid tissue fixation by microwave irradiation may provide a useful means for obtaining reliable values of the tissue cyclic AMP content.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2000

Prostacyclin-induced relaxations of small porcine pulmonary arteries are enhanced by the basal release of endothelium-derived nitric oxide through an effect on cyclic GMP-inhibited-cyclic AMP phosphodiesterase.

AIM: To study the interactions between prostacyclin and endothelium-derived nitric oxide in porcine pulmonary arteries. METHODS: Rings of 5th order of porcine pulmonary arteries were studied in vitro for the measurement of tension and the content in cyclic nucleotides. RESULTS: Prostacyclin, given exogenously, caused endothelium-potentiated relaxations (inhibition of phenylephrine contraction) that were inhibited by the inhibitors of the L-arginine nitric oxide pathway, oxyhemoglobin and N omega-nitro-L-arginine. These inhibitors did not affect the tension in rings without endothelium. Cyclic GMP-concentrations were not increased above basal concentrations in the presence of prostacyclin. Increases were seen with acetylcholine and sodium nitroprusside. Prostacyclin-stimulated cyclic AMP concentrations did not reach statistical significance compared to controls. The addition of 8-bromo-cyclic GMP to prostacyclin, however, increased the cyclic AMP content. The nitric oxide synthase inhibitor, nitro-L-arginine (NLA), reduced the prostacyclin-stimulated cyclic AMP content to basal level. Inhibition of cyclic GMP-inhibited cyclic AMP phosphodiesterase by 8-bromo-cyclic GMP or amrinone (a specific inhibitor of this enzyme) potentiated the prostacyclin-induced relaxations in rings without endothelium to a magnitude similar to that observed in rings with endothelium. CONCLUSION: These data suggest that the augmentation by the endothelium of the prostacyclin-induced relaxation of porcine pulmonary arteries is secondary to the inhibition of cyclic GMP-inhibited cyclic AMP phosphodiesterase by basally released endothelium-derived nitric oxide.

3',5'-Cyclic-AMP Phosphodiesterases↗