Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thyroid hormones regulate lipid metabolism by affecting lipogenesis as well as lipolysis. The present paper discusses the way thyroidectomy induced an enhancement in lipogenesis in rat fat cells. The doubling in the conversion of glucose to CO2 and fatty acids seen after thyroidectomy was found to be due to a modification in the actual pathway of glucose metabolism: there was a preferential stimulation of the conversion of glucose to CO2 by the pentose cycle (utilisation of [1-14C]glucose) while the production of fatty acids and glyceride-glycerol proceeded, respectively, much more, or only slightly more, via the pathway of [6-14C]glucose metabolism. Studies employing the phosphodiesterase inhibitor MIX, or the cyclic AMP analogue, DBcAMP showed that the lipogenic process depends on cyclic AMP. As the stimulatory effect of thyroidectomy was not abolished, however, lipogenesis must be under the independent control of both cyclic AMP and absence of thyroid hormones. Insulin, a further mediator of lipogenesis was found to further enhance the already preexisting high conversion of glucose to CO2 in fat cells from thyroidectomized rats. It is concluded that at least three factors modify lipogenesis: thyroidectomy, cyclic AMP and insulin; each achieving its effect in an independent manner.
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PMID:Cyclic AMP and lipogenesis in fat cells from thyroidectomized rats. 8 52

The effects of various adenosine phosphate compounds, theophylline, histamine,a nd metiamide, on steady rates of acid secretion by isolated fundic mucosa of the rabbit were measured by the pH stat method. Cyclic adenosine 3':5'-monophosphate (cyclic AMP), N(6), O(2')-dibutyryl adenosine 3':5'-monophosphate and theophylline increased the rate of acid secretion. Addition of theophylline in a concentration which has no stimulatory effect, reduces the effective concentrations cyclic AMP or histamine required for stimulation of acid secretion. Measurements of lactate, pyruvate, and CO2 appearances indicated that the increases in acid secretory rates were predominantly due to H+ and not organic acid accumulation in the luminal bath-secretion. Metiamide prevented the stimulatory effects of histamine and ATP. However, metiamide did not prevent the stimulatory effects of N(6),9(2')-dibutyryl adenosine 3':5'-monophosphate, theophylline, or 5'-AMP. The results provide further evidence for a role of cyclic AMP in governing the rate of acid secretion by rabbit stomach. The data also are consistent with histamine and ATP (at least in the concentration used) requiring adenylate cyclase activity for stimulation of acid secretion and 5'-AMP inhibiting phosphodiesterase activity.
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PMID:Effects of cyclic adenosine 3':5'-monophosphate and related agents on acid secretion by isolated rabbit gastric mucosa. 16 24

HN-10200, a nonselective inhibitor of phosphodiesterase, has positive inotropic and vasodilator activity. The present study was designed to determine the role of endothelium in causing relaxation to HN-10200 in isolated canine femoral and basilar arteries. Rings with and without endothelium were suspended for isometric tension recording in Krebs-Ringer bicarbonate solution bubbled with 94% O2, 6% CO2 (t = 37 degrees C; pH = 7.4). HN-10200 and another nonselective phosphodiesterase inhibitor, 3-isobutyl-1-methyl-xanthine (IBMX), caused similar concentration-dependent relaxations in femoral arteries with and without endothelium. In femoral arteries without endothelium, HN-10200 and IBMX significantly augmented relaxations to prostacyclin, but did not affect relaxations to a nitric oxide donor 3-morpholinosydnonimine (SIN-1) or endothelium-derived relaxing factor (EDRF) released by bradykinin. In basilar arteries, relaxations to HN-10200 were augmented by the removal of endothelium, whereas relaxations to IBMX were not affected. Relaxations to prostacyclin, SIN-1, and EDRF were not affected by the presence of phosphodiesterase inhibitors. The results of the present study suggest that HN-10200 causes endothelium-independent relaxations. In addition, it may augment relaxations to prostacyclin but does not affect relaxations to EDRF.
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PMID:HN-10200 causes endothelium-independent relaxations in isolated canine arteries. 138 54

Guanosine 3',5'-cyclic monophosphate (cGMP) and adenosine 3',5'-cyclic monophosphate (cAMP) are mediators of smooth muscle relaxation. In this study, selective inhibitors of phosphodiesterase (PDE) isozymes were used to assess the role of cyclic nucleotide hydrolysis in angiotensin II (ANG II) and hypoxic pulmonary vasoconstriction. In isolated rat lungs, the hypoxic pressor response (HPR) was induced with a 95% N2-5% CO2 gas mixture. When administered during the plateau of the HPR, trequinsin (nonselective PDE inhibitor) and indolidan (cGMP-inhibitable cAMP PDE inhibitor) significantly (P = 0.01) decreased the pulmonary arterial pressure (Ppa) by 60 +/- 7 and 53 +/- 3%, respectively, compared with zaprinast (cGMP PDE inhibitor), rolipram (cGMP-insensitive cAMP PDE inhibitor), and the 0.1% dimethyl sulfoxide (DMSO) vehicle control, which decreased the Ppa by 6 +/- 3, 4 +/- 3, and 0%, respectively. In the trequinsin and indolidan groups, the subsequent ANG II pressor responses and HPRs were significantly (P = 0.01) decreased when compared with the zaprinast, rolipram, and DMSO groups. During normoxia, none of the PDE inhibitor (0.3-30 microM) had an effect on the baseline Ppa. These results suggest that cAMP hydrolysis by the cGMP-inhibitable cAMP PDE play a significant role in pulmonary vascular tone regulation.
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PMID:Selective inhibition of cGMP-inhibitable cAMP phosphodiesterase decreases pulmonary vasoreactivity. 165 13

This study examined the relative contributions of phosphodiesterase inhibition and adenosine receptor blockade in the respiratory-stimulant effects of selected xanthines. The respiratory effects of caffeine, theophylline, 8-phenyltheophylline (8-PT), 8-cyclopentyltheophylline (8-CPT), 3-isobutyl-1-methylxanthine and enprofylline, as well as the nonxanthine phosphodiesterase inhibitor, rolipram, and the adenosine analogs, N6-cyclopentyladenosine (CPA) and 5'-N-ethylcarboxamide adenosine (NECA), were studied in unanesthetized rhesus monkeys. Ventilation was measured continuously by enclosing the monkey's head in a fitted Lexan helmet while a pressure transducer measured differences in pressure produced by inspirations and expirations against a constant flow of air. Drugs were administered (i.m.) using cumulative-dosing procedures while the subjects breathed air or 5% CO2 mixed in air. All xanthines except 8-PT produced dose-related increases in respiratory frequency and less pronounced changes in tidal volume, both in air and in 5% CO2 mixed in air. 8-PT, an adenosine antagonist with little activity as a phosphodiesterase inhibitor, did not have respiratory effects over the range of doses studied. Enprofylline, a phosphodiesterase inhibitor with little activity as an adenosine antagonist, had effects that were comparable to those of caffeine. Rolipram also had effects on respiration that were similar to those of caffeine, and it was approximately 100 times more potent than caffeine. The adenosine A1/A2 agonist, NECA, produced dose-related increases in respiratory frequency, and both CPA (an A1-selective agonist) and NECA produced dose-related decreases in tidal volume; NECA was 30 to 100 times more potent than CPA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Respiratory effects of xanthines and adenosine analogs in rhesus monkeys. 239 11

The distribution of cyclic guanosine 3',5' monophosphate (cGMP) producing cells in various organs of the rat were studied immunocytochemically using antibodies raised against formaldehyde-fixed cGMP. Sodium nitroprusside (SNP), a direct activator of guanylate cyclase and vasodilator, was used to enhance cGMP levels. In order to reach all organs optimally, whole body perfusion was performed using a modified Krebs-Ringer buffer at 37 degrees C, aerated with 5% CO2/95% O2, also containing isobutyl methyl xanthine (IBMX); a phosphodiesterase inhibitor. After 15-min pre-perfusion, SNP was added to the perfusate, followed by fast fixation with ice-cold 4% paraformaldehyde-phosphate buffer. After vehicle perfusion, only the retina showed cGMP immunoreactivity in the photoreceptor and ganglion layer, while other organs lacked cGMP immunoreactivity. After 15-min perfusion with SNP (10 microM), enhanced cGMP immunostaining was seen in smooth muscles of the aorta, amacrine-like cells in the retina, glomeruli of the kidney cortex, blood vessels in the dura mater, as well as cells in the pineal and in the median eminence. The results indicate that the distribution and the reactivity of cGMP producing cells, situated outside the blood brain barrier, can be studied by immunocytochemistry after pharmacological manipulations of the intact tissue with a nitrovasodilator using whole body perfusion.
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PMID:cGMP immunocytochemistry in aorta, kidney, retina and brain tissues of the rat after perfusion with nitroprusside. 255 68

The effects of nutrient urea (240 mM) on H+ secretion, potential difference, and resistance were studied in isolated sheets of bullfrog fundic mucosa. H+ secretion was significantly reduced while transmucosal resistance was significantly increased and potential difference was significantly decreased. Measurement of CO2 utilization by, and distribution across, the mucosal sheets demonstrated that oxidative metabolism is increased (tCO2, 4.93 +/- 0.2 to 5.83 +/- 0.3 mumole/cm2 hr-1, P less than 0.05) and that generation of protons (H+) within the oxyntic cell is stimulated (delta CO2, 1.48 +/- 0.1 to 2.22 +/- 0.2 mumole/cm2 hr-1, P less than 0.05, and nutrient HCO-3 1.35 +/- 0.2 to 2.21 +/- 0.2 mueq/cm2 hr-1, P less than 0.05) in spite of paradoxically diminished H+ appearance on the secretory surface. Studies using 120 and 60 mM urea suggest that the effects may be dose dependent. Results with 240 mM sucrose on the nutrient surface would indicate that those seen with urea cannot be attributed entirely to the hyperosmolality. Pretreatment of the mucosal sheets with metiamide (10(-3) M) resulted in the expected decrease in titratable H+ (to 0) but had no effect on urea-stimulated oxidative metabolism (tCO2, 2.09 +/- 0.2 to 2.91 +/- 0.4 mumole/cm2 hr-1, P less than 0.02) or the generation of protons by the oxyntic cell (delta CO2, 0.68 +/- 0.1 to 1.35 +/- 0.3 mumole/cm2 hr-1, P less than 0.02, and nutrient HCO3- 0.83 +/- 0.1 to 1.65 +/- 0.3 mueq/cm2 hr-1, P less than 0.05). Both simultaneous or subsequent treatment with theophylline (5 X 10(-3) M) reversed the inhibitory effect of urea on H+ secretion. Transmission electron microscopy revealed involution of the secretory membrane following treatment with urea but maintenance of the microvillous secreting configuration of the membrane when theophylline was added to the nutrient solution. These results suggest that although nutrient urea stimulates the generation of H+ within the cell it simultaneously inhibits release of H+ by the secretory membrane. Failure to inhibit urea-stimulated generation of H+ within the cell by metiamide indicates that the increased oxidative metabolism and generation of protons stimulated by nutrient urea is probably not histamine-mediated. It is suggested that urea inhibits adenylyl cyclase and thus cAMP-mediated evolution of the secretory membrane with reduced H+ transport, an effect that can be reversed by inhibiting phosphodiesterase with theophylline.
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PMID:The effects of high-nutrient urea on in vitro bullfrog fundic mucosa. 309 89

Immediately after mounting in the Ussing chamber between choline bicarbonate Ringer solutions devoid of exogenous Na and Cl, the serosal fluid is electronegative to the luminal fluid in bladders from postabsorptive and acidotic turtles; and electropositive in bladders from alkalotic turtles. In bladders from postprandial turtles, the electrical orientation, initially serosal positive, reverses to serosal negative. Serosal additions of 3-isobutyl-1-methylxanthine (IBMX) and adenosine 3',5'-cyclic monophosphate (cAMP) produce no changes in the negative short-circuiting current (Isc) of acidotic turtles but induce large positively-directed increases of Isc in bladders from other turtle groups. With IBMX and cAMP in the (HCO3 + CO2)-rich serosal fluid at pH 7.2 and with luminal pH maintained at 4.0-5.0, the rate at which titratable alkali enters the luminal fluid is electrochemically equal to the positive Isc; and this increased positive Isc is the same as that in the absence of transepithelial gradients. The effects of acetazolamide and 4-acetamido-4-isothiocyanostilbene-2,2'-disulfonic acid on positive and negative Isc are presented. It is concluded that isolated bladders from alkalotic, postprandial or postabsorptive turtles, but not those from acidotic turtles, possess an active electrogenic mechanism for a Na-independent Cl-independent secretion of bicarbonate. This transport process is accelerated by phosphodiesterase inhibitors (IBMX) and cAMP or its eight substituted derivatives.
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PMID:Active electrogenic mechanisms for alkali and acid transport in turtle bladders. 618 18

1. The effect of heat-stable enterotoxin (ST) of Escherichia coli, cholera toxin (CT), and theophylline (a phosphodiesterase inhibitor) on ion and water transport was studied with an in vivo isolated loop system of the pig colon.2. All three agents abolished net Na absorption as a result of a decrease in the lumen to blood Na flux alone. With all three agents, net Cl absorption was reduced, but not abolished, and net HCO(3) secretion was elicited. Luminal p(CO2) was reduced with CT and theophylline from that observed in normal Ringer alone.3. Theophylline resulted in a prompt and sustained increase in both cyclic adenosine monophosphate (cyclic AMP) and cyclic guanosine monophosphate (cyclic GMP) levels in colonic mucosa studied in vitro. ST selectively elevated cyclic GMP, whereas CT selectively elevated cyclic AMP. These responses paralleled the time course and magnitude of response of the transepithelial electrical potential difference (psi(LB)) measured in vivo.4. Ion replacement studies in the presence or absence of theophylline showed that in the absence of Na, Cl absorption was slightly reduced and HCO(3) secretion was elicited; no further additive effects of theophylline in the absence of luminal Na were observed. In the absence of luminal Cl, net Na absorption was abolished and HCO(3) was absorbed; theophylline resulted in significant net Na and HCO(3) secretion. Theophylline also increased psi(LB) in the absence of either luminal Na or Cl.5. Results suggest that in the presence of theophylline or enterotoxin, the coupled Na-H and Cl-HCO(3) exchange processes that are normally responsible for at least half of the net NaCl absorption by this tissue are interrupted. Active HCO(3) secretion is observed and Cl absorption under these conditions can be entirely explained as a consequence of psi(LB). Thus, these studies indicate that the colon may participate in the production of diarrhoea of enterotoxigenic origin. They also suggest an important functional role of cyclic nucleotides in controlling the acidity and volume of colonic contents.
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PMID:Effect of Escherichia coli heat-stable enterotoxin, cholera toxin and theophylline on ion transport in porcine colon. 627 79

1. Acid extrusion through Na(+)-H+ exchange was studied in the sheep cardiac Purkinje fibre (bathed in Hepes-buffered solution, nominally free of CO2-HCO3-) by examining (i) intracellular pH (pHi) recovery from an intracellular acid load (induced by 20 mM NH4Cl prepulse) and (ii) the rate of rise of intracellular Na+ activity (aiNa) following the ammonium prepulse (used as an estimate of apparent Na+ influx on Na(+)-H+ exchange). The pHi and aiNa were recorded using ion-selective microelectrodes. 2. The pHi recovery and rise of aiNa were both greatly slowed in the presence of 2-deoxyglucose (DOG; glucose-free solution), an inhibitor of glycolysis, indicating inhibition of Na(+)-H+ exchange. 3. Cyanide moderately slowed pHi recovery rate but did not significantly affect the rise of aiNa. Estimates of beta 1 (intracellular buffering power) indicated an increase of approximately 50% in the presence of cyanide; such an increase accounts for most of the observed slowing of pHi recovery. It is concluded that oxidative inhibition with cyanide does not inhibit Na(+)-H+ exchange. 4. Intracellular ATP, measured from luciferin-luciferase luminescence, was reduced by a similar amount (approximately 70%) by either DOG or cyanide. This suggests that, if intracellular ATP (ATPi) reduction is the cause of exchanger inhibition by metabolic inhibitors, then ATPi generated glycolytically is more important for activation of the exchange. 5. 3-Isobutyl-1-methylxanthine (IBMX; a non-specific phosphodiesterase inhibitor which can elevate intracellular [cAMP]) slowed acid extrusion and reduced apparent Na+ influx by a similar amount, whereas addition of sodium nitroprusside (to elevate intracellular [cGMP]) had no effect, suggesting that raising intracellular [cAMP] downregulates Na(+)-H+ exchange, whereas raising intracellular [cGMP] does not. 6. Application of trifluorperazine (TFP; a non-specific calcium-calmodulin inhibitor) completely reversed the inhibitory effects of IBMX upon pHi recovery and aiNa. Under control conditions (no IBMX), TFP had no effect on pHi recovery or upon resting pHi. 7. The phorbol ester 12-O-tetradecanoyl phorbol 13-acetate (TPA) had no significant effect on pHi recovery or apparent Na+ efflux. 8. We conclude that inhibition of glycolysis or elevation of cAMP produces downregulation of Na(+)-H+ exchange in the cardiac Purkinje fibre. Possible reasons for the lack of inhibitory effect of oxidative inhibitors are discussed.
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PMID:Effect of metabolic inhibitors and second messengers upon Na(+)-H+ exchange in the sheep cardiac Purkinje fibre. 752 44


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