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)

We have characterized the effects of eight different drugs on the IgE-mediated histamine release (HR) and leukotriene C4 (LTC4R) from human basophils. Arachidonic acid analogues 5,8,11 eicosatriynoic acid and 5,8,11,15 eicosatetraynoic acid inhibit the release of both mediators in the range 10(-6) to 10(-4) mol/L with almost total (80% to 100%) inhibition of release at 10(4) mol/L. The inhibition of LTC4R was significantly (p less than 0.05) greater than the inhibition of HR only at intermediate (10(-5) to 3 X 10(-5) mol/L) doses of the drugs. Two other inhibitors of phospholipase A2 (bromophenacyl bromide and phenidone) affected the release of both mediators equally. Two drugs that activate adenylate cyclase (prostaglandin E1 and dimaprit) inhibited release in a dose-dependent fashion but failed to preferentially affect either HR or LTC4R. Isoproterenol (10(-6) to 10(-4) mol/L), a third activator of adenylate cyclase, caused only moderate (30%) inhibition of HR, even when the reaction was staged, but was slightly (0.1 less than p less than 0.05) more potent against leukotriene release. The final drug tested was the phosphodiesterase inhibitor, isobutylmethylxanthine, which proved to be an effective (50% to 100%) inhibitor of both mediators in the range 10(-5) to 10(-3) mol/L.
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PMID:The pharmacologic modulation of mediator release from human basophils. 245 75

1. Isolated segments of the guinea-pig ileum were vascularly perfused and the release of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) into the portal venous effluent was determined by h.p.l.c. with electrochemical detection. Test substances were applied via the arterial perfusion medium. 2. Isoprenaline (0.1 microM) increased the outflow of 5-HT and 5-HIAA maximally by about 75% and this was antagonized by propranolol (0.1 microM). Forskolin (1-10 microM) increased the outflow of 5-HT by approximately 105% and that of 5-HIAA by approximately 55%. The phosphodiesterase inhibitor AH 21-132 (0.1-1 microM) increased the outflow of 5-HT and 5-HIAA by about 70%. Isoprenaline (1 nM) and AH 21-132 (10 nM), which alone had no effect, increased the outflow of 5-HT and 5-HIAA by 75%, when applied in combination. 3. Clonidine (1 microM) reduced the outflow of 5-HT by 45%, an effect blocked by tolazoline (1 microM), but not by prazosin (0.1 microM). 4. The effects of isoprenaline, forskolin and clonidine were also observed in the presence of tetrodotoxin (1 microM) demonstrating a direct modulation of 5-HT release from the enterochromaffin cells. 5. In conclusion, the release of 5-HT from enterochromaffin cells is facilitated by activation of beta-adrenoceptors and inhibited via alpha 2-adrenoceptors. Enhancing intracellular cyclic AMP, by direct stimulation of adenylate cyclase with forskolin or by inhibition of phosphodiesterase, also facilitates the release of 5-HT. The beta-adrenoceptor-mediated effect on 5-HT release appears to involve an increase in cyclic AMP, as the effect of isoprenaline was potentiated after inhibition of phosphodiesterase.
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PMID:Adrenergic modulation of the release of 5-hydroxytryptamine from the vascularly perfused ileum of the guinea-pig. 246 31

The influence of selective (milrinone: 10, 50, 100 microM) and nonselective phosphodiesterase (isobutylmethylxanthine: 0.1, 10, 100 microM) inhibitors and beta-adrenergic stimulation (isoproterenol: 0.01, 0.1 microM) on phospholamban and myofibrillar protein phosphorylation was studied in guinea pig hearts perfused with [32P]orthophosphate. Changes in protein phosphorylation were compared to alterations in tissue cyclic AMP (cAMP) levels and positive inotropic effects induced by these agents. Isoproterenol (0.01 microM), milrinone (50 microM), and isobutylmethylxanthine (100 microM) all produced similar, twofold increases in dP/dt and -dP/dt but only stimulation with isobutylmethylxanthine and isoproterenol was associated with significant increases in phospholamban phosphorylation. At these equipotent doses, the effects of isobutylmethylxanthine were associated with higher increases (3.1-fold) in cAMP than those observed with isoproterenol (twofold). Milrinone (50 microM) produced a 2.5-fold increase in cAMP levels but failed to change phospholamban phosphorylation. Higher doses of milrinone (100 microM) resulted in relatively high (4.1-fold) cAMP levels, and this was associated with increased (1.5-fold) phosphorylation of phospholamban. Phosphorylation of troponin I was significantly increased at 0.01 microM and 0.1 microM isoproterenol, while phosphorylation of C protein was observed only at 0.1 microM isoproterenol. Isobutylmethylxanthine and milrinone did not significantly increase phosphorylation of either troponin I or C protein at any of the doses studied. These findings indicate that cardiotonic agents acting via the cAMP pathway may produce similar inotropic responses at different levels of cAMP and phosphorylation of sarcoplasmic reticulum and myofibrillar proteins.
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PMID:Inotropic responses to isoproterenol and phosphodiesterase inhibitors in intact guinea pig hearts: comparison of cyclic AMP levels and phosphorylation of sarcoplasmic reticulum and myofibrillar proteins. 253 95

The time-courses of isoproterenol activation of rat adipocyte particulate low Km cAMP phosphodiesterase (PDE) activity, cAMP-dependent protein kinase (A-kinase), and glycerol production were measured in the presence and absence of insulin. Isoproterenol (100 nM) alone rapidly activated A-kinase 8- to 10-fold and increased particulate cAMP PDE by approximately 100%. A-kinase and PDE activity remained relatively constant for at least 25 to 30 min. Kact values for isoproterenol activation of PDE and lipolysis were similar. In comparison with isoproterenol, insulin (0.1-0.3 nM) alone increased particulate cAMP PDE at a slower rate and to a lesser extent (by approximately 50% within 12 to 16 min) and without any change in A-kinase. With insulin plus isoproterenol there was a rapid, transient, and synergistic activation of particulate cAMP PDE, which temporally correlated with a decrease in A-kinase and reduction in lipolysis. These and other data suggest the following: 1) there is a close concentration-dependent and temporal relationship in isoproterenol activation of adenylate cyclase, of A-kinase, and of particulate cAMP PDE; 2) isoproterenol and insulin activate particulate cAMP PDE by two distinct mechanisms; 3) the temporal changes in PDE and A-kinase in the presence of insulin and isoproterenol suggest that insulin activation of the PDE does not require, but may be enhanced by, elevated cAMP and is important in the antilipolytic action of insulin.
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PMID:Role of hormone-sensitive low Km cAMP phosphodiesterase in regulation of cAMP-dependent protein kinase and lipolysis in rat adipocytes. 253 13

1. In this study we have investigated the effects of a novel inotropic agent, pimobendan (UDCG 115-BS), on skinned and intact ventricular muscle from ferrets. 2. Pimobendan (20 or 100 mumol/l) increased tension at a given free [Ca2+] when applied to skinned ventricular muscle, i.e. it increased the Ca2+ sensitivity of the myofibrils. 3. Tension and intracellular free Ca2+ [( Ca2+]i) were measured simultaneously in intact papillary muscles using the aequorin technique. When 25 mumol/l pimobendan was added to the superfusing solution, a slowly developing positive ionotropic effect was produced, which was accompanied by an increase in the size of the systolic rise in [Ca2+]i (Ca2+ transients) with a similar time course. 4. In order to determine whether pimobendan increased the Ca2+ sensitivity of myofibrils in an intact papillary muscle, we compared the increase in Ca2+ transients and tension observed in response to changes in extracellular [Ca2+] with those observed in response to pimobendan. The result of this comparison was that in intact muscle pimobendan caused no apparent increase in myofibrillar Ca2+ sensitivity. 5. Pimobendan caused an abbreviation of the time course of the Ca2+ transients, but the twitch was slightly prolonged. 6. When isoprenaline was added to the superfusing solution, a positive inotropic effect was produced, which was accompanied by a marked increase in the size of the Ca2+ transients. Isoprenaline caused an abbreviation of the time course of both the Ca2+ transients and the twitch. When the Ca2+ sensitivity of the intact myofibrils was determined as described above, isoprenaline caused a desensitization. Pimobendan produced a sensitization when compared with isoprenaline. 7. These results are consistent with the hypothesis that pimobendan produces an inotropic effect in isolated cardiac muscle which is mediated both by an increase in Ca2+ sensitivity and by an increase in adenosine 3':5'-cyclic monophosphate due to its phosphodiesterase-inhibiting activity. Such a combination of activities may be particularly advantageous for an inotropic agent.
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PMID:Effects of pimobendan, a novel inotropic agent, on intracellular calcium and tension in isolated ferret ventricular muscle. 254 44

The effect of neuropeptide Y (NPY) on cell contractions of ventricular myocytes isolated from the adult rat heart was investigated. Maximum changes in cell length (dL) during stimulated (0.5 Hz) contractions were determined in presence of the phosphodiesterase inhibitor Ro 20-1724 (0.5 mM) and adenosine deaminase (5 U/ml). Under these basal conditions NPY (10(-6) M) reduced dL by 39% of control. Isoproterenol (10(-6) M) increased dL by 105% of control; the EC50 was 2 x 10(-9) M. NPY reduced the increase in dL achieved by isoproterenol in a dose dependent manner. The IC50 value was 1 x 10(-9) M and NPY (10(-6) M) produced complete inhibition. In the absence of the phosphodiesterase inhibitor the IC50 was 4 x 10(-9) M. The EC50 of isoproterenol and IC50 of NPY producing accumulation of cAMP in myocytes (Millar et al. 1988) exceeded the respective values of dL by one order of magnitude. Prior treatment of the myocytes with pertussis toxin abolished the potency of NPY to antagonize the increase in dL by isoproterenol while not interfering with the response to the beta-agonist. These results demonstrate a negative inotropic effect of NPY on the ventricular myocardial cell. Complete abolition of the effect of NPY by pertussis toxin indicate that this effect is mediated by a sarcolemmal receptor for NPY linked to adenylate cyclase via an inhibitory guanine nucleotide binding protein.
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PMID:The negative inotropic effect of neuropeptide Y on the ventricular cardiomyocyte. 255 54

In the present study the effects of adenosine analogues were investigated on cAMP content and contractile response in guinea-pig ventricular myocytes. The adenosine analogues (-)-N6-phenylisopropyladenosine (R-PIA), 5'-N-ethylcarboxamideadenosine (NECA) and (+)-N6-phenylisopropyladenosine (S-PIA) in the presence of 0.01 mumol/l isoprenaline reduced contractile response concentration-dependently. R-PIA and NECA were about equipotent (IC25: 0.01 mumol/l and 0.039 mumol/l respectively), while S-PIA was less potent (IC25: 0.6 mumol/l). Isoprenaline stimulated cAMP content was reduced by R-PIA (IC25: 0.004 mumol/l) and with lower potency by S-PIA (IC25: 0.15 mumol/l), but the extent of reduction of cAMP by R-PIA and S-PIA (to 55% and 64% respectively) was less than the reduction of contractile response (to 26% and 55% respectively). This suggests that the effects of R- and S-PIA on contractile response are only in part due to a reduction in cAMP content. In addition, NECA did not decrease cAMP content but decreased contractile response to the same extent as R-PIA. Similar results were obtained in the presence of the phosphodiesterase inhibitor Ro 20-1724. Time course studies revealed that the effects of R-PIA (1 mumol/l) on cAMP content and contractile response coincided reaching steady state after 5 min and remained stable thereafter. The effects of NECA (1 mumol/l) on contractility also reached steady state within 5 min, whereas it did not change cAMP content. It is concluded that the reduction of contractility by adenosine analogues in the presence of isoprenaline can only in part be explained by a reduction of cAMP content.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of adenosine analogues on contractile response and cAMP content in guinea-pig isolated ventricular myocytes. 255 37

The effects of the beta-adrenoceptor agonist, isoprenaline, on Ca2+ mobilization and inositol phosphate formation in parotid acinar cells were examined. Isoprenaline (2 microM) failed to increase cytosolic [Ca2+] in acinar cells, as measured by Fura-2 fluorescence, even in the presence of a phosphodiesterase inhibitor. Likewise, neither the 8-bromo nor the dibutyryl derivatives of cAMP (both at 2 mM concentration) increased [Ca2+]i. However, in confirmation of results previously published, a higher concentration of isoprenaline (200 microM) increased cytosolic [Ca2+]i of rat parotid acinar cells, from 104 +/- 4 nM to 151 +/- 18 nM. The increase in [Ca2+]i in response to isoprenaline, while transient in the absence of extracellular Ca2+, was sustained in Ca2(+)-containing medium. This isoprenaline-stimulated Ca2+ signal was more potently antagonized by phentolamine than by propranolol, suggesting that the higher concentration of isoprenaline activated alpha-adrenoceptors. Furthermore, the Ca2+ signal generated in response to the alpha-adrenoceptor agonist, phenylephrine, also was blocked by the same concentrations of propranolol necessary to block the effects of isoprenaline, suggesting that propranolol may block alpha-adrenoceptors under certain experimental conditions. The high concentration of (-)isoprenaline (200 microM) also increased inositol (1,4,5) trisphosphate and inositol (1,3,4) trisphosphate formation 45% within 30 s. Analogous to the increase in intracellular Ca2+, the formation of inositol phosphates stimulated by isoprenaline was more potently antagonized by the alpha-adrenoceptor antagonist, phentolamine, than by the beta-adrenoceptor antagonist, propranolol, again suggesting that isoprenaline interacts with alpha-adrenoceptors on parotid cells. Thus, the effects of isoprenaline on [Ca2+]i do not appear to be mediated by cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Does beta-adrenoceptor activation stimulate Ca2+ mobilization and inositol trisphosphate formation in parotid acinar cells? 255 9

The aim of the present work was to demonstrate the presence of presynaptic beta-adrenoceptors in the rabbit isolated pulmonary artery by investigating the effect of isoprenaline on 3H-noradrenaline (3H-NA) release evoked by electrical field stimulation. (-)-Isoprenaline (10(-7)-10(-6) mol/l) had no effect on the 3H-overflow evoked by stimulation (3 Hz) of the pulmonary artery preloaded with 3H-NA. At 10(-5) mol/l, (-)-isoprenaline reduced the 3H-overflow by maximally 39%. (-)-Isoprenaline (10(-5) mol/l) caused an inhibition that remained almost constant with time. The same results were obtained with (-)-isoprenaline (10(-7)-3 X 10(-5) mol/l) in the presence of cocaine (3 X 10(-5) mol/l), corticosterone (4 X 10(-5) mol/l), and the catechol-O-methyltransferase inhibitor U-0521 (3',4'-dihydroxy-2-methylpropiophenone) (10(-4) mol/l). In the presence of cocaine plus corticosterone, (-)-isoprenaline (3 X 10(-10)-10(-7) mol/l) had no effect on the 3H-overflow evoked by stimulation at 1 Hz. At 10(-6) mol/l, (-)-isoprenaline slightly reduced the 3H-overflow. At 10 Hz, (-)-isoprenaline (10(-6)-3 X 10(-5) mol/l) decreased the 3H-overflow and had no effect at 10(-7) mol/l. In the presence of either rauwolscine (10(-6) mol/l), phentolamine (10(-6) mol/l) or the phosphodiesterase inhibitor ICI 63,197 (3 X 10(-5) mol/l), (-)-isoprenaline (10(-7)-10(-6) mol/l) did not enhance the stimulation-evoked 3H-overflow. (+/-)-Propranolol (10(-7)-10(-5) mol/l) did not alter the stimulation-evoked 3H-overflow.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of isoprenaline on noradrenaline release from sympathetic neurones in rabbit isolated pulmonary artery. 282 40

Cyclic GMP inhibits the slow inward Ca current of cardiac cells. This effect could be due to a cyclic GMP-mediated phosphorylation of the Ca channel (or some protein modifying Ca channel activity), or alternatively, to enhanced degradation of cyclic AMP owing to stimulation of a phosphodiesterase by cyclic GMP. To test the latter possibility, we examined the effect of extracellular 8-bromo-cyclic GMP on cyclic AMP levels in guinea pig papillary muscles, in parallel with electrophysiological experiments. Isoproterenol (10(-6) M) significantly increased the cyclic AMP levels and induced Ca-dependent slow action potentials. Superfusion with 8-bromo-cyclic GMP (10(-3) M) inhibited the slow action potentials induced by isoproterenol. However, muscles superfused with 8-bromo-cyclic GMP had cyclic AMP levels identical to those of muscles superfused with isoproterenol alone. Similarly, 8-bromo-cyclic GMP had no effect on the increase in cyclic AMP levels of muscles treated with forskolin (10(-6) M) or histamine (10(-6) M). We conclude that the inhibitory effect of cyclic GMP on slow Ca channels in guinea pig ventricular cells is not due to a decrease in the cyclic AMP levels. We hypothesize that a cyclic GMP-mediated phosphorylation is the most likely explanation for the Ca channel inhibition observed in this preparation.
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PMID:Inhibition of cardiac slow action potentials by 8-bromo-cyclic GMP occurs independent of changes in cyclic AMP levels. 284 36


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