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

---

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

Isolated adult canine ventricular myocytes were used to study the role of compartmentation of cAMP in the diverse functional responses to various drugs that elevate cAMP. Myocytes presented with the beta-agonist isoproterenol accumulated cAMP with a half maximally effective concentration (EC50) of 3.55 x 10(-8) M. Approximately 45% of the total cAMP was recovered in the particulate fraction of digitonin-lysed myocytes under these conditions. With phosphodiesterase inhibition (10 microM isobutylmethylxanthine), isoproterenol-stimulated cAMP production was up to 3.4-fold greater, but the proportion of total cAMP residing in the particulate fraction declined to less than 20%. Similar results were obtained with forskolin, a direct activator of adenylate cyclase. Treatment with isoproterenol shortened the duration at 50% maximum peak height (T 1/2) and increased the peak fluorescence ratio of electrically triggered single-cell free Ca2+ transients in fura-2-loaded canine myocytes. Isoproterenol dose-response curves gave EC50 values of 1.7 x 10(-9) and 4.4 x 10(-9) M for effects on T 1/2 and peak height, respectively. Alterations in peak height and T 1/2 of Ca2+ transients also showed a dose dependency on isobutylmethylxanthine and forskolin. Comparison of myocyte cAMP content with the corresponding changes in free Ca2+ transients demonstrated a close correlation between particulate cAMP and the extent of shortening or increase in peak height of the fura-2 Ca2+ transients (r = 0.92 for each). However, when these two parameters were plotted as a function of total cAMP, the resulting curves were nonlinear and divergent for each agent tested. The results support the hypothesis that differences in responses to agents that augment cAMP can be explained in part by compartmentation of cAMP. Furthermore, Ca2+ mobilization seems to be most affected by cAMP located in the particulate compartment of canine cardiac myocytes.
...
PMID:Compartmentation of cAMP in adult canine ventricular myocytes. Relation to single-cell free Ca2+ transients. 168 66

1. The effect of carbachol on force of contraction, contraction duration, intracellular Na+ activity and cyclic AMP content was studied in papillary muscles of the guinea-pig exposed to isoprenaline or the phosphodiesterase inhibitor 3-isobutyl, 1-methyl xanthine (IBMX). The preparations were obtained from reserpine-pretreated animals and were electrically driven at a frequency of 0.2 Hz. 2. Isoprenaline (10 nM) and IBMX (100 microM) produced comparable positive inotropic effects of 9.8 and 9.7 mN, respectively. Carbachol (3 microM) attenuated the inotropic effects by 82% (isoprenaline) and by 79% (IBMX). The shortening of contraction duration which accompanied the positive inotropic effect of isoprenaline (by 14.9%) and of IBMX (by 22.4%) was not significantly affected by 3 microM carbachol. 3. The positive inotropic effect of 10 nM isoprenaline and of 100 microM IBMX was accompanied by an increase in cellular cyclic AMP content of 58 and 114%, respectively. Carbachol (3 microM) failed to reduce significantly the elevated cyclic AMP content of muscles exposed to either isoprenaline or IBMX. 4. In the quiescent papillary muscle, isoprenaline (10 nM) and IBMX (100 microM) reduced the intracellular Na+ activity by 28 and 17%, respectively. This decline was not influenced by the additional application of 3 microM carbachol. 5. The results demonstrate that muscarinic antagonism in guinea-pig ventricular myocardium exposed to cyclic AMP-elevating drugs is restricted to force of contraction. The underlying mechanism does not apparently involve the cytosolic signal molecule cyclic AMP.
...
PMID:Muscarinic receptor stimulation and cyclic AMP-dependent effects in guinea-pig ventricular myocardium. 169 77

Neutrophils (PMN) treated with cAMP elevating agents were evaluated for their chemotactic responsiveness to FMLP and leukotriene B4 (LTB4). PGE1 and isoproterenol, increased PMN cyclic AMP production and inhibited chemotaxis to both FMLP and LTB4. In contrast, forskolin, which activates adenylate cyclase directly, inhibited chemotaxis to FMLP but not to LTB4. The phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX), was required for inhibition of PMN chemotaxis to FMLP by forskolin, PGE1, and isoproterenol. Isoproterenol and PGE1 inhibited PMN chemotaxis to LTB4 in the absence of IBMX and chemotaxis was further inhibited in the presence of IBMX. PMN cAMP levels were stimulated 2- to 3-fold with isoproterenol, 6- to 10-fold with PGE1, and 5- to 7-fold with forskolin over basal levels in the presence of IBMX. These observations demonstrate that total cellular cAMP concentration is not correlated with inhibition of PMN chemotaxis to all stimuli; forskolin, which increased cyclic AMP 5- to 7-fold over basal levels, did not inhibit chemotaxis to LTB4, whereas isoproterenol, which increased cyclic AMP only 2- to 3-fold over basal levels, inhibited chemotaxis to LTB4. PMN cAMP extrusion was determined under basal conditions and in the presence of PGE1, isoproterenol, or forskolin. PMN extruded cAMP under all conditions examined.
...
PMID:cAMP and human neutrophil chemotaxis. Elevation of cAMP differentially affects chemotactic responsiveness. 170 93

1. beta-adrenoceptors on human alveolar macrophages obtained by bronchoalveolar lavage (BAL) from healthy smoking volunteers (n = 26) were characterized by studying cyclic AMP (cAMP) accumulation in intact macrophages evoked by adrenaline or isoprenaline, with or without appropriate antagonists and by radioligand binding to macrophage membranes, using [125I]-iodopindolol (125IPIN) as beta-adrenoceptor ligand. 2. In a second study, cAMP responses of alveolar macrophages to isoprenaline and PGE1 and of peripheral blood lymphocytes to isoprenaline were compared in smoking and non-smoking healthy volunteers (n = 9 + 9), as our initial studies were performed in smokers, due to their higher cell yield. 3. BAL yielded 47 +/- 23 x 10(6) cells in smokers and 12 +/- 6 x 10(6) cells in non-smokers with a recovery of 82 +/- 8% in the elutriation step (means +/- s.d.). The cell preparation consisted of 99.2 +/- 0.8% macrophages and their viability (trypan blue exclusion) was 97.5 +/- 5.2%. 4. Isoprenaline or adrenaline increased cAMP accumulation approximately 40-fold with or without the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX, 10(-4) M), which enhanced basal and stimulated cAMP accumulation approximately five-fold. Peak responses were seen after 2 min. EC50s for isoprenaline and adrenaline were 3-5 x 10(-7) M. Phentolamine did not alter responses to adrenaline, indicating absence of inhibitory alpha 2-adrenoceptors. Propranolol inhibited isoprenaline induced cAMP accumulation stereoselectively; pD2-values were 8.2 for (-)-propranolol, 5.6 for atenolol and 7.5 for ICI 118,551, suggesting a predominance of beta 2-adrenoceptors. 5. Specific 125IPIN binding to macrophage membranes was rapid and saturable. Non-specific binding was determined in the presence of 1 microM (-)-propranolol. KD values were 71 +/- 7 pM and the density of specific binding sites was 36 +/- 3 fmol mg-1 protein (three experiments on a membrane pool from 10 subjects; r values for Scatchard analyses = 0.98 +/- 0.01). Similar values were obtained when 200 microM isoprenaline (+ GTP) was used to assess non-specific binding. Competition experiments again showed stereoselectivity for propranolol and a predominance of beta 2-adrenoceptors, as judged by the displacement of specific 125IPIN binding by atenolol and ICI 118,551. 6. Macrophages from smokers responded with less marked cAMP accumulation upon stimulation with isoprenaline or PGE1 than did cells from non-smokers (difference approximately 30%; P less than 0.05 for both agonists) in the presence of IBMX. Thus macrophages from smokers may produce less cAMP due to post-receptor changes in responsiveness.(ABSTRACT TRUNCATED AT 400 WORDS)
...
PMID:Beta-adrenoceptors in human alveolar macrophages isolated by elutriation. 170 82

We have previously shown that cultured rabbit renal preglomerular microvascular endothelial cells have the ability to synthesize a number of common prostaglandins. In the present study we have examined whether endogenous cyclic AMP is involved in the regulation of PGI2 and PGE2 biosynthesis in these cultured cells. Isoproterenol and forskolin produced an increase in cyclic AMP accumulation in these cells but had no effect on PGI2 or PGE2 biosynthesis either in the presence or absence of A23187. Similar results were noted in the presence of 3-isobutyl-1-methylxanthine, a cyclic AMP-phosphodiesterase inhibitor. These studies suggested that endogenous cyclic AMP does not regulate the biosynthesis of PGI2 or PGE2 in cultured renal preglomerular microvascular endothelial cells either under basal or A23187-stimulated condition. They further suggested that the effect of 3-isobutyl-1-methylxanthine on prostaglandin biosynthesis in these cultured cells was not secondary to its effects on phosphodiesterase.
...
PMID:Cyclic AMP does not inhibit A23187-induced prostaglandin biosynthesis in cultured rabbit renal microvascular endothelial cells. 170 11

Beta-adrenergic drugs affect lens epithelial and fiber cells. The regulation and cellular integration of lens beta-adrenergic responses are largely unknown. These studies further characterize beta-adrenergic receptors in lens cells with respect to cyclic adenosine monophosphate (cAMP) production and identification of receptor polypeptides. Stimulation of beta-adrenergic receptors in organ-cultured chick lenses resulted in dose-dependent increases in intracellular cAMP levels. Isoproterenol-elicited cAMP accumulation was found in both epithelial/superficial fiber cells and cortical fiber cells. Hormonal stimulation also apparently initiated additional mechanisms involved in the regulation of cAMP levels (ie, phosphodiesterase activation/receptor desensitization). Individual receptor polypeptides were identified in epithelial and fiber membranes with the photoaffinity probe 125I-iodocyanopindolol diazarine. The probe specifically labeled distinct populations of receptor polypeptides in the two cell types. Lens beta-adrenergic receptors were also shown to bind (-) stereoisomers of adrenergic ligands preferentially. These results indicate that differentiating fiber cells are hormonally sensitive to beta-adrenergic stimulation and that epithelial and fiber cells may respond differentially to beta-adrenergic drugs, at least in part, because of their distinct receptor polypeptides.
...
PMID:Lens beta-adrenergic receptors. Functional coupling to adenylate cyclase and photoaffinity labeling. 170 23

LY171883, (1-[2-hydroxy-3-propyl-4-[4(1H-tetrazol-5-yl)butoxy)phenyl]etha none), a leukotriene (LT) D4/E4 receptor antagonist, was assessed in comparison with two well known phosphodiesterase inhibitors, isobutylmethyl-xanthine (IBMX) and theophylline, for its ability to augment beta-receptor-mediated responses. Relaxation of carbachol-contracted guinea-pig trachea by isoprenaline was enhanced by the three agents in a dose-dependent manner. A two-fold enhancement of isoprenaline-induced smooth muscle relaxation was produced by 2.5 microM IBMX, 28 microM LY171883, or 140 microM theophylline. Similar concentrations of IBMX or theophylline did not antagonize LTE4-induced tracheal contractions; LY171883 totally inhibited the response and had significant LTE4 receptor antagonist activity even at 10-fold lower concentrations. Antigen-induced release of histamine and LTC4 from guinea-pig lung was reduced by isoprenaline. Prior treatment with LY171883, IBMX, or theophylline did not enhance this action. Isoprenaline reduced histamine-induced bronchospasm in anaesthetized guinea-pigs. LY171883, 30 mg kg-1, or IBMX, 1 mg kg-1, did not affect the isoprenaline-induced decrease in the histamine response. IBMX, 3 mg kg-1, and theophylline, 30 mg kg-1, augmented the isoprenaline-induced bronchodilation. LTE4-induced bronchoconstriction was not affected by IBMX or theophylline whereas LY171883 antagonized this response at doses as low as 3 mg kg-1. Therefore, in both in-vitro and in-vivo test systems, LY171883 functioned primarily as a leukotriene receptor antagonist with minimal pharmacological activity attributable to its ability to potentiate isoprenaline.
...
PMID:Leukotriene receptor antagonism and augmentation of beta-receptor-mediated events by LY171883. 170 65

KCl-contracted aortic rings from 18-month-old rats, in contrast with those from 2-month-old rats, showed a substantial reduction in the relaxant effects of the non-selective beta-adrenoceptor agonist, isoproterenol, and of the selective beta 2-adrenoceptor agonist, clenbuterol, without changes in the relaxant actions of forskolin (an activator of the adenylate cyclase), 3-isobutyl-1-methyl-xanthine (a phosphodiesterase inhibitor) or acetylcholine (an endothelium- and cyclic GMP-dependent vasodilator). The relaxant responses induced by adenosine and 2-Cl-adenosine were also reduced in aged aortas. Isoproterenol and cholera toxin (an inhibitor of GTPase activity of the stimulatory GTP-binding protein) reduced cAMP production in aortas from 18-month-old rats. It is suggested that a decrease in the function of the stimulatory GTP-binding protein may contribute at least in part to the impairment in the vasodilation induced by activation of beta-adrenoceptors in aortas from aged rats.
...
PMID:Decreased beta-adrenoceptor-mediated vasodilation in aorta from aged rats: possible involvement of a stimulatory GTP-binding protein. 171 50

The interactions between isoprenaline, sodium nitroprusside, and the isozyme-selective phosphodiesterase inhibitors OPC 3911 ("cAMP specific") and zaprinast ("cGMP specific") on platelet aggregation induced by adenosine diphosphate (ADP) and on levels of cAMP and cGMP were studied. Isoprenaline at 10(-6)M diminished aggregation by 28%, and this effect was enhanced by 10(-7)-10(-6)M OPC 3911. Neither 10(-6) M isoprenaline nor 10(-7)M OPC 3911 elevated cAMP, but in combination they caused a significant rise in cAMP (27% above the basal level), accompanying the synergistic functional inhibition, without affecting cGMP levels. Sodium nitroprusside at 10(-5) M diminished aggregation by 39%, elevated cGMP levels (81-110%), but also caused a statistically significant increase in cAMP (21-32%), and enhanced the effects of 10(-6)M isoprenaline on cAMP levels. Zaprinast at 10(-5) M caused a modest inhibition of aggregation by 20%, and a small increase in cGMP (20%), and it clearly enhanced the effects of 10(-5)M sodium nitroprusside on both cGMP and cAMP levels, but not on aggregation. The cAMP-increasing effect of sodium nitroprusside might be a consequence of a cGMP-mediated inhibition of the "low-Km cGMP-inhibited phosphodiesterase" that is also inhibited by OPC 3911. The effects of all of the drugs on ADP-induced aggregation seem to depend more on their effect on cAMP levels than on the levels on cGMP.
...
PMID:Interactions between isoprenaline, sodium nitroprusside, and isozyme-selective phosphodiesterase inhibitors on ADP-induced aggregation and cyclic nucleotide levels in human platelets. 171 85

We have tested the ability of various compounds to raise intracellular cyclic AMP (cAMP) levels and, either alone or in combination with retinoic acid (RA), to promote differentiation of two "RA-resistant" sublines of LA-N-5 human neuroblastoma cells, designated LA-N-5HP and LA-N-5R9. Direct activation of adenylate cyclase by forskolin and cholera toxin increased intracellular cAMP levels over 10-fold in both cell lines after 1 h of treatment, after which the levels slowly declined for the next 16 to 24 h. After 5 days of continuous treatment, cAMP levels still remained 2- to 7-fold elevated above controls and were accompanied by a decrease in cell proliferation and an increase in neurite outgrowth. All these effects were exaggerated when the agents were combined with phosphodiesterase enzyme inhibitors. Increasing cAMP levels (up to 24-fold) with N6,O2'-dibutyryl cyclic AMP (dbcAMP) or 8-bromo-cAMP also resulted in decreased proliferation and an increase in morphological differentiation. Isoproterenol and epinephrine did not alter cAMP levels and had no discernible biological effects. Of the agents that raised cAMP levels, only dbcAMP caused an increase in acetylcholinesterase activity. This effect was duplicated with sodium butyrate and prostaglandin E1 in the absence of an increase in cAMP. RA promoted differentiation but also had little effect on cAMP levels. Combination treatment of cells with RA plus agents that raised cAMP levels resulted in greater degrees of differentiation than seen with single agent treatments. We conclude that: (a) the cAMP synthetic and degradative pathways are functional in LA-N-5HP and LA-N-5R9 cells; (b) elevation of cAMP is sufficient for inhibiting proliferation and promoting neurite outgrowth from these cells, but is not a necessary condition for inducing differentiation; and (c) elevation of intracellular cAMP potentiates the differentiation-inducing activity of RA.
...
PMID:Modulation of intracellular cyclic adenosine monophosphate levels and the differentiation response of human neuroblastoma cells. 215 44


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---