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)

Concentration-dependent inotropic effects of (-)-norepinephrine and of (+/-)-isoproterenol were compared in isometrically contracting guinea pig papillary muscles stimulated at a frequency of 0.2 Hz. (-)-Norepinephrine (0.1-100 mumol/l) elicited a positive inotropic effect that was not antagonized by carbachol, failed to produce a positive inotropic staircase after resumption of stimulation and shortened relaxation time in a concentration-dependent fashion.(+/-)-Isoproterenol had a dual action: at low and moderately effective concentrations (1-30 nmol/l), the positive inotropic effect was antagonized by carbachol, a positive inotropic staircase was elicited and time to peak force was shortened. At (+/-)-isoproterenol concentrations exceeding an EC80 for the positive inotropic effect (greater than 30 nmol/l), relaxation time became shorter, staircase and carbachol-induced antagonism became less pronounced until at 300 nmol/l inotropic effects of (+/-)-isoproterenol resembled closely those of (-)-norepinephrine. Cyclic AMP derivatives and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine mimicked (+/-)-isoproterenol in their inotropic actions. Impairment of neuronal uptake caused (-)-norepinephrine 1) to produce (+/-)-isoproterenol-like effects on the isometric contraction, 2) to induce a positive inotropic staircase and 3) to become sensitive to carbachol-induced antagonism. The results are compatible with the concept that neuronal uptake produces a distribution of (-)-norepinephrine within the papillary muscle which allows predominantly high concentrations of (-)-norepinephrine to become effective in the receptor compartment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential effects of (-)-norepinephrine and of (+/-)-isoproterenol on cardiac contraction, an uptake phenomenon. 284 63

The relationship of hepatic ornithine decarboxylase (ODC) activity to cyclic AMP levels and nutritional status was studied in the pre-weanling rat. Previous studies demonstrated that 2 hr without food causes a loss of hepatic ODC induction after glucagon or catecholamine injection. Isoproterenol or glucagon administration produced increased hepatic cyclic AMP and tyrosine aminotransferase activity which were not prevented by nutritional deprivation. Blockade of hepatic beta 2 receptors by the selective antagonist ICI 118,551 prevented increased cAMP levels and ODC activity after isoproterenol administration. Blockade of beta 1 receptors by atenolol did not prevent increased cAMP levels or ODC induction by isoproterenol although it did block activation of cardiac ODC. The phosphodiesterase inhibitor RO20-1724 increased hepatic cAMP levels as well as ODC and TAT activities, although the increase in ODC activity was attenuated by nutritional deprivation. RO20-1724 also potentiated the induction of hepatic ODC after glucagon or isoproterenol administration. Administration of 8-bromo cAMP elevated hepatic ODC activity regardless of nutritional status but also elevated serum levels of growth hormone and corticosterone. Hepatic ODC induction by glucagon or beta 2 agonists can be dissociated from changes in cAMP levels during nutritional deprivation.
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PMID:Hepatic cyclic AMP generation and ornithine decarboxylase induction by glucagon and beta adrenergic agonists. 286 May 51

The time course of the effects of isoprenaline (3 X 10(-7) mol/l) on contractile force and on the cyclic AMP level was studied in the electrically driven isolated muscle strip of the human right atrium. Isoprenaline produced a rise in cyclic AMP content (maximum increase after 60 s) preceding the increase in contractile force. The effects of isoprenaline on contractile force and on the intracellular level of cyclic AMP were enhanced in the presence of the phosphodiesterase inhibitor papaverine (10(-5) mol/l). On the other hand, the beta-adrenoceptor antagonist propranolol (10(-7) mol/l) suppressed isoprenaline-induced cyclic AMP increases, but reduced the increase in force of contraction by only 35%. In addition, both the beta 1-selective antagonist bisoprolol (3 X 10(-9)-3 X 10(-8) mol/l) and the beta 2-selective antagonist ICI 118,551 (3 X 10(-9)-3 X 10(-8) mol/l) inhibited the isoprenaline-induced cyclic AMP increase concentration-dependently; ICI 118,551 produced more pronounced inhibition than bisoprolol. It is concluded that cyclic AMP is involved in the positive inotropic action of isoprenaline evoked by beta 1- and beta 2-adrenoceptor stimulation in isolated human right atrium; however, an additional cyclic AMP independent mechanism cannot be ruled out.
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PMID:The role of cyclic AMP in the positive inotropic effect mediated by beta 1- and beta 2-adrenoceptors in isolated human right atrium. 288 23

Topical 1 percent isoproterenol in the presence of the phosphodiesterase inhibitor theophylline was tested for its ability to stimulate the rate of aqueous humor flow through the anterior chamber of the normal and the partially adrenergically denervated human eye (Horner's syndrome). Both the affected eye and the unaffected eye were observed to have lower flows at night than during the day. Isoproterenol had no significant effect on flow during the day in normal eyes or in Horner's syndrome, but during sleep this beta-adrenergic agonist increased flow in the normal eye by 34% and in the Horner's eye by 50%. We interpret the results as indicating that beta-adrenergic activity in the human eye can stimulate aqueous formation under some conditions. However, the observed stimulation could have been due to something other than increased beta-adrenergic activity in the ciliary epithelium.
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PMID:Isoproterenol stimulates aqueous flow in humans with Horner's syndrome. 289 54

The effects of insulin and secretory agonists on amino acid incorporation into submandibular gland proteins were studied using isolated acinar cell aggregates. Insulin stimulated the incorporation of 3H-leucine into TCA-precipitable proteins in a rapid, dose-dependent manner (half-maximal response at 1 nM). Isoproterenol, a beta-adrenergic agonist, also stimulated amino acid incorporation, and this effect was mimicked by both dibutyryl cAMP and IBMX, a phosphodiesterase inhibitor. Although insulin further stimulated incorporation in the presence of isoproterenol and IBMX, no additional increase in the rate of synthesis was observed after stimulation by dibutyryl cAMP. High concentrations of carbamylcholine, a cholinergic agonist, inhibited both basal and insulin-stimulated incorporation. At low concentrations, however, carbamylcholine stimulated synthesis, and the effects of insulin and carbamylcholine were additive. A23187, a calcium ionophore, also inhibited 3H-leucine incorporation and insulin stimulation, but in contrast to carbamylcholine, low concentrations of A23187 neither inhibited nor enhanced the rate of synthesis. Thus, protein synthesis in the rat submandibular gland is regulated by both insulin and neurotransmitters. Whereas beta-adrenergic stimulation appears to be mediated through cAMP, the intracellular signals mediating the actions of insulin and cholinergic agonists remain to be elucidated.
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PMID:Insulin-stimulated protein synthesis in submandibular acinar cells: interactions with adrenergic and cholinergic agonists. 289 24

Previously, we reported that amrinone increases isometric twitch force but relaxes K+-induced contracture in muscles from normal cat right ventricle. This study evaluated its effects on diseased cardiac tissue. Right-ventricular papillary muscles were obtained from cats with subacute right-ventricular failure (3-14 days after partial pulmonary-artery ligation) and studied in vitro during stimulation (0.5 Hz) and exposure to high-K+ Tyrode solution. Active isometric twitch force and rate of force development (dP/dt) were significantly lower in muscles from hearts with right-ventricular failure compared to control muscles. In addition, while time to peak force was not different, duration of the twitch was significantly longer. In contrast to its positive inotropic actions in control muscles, amrinone (5.3 X 10(-4) M) had no significant effects on twitch force and dP/dt in muscles from failed ventricles. Time to peak force was not changed by amrinone in either group, but unlike its action in control muscle, duration of the twitch was reduced in failed muscle. Amrinone reduced K+-contracture force similarly in both control and failed muscles. Isoproterenol (10(-6) M) significantly increased twitch force and dP/dt and reduced K+-contracture force in both muscle groups. Since amrinone appears to be a phosphodiesterase inhibitor, our data indicate that cyclic AMP (cAMP)-related relaxation processes, but not cAMP-related contractile processes, can be enhanced by phosphodiesterase inhibitors in experimental heart failure. Furthermore, amrinone's reduced positive inotropic effect in failed myocardium suggests that its improvement of ventricular function in patients reflects, in part, enhancement of relaxation.
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PMID:Enhanced relaxation and reduced positive inotropic effects of amrinone in ventricular muscle from cats with subacute heart failure. Implications for drug therapy. 298 64

The adenosine-sensitive cyclic AMP phosphodiesterase of rat adipocytes was found to reside in the same subcellular fraction as the enzyme sensitive to insulin. There were several similarities between the action of adenosine and that of insulin on the enzyme. The action of adenosine on the phosphodiesterase is probably like that of insulin, both being receptor-mediated, although different sites or different receptors could be involved. Adenosine analogues with intact ribose but a modified purine moiety elicited a response similar to that of adenosine. Added Ca2+ was also not a requirement for the action of adenosine. The action of adenosine was not synergistic with that of insulin, neither was adenosine essential for insulin action. Insulin stimulated the enzyme even at low cell concentrations and in the presence of adenosine deaminase. Adenosine, however, enhanced the effect of insulin, but only at insulin concentrations that produced submaximal effects. Thus the mechanisms of action could be similar or related. The time-course effect of a suboptimal concentration of insulin was transitory, like that of adenosine, and was influenced by the presence of adenosine, whereas that of a maximally effective concentration of insulin was sustained for at least 20 min and was not affected by the presence of adenosine. Isoprenaline enhanced phosphodiesterase activity stimulated by optimal concentrations of either adenosine or insulin, suggesting that their effects were mediated through different mechanisms of action.
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PMID:The action of adenosine in relation to that of insulin on the low-Km cyclic AMP phosphodiesterase in rat adipocytes. 298 6

Changes in the concentration of cytosolic Ca2+ are assumed to alter the activity of Ca2+-calmodulin-sensitive cyclic nucleotide phosphodiesterase in intact cells. However, this assumption is based on indirect evidence and by analogy from studies of enzyme activities in broken cell systems. We have developed a procedure for estimating the fraction of Ca2+-calmodulin-sensitive phosphodiesterase that is in an activated, ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) sensitive state in intact porcine coronary artery strips. The experimental approach involves homogenization of the strips and assay of cyclic guanosine monophosphate (cyclic GMP) phosphodiesterase activity under conditions that retard changes in the amount of the complex Ca2+-calmodulin-phosphodiesterase. Our findings indicate that cyclic GMP phosphodiesterase in intact coronary artery strips does associate with Ca2+-calmodulin and that interventions that change the concentration of Ca2+ in the cytosol of the intact strip change the extent of this functional association. Exposure to histamine (10 or 100 microM) or 50 mM KCl caused contraction and an increase in EGTA-sensitive cyclic GMP phosphodiesterase activity. Isoproterenol-induced relaxation of tissues that had been caused to contract with 10 microM histamine was accompanied by a reduction in EGTA-sensitive cyclic GMP phosphodiesterase activity to the same level as that present before contraction was initiated.
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PMID:Differences in the association of calmodulin with cyclic nucleotide phosphodiesterase in relaxed and contracted arterial strips. 298 4

The contractile responses of an alpha-adrenoceptor agonist, phenylephrine, and of histamine were compared in the intimal and medial smooth muscle layers of the pig aortic arch. Further, the relaxant effects evoked by some compounds influencing the cyclic AMP system were compared in the two muscle layers, as well as their effects on the cyclic AMP content and phosphodiesterase activity. Phenylephrine and histamine induced contraction of the smooth muscle layers. The increase in tension was faster in the intimal than in the medial layer. The alpha-adrenoceptor agonist phenylephrine was a more potent contractile agent in the intimal than in the medial smooth muscle. With histamine, no significant difference in the dose-response curves between the two muscle layers was found. Histamine-contracted muscle preparations were relaxed in a dose-dependent manner by the phosphodiesterase-inhibiting compound 3-isobutyl-1-methylaxanthine (MIX) and by 8-bromo-cyclic AMP. The two substances were more potent relaxants in the medial than in the intimal smooth muscle layer. The content of cyclic AMP in the intimal and the medial smooth muscle was increased by MIX. Isoprenaline had no relaxing effect on the muscle preparations and did not change the content of cyclic AMP. There were no differences in the basal levels of cyclic AMP in the intima and media. Vmax of phosphodiesterase activities differed, however, between the two preparations. This study demonstrates that the intimal layer is characterized by a larger contractile responsiveness to phenylephrine and a lower relaxant response to compounds influencing the cyclic AMP-system than those of the medial layer.
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PMID:Contraction and cyclic AMP-related relaxation of the intimal and medial smooth muscle layers of pig thoracic aorta. 299 65

We have reported that the divalent cation ionophore A23187, like the beta-adrenergic agonist isoproterenol, increased the force of contraction and rate of relaxation and shortened the duration of contraction of papillary muscles isolated from guinea pigs. A23187 produced a fall in resting tension and decreased the contracture tension of K +/- depolarized muscles, as did isoproterenol. In the present studies, isoproterenol produced a concentration-dependent, rapid, and sustained increase in the cyclic AMP (cAMP) content of papillary muscle. In contrast, A23187 had no detectable effect on cAMP levels, even in the presence of the phosphodiesterase inhibitor, papaverine. Neither drug, at concentrations maximal for contractile effects, altered cyclic GMP (cGMP). Isoproterenol increased the cAMP-dependent protein kinase activity ratio, whereas A23187 did not change the activity of this enzyme. However, both A23187 and isoproterenol produced a concentration-dependent increase in phosphorylase activity. Concentrations of A23187 or isoproterenol that enhanced contractility maximally increased the alkali-labile phosphate (by ca. 35%) but were without effect on the acid-labile, alkali-stable phosphate in the total acid precipitable protein. Contractile effects of isoproterenol, which reflect activated Ca2+ uptake, and the increase in phosphorylase activity produced by this agent are believed to be due to an increase in cAMP with subsequent activation of cAMP-dependent protein kinases and phosphorylation of proteins. A23187 may produce similar contractile effects without an increase in cAMP or cAMP-dependent protein kinase activity by activating other protein kinases and/or inhibiting phosphoprotein phosphatases, most likely by its effects on intracellular calcium.
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PMID:Biochemical changes accompanying enhanced cardiac contractility by ionophore A23187. 300 Jan 97


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