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)

Multiple isozymes of cyclic nucleotide phosphodiesterase (PDE) exist in mammalian cells. At least 5 major types of PDE isozymes have been identified; they differ by substrate affinity, maximal activity, intracellular regulation or mechanism of pharmacologic inhibition. A low Michaelis constant (Km) cyclic adenosine monophosphate (cAMP) PDE, whose activity is inhibited by submicromolar concentrations of cyclic guanosine monophosphate and stimulated by cAMP-mediated phosphorylation, is present in both cardiac muscle and vascular smooth muscle. This PDE isozyme (referred to as peak IIIc PDE) is sensitive to selective inhibition by amrinone, milrinone, imazodan, CI-930, piroximone, and numerous other PDE inhibitors. The subcellular distribution of cardiac PDE IIIc varies according to species; it is found in the soluble fraction of guinea pig myocardium, in the particulate fraction of canine myocardium, and in both fractions of primate (simian and human) myocardium. Another PDE isozyme, which is sensitive to inhibition by rolipram and is less sensitive to inhibition by PDE IIIc inhibitors, is found in cardiac muscle of some species (i.e., soluble fractions of rat and canine myocardium) and is apparently not related to direct regulation of positive inotropy. Both positive inotropy and vasorelaxation by milrinone and other PDE IIIc inhibitors can be linked to inhibition of PDE IIIc and activation of the cAMP system. These significant relations are similar to those obtained for other cAMP-related positive inotrope/vasodilators (such as beta-adrenoreceptor agonists). Moreover, an increased rate of ventricular relaxation (lusitropy), which is apparent with PDE IIIc inhibitors, may also be attributable to activation of the cAMP system.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Biochemical aspects of inhibition of cardiovascular low (Km) cyclic adenosine monophosphate phosphodiesterase. 253 10

LY186126 was found to be a potent inhibitor of type IV cyclic AMP phosphodiesterase located in the sarcoplasmic reticulum of canine cardiac muscle. This compound, a close structural analogue of indolidan (LY195115), was prepared in high specific activity, tritiated form to study the positive inotropic receptor(s) for cardiotonic phosphodiesterase inhibitors such as indolidan and milrinone. A high-affinity binding site for [3H]LY186126 was observed (Kd = 4 nM) in purified preparations of canine cardiac sarcoplasmic reticulum vesicles. Binding was proportional to vesicle protein, was inactivated by subjecting membranes to proteolysis or boiling, and was dependent on added Mg2+. Scatchard analysis suggested the presence of a single class of binding sites in the membrane preparation. Indolidan, milrinone, and LY186126 (all at 1 microM) produced essentially complete displacement of bound [3H]LY186126, while nifedipine, propranolol, and prazosin had little or no effect at this concentration. This represents the first reported use of a radioactive analogue to label the inotropic receptor for cardiotonic phosphodiesterase inhibitors. The results suggest that [3H]LY186126 is a useful radioligand for examining the subcellular site(s) responsible for positive inotropic effects of these drugs.
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PMID:Specific binding of [3H]LY186126, an analogue of indolidan (LY195115), to cardiac membranes enriched in sarcoplasmic reticulum vesicles. 253 21

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

Milrinone is a positive inotropic and vasodilator agent when tested in experimental animals and in human heart-failure patients. It is generally believed that milrinone acts by inhibiting phosphodiesterase IV, thus increasing cyclic AMP, [Ca++]i and cardiac contractile force and relaxation. Maximal force produced by milrinone is greater when single-dose response curves are compared to cumulative dose-response curves. In vitro, milrinone produces a tachyphylaxis, the extent of which is both dose- and time-dependent. Recovery of tachyphylaxis is both dose- and time-dependent and is not influenced by inhibitors of protein or RNA synthesis. There is a specific cross-tachyphylaxis between milrinone and amrinone, theophylline, papaverine, and Bay K8644. This tachyphylaxis may explain the low maximal contractile response of the cumulative dose-response observed in isolated tissues. Milrinone increased cyclic AMP in dog and guinea pig cardiac muscle. As previously shown by Endoh et al., milrinone in low doses produced a biphasic effect on cyclic AMP. The early increase (first 60-70 s) in cyclic AMP shows a good correlation with contractile force changes. If cyclic AMP is determined at maximal contractile force this correlation was poor. Here we also present instances where the increase in cyclic AMP after milrinone (determined at maximal effect) does not correlate with the contractile response. The cross-tachyphylaxis of milrinone with Bay K8644 suggests that milrinone has an action on the sarcolemmal Ca++ channels. Bay K8644 suppresses the positive inotropic effect of catecholamines by 50%, but not the cyclic AMP response. The inotropic effect of milrinone, in contrast to norepinephrine is highly sensitive to [Ca++]0, stimulation rate, and [K+]0. In this respect milrinone behaves more like Bay K8644. We postulate that the main inotropic action of milrinone is due to a sarcolemmal effect. The early cyclic AMP production described could be in the sarcolemmal compartment and this may explain some of the similarities of milrinone's actions with those of Bay K8644. The tachyphylaxis observed with the inotropic effect of milrinone does not extend to the decreases in relaxation time. This and other findings to be discussed suggest that the positive inotropic and reduction in relaxation time by milrinone depend on different mechanisms, possibly through differential compartmentalization of cyclic AMP.
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PMID:Studies on the mechanism of action of the bipyridine milrinone on the heart. 255 75

Mammalian cells contain multiple molecular forms of cyclic nucleotide phosphodiesterase that differ in substrate specificity and kinetic and regulatory properties. Calcium/calmodulin and cyclic GMP are important regulators of the hydrolysis of cyclic AMP by either stimulating or inhibiting the activity of distinct forms of phosphodiesterase. Several isozymes of cyclic nucleotide phosphodiesterase have been purified to apparent homogeneity. Although some sequence homology is observed the isozymes appear genetically distinct by immunological criteria. Cyclic AMP- and calmodulin-dependent protein kinases can phosphorylate these enzymes and alter their kinetic and regulatory properties. Both tissue specificity and pharmacological selectivity of isozymes have been demonstrated for several drugs. In certain cases, e.g. cardiac muscle, the selective inhibition of a high affinity cAMP phosphodiesterase activity in a specific subcellular fraction correlates with pharmacologic responses. The results from molecular and pharmacologic studies of cyclic nucleotide phosphodiesterases have indeed expanded the role this system of isoenzymes exerts in the regulation of cellular function.
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PMID:Molecular properties of cyclic nucleotide phosphodiesterase isozymes. 255 3

New knowledge and insight into cardiac muscle physiology and pharmacology together with the development of novel drugs may change the treatment of congestive heart failure in the future. This article reviews two newer inotropic mechanisms currently under investigation. It will place special emphasis on the mechanisms of action of selective cardiac phosphodiesterase inhibition and of alpha 1-adrenoceptor mediated stimulation of the phosphoinositide pathway.
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PMID:New positive inotropic agents acting by phosphodiesterase inhibition or alpha 1-adrenergic stimulation. 257 Apr 16

Several novel cardiotonic vasodilators including bipyridines (amrinone and milrinone), imidazolones (enoximone and piroximone), dihydropyridazinones (Cl-914, Cl-930 and LY195115) and an imidazopyridine (isomazole) relaxed rat aortic strips contracted previously with 30 microM serotonin. LY195115 and Cl-930 were the most potent vasorelaxant agonists (ED50 approximately 10(-7) M), whereas piroximone and amrinone were the least potent (ED50 approximately 10(-5) M). In addition to these positive inotropic agents, vascular relaxation was examined further for a series of novel dihydropyridazinones, and relaxant potencies correlated directly with the ability of these agents to inhibit an isozyme of cyclic nucleotide phosphodiesterase (PDE) located in the sarcoplasmic reticulum of cardiac muscle (SR-PDE) (r = 0.87, P less than .01). This excellent correlation suggests that vascular relaxation produced by these agents is related to their ability to inhibit a vascular enzyme similar or identical to SR-PDE. Furthermore, LY195115, milrinone and isomazole (10(-4) M) produced significant increases in both aortic cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Time courses for these changes were consistent with a role for cyclic nucleotides in relaxation; however, differences between the relative increases in cAMP or cGMP produced by these drugs were evident. Removal of the aortic endothelium had no effect upon relaxation produced by milrione and only a modest (approximately 2-fold decrease in potency) effect on relaxation produced by LY195115 and isomazole, indicating that the relaxant effect of these cardiotonics is primarily an endothelium-independent event.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vitro vascular relaxation by new inotropic agents: relationship to phosphodiesterase inhibition and cyclic nucleotides. 282 Dec 28

Extraction of frozen canine cardiac muscle rendered soluble over 90% of the cyclic AMP phosphodiesterase activity. The residual activity was membrane-bound. Ion exchange chromatography of the soluble activity on DE-52 allowed for the resolution of three distinct cyclic AMP phosphodiesterase fractions termed PDE-I, PDE-II and PDE-III in order of elution from the column by a linear NaCl gradient. The relative ratio of cyclic AMP phosphodiesterase activity exhibited by these three peaks was 1:0.65:0.82 and of cyclic GMP phosphodiesterase activity was 1:0.52:0.05 for PDE-I, PDE-II and PDE-III respectively. PDE-II and PDE-III were further purified by re-chromatography on DE-52. Fractions PDE-II and PDE-III were thermolabile at 50 degrees, decaying as single exponentials with half lives of 180 sec and 77 sec respectively. All three species exhibited non-linear Lineweaver-Burke plots for the hydrolysis of cyclic AMP, exhibiting both high and low affinity components. Hydrolysis of cyclic GMP by all three components obeyed normal kinetics, yielding linear plots. PDE-I was a Ca2+/calmodulin-activated species which exhibited a low Km for both cyclic AMP and cyclic GMP but hydrolysed cyclic GMP with a higher Vmax than for cyclic AMP. PDE-II exhibited a much lower Km for cyclic AMP than for cyclic GMP and a much higher Vmax for the hydrolysis of cyclic AMP. PDE-III exhibited a low Km for both cyclic AMP and cyclic GMP, however, its Vmax for cyclic AMP was about 40-fold higher than for cyclic GMP. Cyclic GMP acted as a potent inhibitor (IC50 = 6.3 microM) of cyclic AMP hydrolysis catalysed by PDE-III but not of the hydrolysis of cyclic AMP by PDE-II (IC50 = 33.2 microM). The phosphodiesterase inhibitors milrinone, CI-930, UK-35,493, carbazeran and buquineran acted as potent inhibitors of cyclic AMP hydrolysis catalysed by both PDE-II and PDE-III enzymes. They did not inhibit PDE-I activity. PDE-II, when prepared in the absence of protease inhibitors exhibited a reduced potency to inhibition by these compounds. Treatment of purified PDE-II with trypsin caused a reduction in enzyme activity and reduced dramatically the sensitivity of PDE-II activity to inhibition by these various compounds. The action of proteolysis in attenuating the inhibitory effect of these compounds on PDE-II was most dramatic with CI-930, milrinone, amrinone, buquineran and UK35,493 and least dramatic with carbazeran and IBMX.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Proteolysis of cyclic AMP phosphodiesterase-II attenuates its ability to be inhibited by compounds which exert positive inotropic actions in cardiac tissue. 282 12

Two approaches were taken to examine the role which the different forms of phosphodiesterase present in cardiac muscle play in regulating contractility. In an initial study, the effect of selective inhibitors of i) the calmodulin-stimulated phosphodiesterase (M & B 22, 948), ii) the cyclic GMP-stimulated phosphodiesterase (dipyridamole), and iii) the low Km, cyclic AMP-specific phosphodiesterase (imazodan) on the contractility of isolated guinea pig left atria was examined. Of the three selective phosphodiesterase inhibitors, only imazodan increased atrial contractility. In a subsequent study, the effect of imazodan on in vivo contractility was evaluated. Imazodan was found to potently increase contractility in the dog and the Rhesus monkey, while exerting only modest-to-minimal effects of contractility in the guinea pig and the hamster. Imazodan produced no positive inotropic effect in the rat. These species differences can apparently be attributed to i) the presence of subclasses of the low Km, cyclic AMP-specific phosphodiesterase (PDE III) in cardiac muscle, one of which is potently inhibited by the selective PDE III inhibitors imazodan, cyclic GMP and cilostamide, and the other which is selectively inhibited by rolipram and Ro 20-1724, and ii) variations in the intracellular localization of imazodan-sensitive subclass of PDE III. Thus, the maximum inotropic response to imazodan was observed only in those species in which the imazodan-sensitive subclass of PDE III was present and was membrane-bound, e.g., Rhesus monkey and dog. In the dog, the imazodan-insensitive subclass PDE III does not appear to play an important role in regulating cardiac contractility. These observations provide further support for the hypothesis that the inotropic response to imazodan, amrinone and related cardiotonics is due to their inhibitory effects on the cyclic AMP-specific form of phosphodiesterase, and also provides new insight into the relationship between cyclic AMP, phosphodiesterase and myocardial contractility.
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PMID:Multiple molecular forms of phosphodiesterase and the regulation of cardiac muscle contractility. 283 Dec 59

Phosphodiesterase isozymes were isolated by diethylaminoethyl ether (DEAE) column chromatography from cardiac muscle (canine, guinea pig), vascular (canine and guinea pig aortic) and airway (canine tracheal) smooth muscle. All peak I phosphodiesterases had a low apparent Km (0.29-0.49 microM) for guanosine 3':5' cyclic monophosphate (cGMP) and all peak III phosphodiesterases had a low apparent Km (0.35-0.58 microM) for adenosine 3':5' cyclic monophosphate (cAMP); trachealis peak III also had a high Km for cAMP (32 microM). The potency and selectivity for inhibition of peak I or peak III phosphodiesterase by theophylline and papaverine, the peak I selective inhibitor M + B 22948, and the peak III selective inhibitors amrinone, milrinone, imazodan, CI-930 and piroximone were approximately equal when isozymes isolated from aortic smooth muscle were compared to isozymes isolated from cardiac muscle of both species. Rolipram was relatively potent as a peak III phosphodiesterase inhibitor in canine cardiac muscle, but was impotent in the other cardiovascular peak IIIs. In tracheal smooth muscle, the cardiovascular selective peak III phosphodiesterase selective inhibitors were substantially less potent while rolipram was more potent as a peak III inhibitor. In summary, these studies show that while cardiac and vascular smooth muscle phosphodiesterase isozymes are pharmacologically similar, there is pharmacological and substrate heterogeneity of peak III phosphodiesterase in aortic vs. trachea smooth muscle within the same species.
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PMID:Differential pharmacologic sensitivity of cyclic nucleotide phosphodiesterase isozymes isolated from cardiac muscle, arterial and airway smooth muscle. 284 Nov 46


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