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)

Class III antiarrhythmic agents may prolong refractoriness via modulation of ion channels, which may be sensitive to Ca2+ regulatory proteins or enzymes. Accordingly, the purpose of this study was to quantitate the effects of several structurally diverse class III antiarrhythmic agents on calmodulin-regulated enzymes and protein kinase C activity, and to evaluate the ability of these agents and known calmodulin antagonists to prolong cardiac refractoriness in vivo. The rank order of potency (IC50;microM) of selected class III antiarrhythmic agents and reference calmodulin antagonists as inhibitors of calmodulin-regulated phosphodiesterase activity were: calmidazolium (0.12 microM) greater than amiodarone (0.62 microM) greater than desethylamiodarone (1.5 microM) greater than trifluoperazine (4.3 microM), bepridil (5 microM) greater than W-7 (7.5 microM), clofilium (13 microM). Similar concentration-related inhibition was evident in a second calmodulin-regulated system, inhibition of myosin light-chain phosphorylation and superprecipitation of arterial actomyosin. Sotalol and tetraethylammonium were inactive at 100 microM. Protein kinase C activity was also inhibited by some of these agents; desethylamiodarone (IC50 = 11 microM) was more potent than the reference agent, H-7 (IC50 = 79 microM), or amiodarone (38% inhibition at 100 microM) and clofilium (32% inhibition at 100 microM). In vivo, the minimally effective doses required to increase ventricular effective refractory periods in paced guinea pigs were (in mg/kg) bepridil, sotalol [1] greater than clofilium [3] greater than amiodarone [10] greater than W-7, desethylamiodarone [20]. No changes in refractory period were noted with maximum testable doses of calmidazolium or trifluoperazine. These studies show that some, but not all, class III antiarrhythmic agents are effective and potent calmodulin antagonists or protein kinase C inhibitors. Moreover, some calmodulin antagonists are effective at prolonging refractoriness in vivo. However, a lack of correlation between these agents suggests that these mechanisms are not solely responsible for the prolongation of refractoriness of all class III agents.
Cardiovasc Drugs Ther 1989 Oct
PMID:Inhibition of calmodulin and protein kinase C by amiodarone and other class III antiarrhythmic agents. 248 7

With scanning electron microscopy, we examined the behavior of platelets and leukocytes on the luminal surface of small caliber polyurethane grafts implanted into small arteries of dogs. Thirty-five grafts were implanted to the carotid and/or femoral arteries. The animals were treated with aspirin and/or DN9693, an inhibitor of phosphodiesterase. In the group treated with aspirin (40 mg/kg i.v.), the deposition of platelets on the luminal surface of the implanted polyurethane grafts was suppressed and the luminal surface was covered with adherent leukocytes. Fibrin nets were formed on the adherent leukocytes. In addition, the adhesion of leukocytes on the grafts was considerably suppressed in the group treated with DN9693 (50 micrograms/kg/min i.v.), and the formation of fibrin nets was markedly reduced. In contrast, in the control group the luminal surface was covered with numerous platelets and some leukocytes, which formed thrombi. These findings suggest that leukocytes adhere primarily to the prosthetic graft and play an important role in the initiation of fibrin formation.
J Cardiovasc Surg (Torino)
PMID:Behavior of platelets and leukocytes on the luminal surface of small caliber polyurethane grafts. 255 Apr 68

A method is described for studying platelet function in human whole blood immediately after venepuncture in order to evaluate the antithrombotic potential of new pharmacological agents. In this method, platelet aggregation is quantified by measuring the fall in single platelet count, by using a whole blood platelet counter. We have investigated the platelet aggregation inhibitory effects of the new positive inotropic agents pimobendan and UD CG 212 (reported to be Ca++ sensitisers and phosphodiesterase inhibitors), alone and in combination with dipyridamole. Venous blood was drawn directly into prewarmed (37 degrees C) plastic syringes containing anticoagulants (3.2% trisodium citrate solution) plus a platelet aggregation inhibitor. Spontaneous platelet aggregation (SPA) was studied by roller mixing aliquots of blood in the collecting syringes for 6 min at 37 degrees C. Collagen induced platelet aggregation was studied by incubating aliquots of blood with 1 microgram/ml collagen on a shaking water bath for 3 min. In the absence of an inhibitor, there was a 50% fall in single platelet count due to SPA and a 65% fall was induced by collagen. Both SPA and collagen induced aggregation responses were inhibited by pimobendan (0.5-10 microM) and UD CG 212 (0.5-10 microM), in a dose dependent manner. A combination of 10 microM dipyridamole with 2 microM pimobendan or UD CG 212 was markedly a more effective inhibitor of platelet aggregation than a high dose of either inhibitor alone. It is suggested that the present method is simple and rapid, with minimal sample processing, and therefore the results may be protected from serious artifacts.(ABSTRACT TRUNCATED AT 250 WORDS)
Cardiovasc Res 1989 Mar
PMID:Platelet aggregation inhibitory effects of the new positive inotropic agents pimobendan and UD CG 212 in whole blood. 259 Sep 3

Annual mortality from congestive heart failure ranges from 15% to 60%, depending on the severity of the left ventricular damage and underlying disease. Most controlled trials have been too small to detect any beneficial effect on survival from the newer vasodilator and inotropic drugs. However, the results of two recent studies strongly suggest that some vasodilator drugs improve prognosis. In one study, a hydralazine-nitrate combination reduced 2-year mortality by 34%, while in another study, enalapril, in addition to diuretics, digitalis, and directly acting vasodilators, reduced 1-year mortality by 31%. Thus far no large studies have been published with the new phosphodiesterase-inhibiting agents. Although preliminary reports of large-scale trials did not demonstrate changes in survival rate, they have been shown to improve well-being in class III-IV congestive heart failure patients.
Cardiovasc Drugs Ther 1988 Nov
PMID:Therapeutic advances in heart failure. 315 50

Isolated rabbit coronary arteries, aortic strips, and a working rabbit heart preparation were used to assess the positive inotropic and vasodilator effects of a newly developed positive inotropic compound, CI 914. The substance had a relaxing effect on histamine preconstricted coronary arteries and aortic strips. At concentrations of 10(-4) mol.litre-1 the relaxing effect on the coronary arteries was significant only at a histamine concentration of 3 x 10(-4) mol.litre-1 (p less than 0.01) whereas at a concentration of 10(-3) mol.litre-1 the relaxing effect was significant at histamine concentrations of from 3 x 10(-5) mol.litre-1 to 3 x 10(-4) mol.litre-1. Aortic strips were more sensitive to the relaxing effect of CI 914, which was significant with 10(-4) mol.litre-1 at histamine concentrations of 3 x 10(-6) to 3 x 10(-4) (p less than 0.05 to p less than 0.01). In the isolated working heart preparation topically sprayed histamine significantly increased total and large coronary artery resistances (p less than 0.001 and p less than .01). This effect was significantly reduced (p less than 0.01 and p less than 0.02) when CI 914 10(-4) mol.litre-1 was present in the perfusion fluid. These findings show that the phosphodiesterase inhibitor CI 914, a positive inotropic agent, induces vasodilation in isolated coronary arteries and aortic strips of the rabbit and reduces the constriction of coronary arteries induced by histamine in the isolated working rabbit heart preparation.
Cardiovasc Res 1987 Aug
PMID:Effect of a new phosphodiesterase type III inhibitor as a coronary vasodilator and positive inotropic agent. 344 63

The purpose of these studies was to characterize mechanisms of activation of vascular tissues in order to clarify possible theoretical bases for Ca2+-antagonist (CAt) selectivity. Activation of rabbit aorta, mesenteric artery, and mesenteric resistance vessels by agonists and depolarizing potassium (K+) solution, and inhibition by CAts were studied by measurement of contractions, 45Ca fluxes, and membrane potentials (via intracellular electrodes). We found that the CAts studied (D-600, diltiazem, and nisoldipine) inhibited K+-induced Ca2+ influx and contractions in a closely correlated manner, suggesting inhibition of Ca2+ entry as their primary, if not sole, mechanism of action. Diltiazem and nisoldipine had no effect on intracellular Ca2+ release or on the contractile protein system. The following evidence was obtained to support the tenet that norepinephrine (NE) and 80 mM K+ open two distinct Ca2+ channels, one receptor-operated (ROC) and the other potential-operated (POC): (a) NE activated the rabbit aorta without eliciting a change in membrane potential; (b) NE activation of the rabbit mesenteric resistance vessels was accompanied by membrane depolarization, but this depolarization was blocked by 10(-5) M diltiazem, whereas that induced by 80 mM K+ was not; (c) 45Ca influx stimulated by 80 mM K+ and that stimulated by a maximal [NE] were additive when the two agents were administered together in the aorta and the resistance vessels; (d) the Ca2+-channel agonist Bay K8644 opens the POC but not the ROC in rabbit aorta, as it is capable of stimulating Ca2+ influx in addition to 10(-5) M NE, but not to 80 mM K+; (e) the CAts show selective inhibition of the POC over the ROC in the aorta, whereas diltiazem preferentially inhibits the ROC in the resistance vessels; and (f) alpha adrenoreceptor occupation, phosphodiesterase inhibition, or dibutyryl cyclic AMP selectively inhibits the POC over the ROC in the aorta.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol 1984
PMID:Theoretical bases for vascular selectivity of Ca2+ antagonists. 608 5

In vitro studies have demonstrated that AR-L 115BS (AR-L), a new orally active nonglycosidic inotropic agent with vasodilator properties, does not act via adrenergic receptors. However, because AR-L is a phosphodiesterase inhibitor and interaction with the adrenergic nervous system may exist in vivo, we compared the actions of intravenous AR-L, isoproterenol, and propranolol, alone and in combination, in normal dogs. In seven awake morphine-sedated dogs, AR-L (4 mg/kg i.v.) did not alter circulating catecholamines despite increasing maximum rate of change of left ventricular pressure (dP/dt) by 76%. In anesthetized dogs, peak inotropic effect of AR-L occurred at 6 mg/kg (dP/dt from 5,450 +/- 1,280 to 12,000 +/- 3,050 mm Hg/s). Propranolol (1 mg/kg) depressed dP/dt from 5,725 +/- 2,032 to 2,530 +/- 631 mm Hg/s, and this was completely reversed by increasing doses of AR-L (2-30 mg/kg) but the maximum dP/dt attained in these dogs (6,050 +/- 221 mm Hg/s) remained below the level achieved by AR-L in the absence of propranolol. To determine if that difference was due to an interaction of AR-L with the adrenergic nervous system, the effect of AR-L on isoproterenol activity was studied in groups of beta-blocked and unblocked animals. In either group, the dose-response curve of dP/dt to isoproterenol was shifted upward by AR-L, but the actions of the two drugs were additive without real synergism (e.g., after propranolol:isoproterenol 10 micrograms/min 73%; AR-L 6 mg/kg 81%; both 160%. In unblocked dogs, the results were: isoproterenol 2 micrograms/min 96%; AR-L 1 mg/min 39%; both 138%). Similarly, isoproterenol and AR-L were only additive in their effects on heart rate and systemic vascular resistance. Thus, although AR-L is a phosphodiesterase inhibitor, its predominant mechanism of action appears to be independent of the adrenergic nervous system.
J Cardiovasc Pharmacol
PMID:In vivo interaction of AR-L 115BS (Vardax) with the adrenergic nervous system. 608 57

We examined the role of beta-adrenoceptors in regulating cardiac cell cyclic adenosine monophosphate (cyclic AMP) in concentrations during beta-receptor activation. Chick embryo cardiac cells in primary tissue culture respond to 50 microM isoprenaline with a rapid, but transient, increase in intracellular cyclic AMP. Continued exposure of these cells to this concentration of isoprenaline results in a rapid time-dependent decrease in maximum beta-receptor responsiveness. In vitro determination of adenylate cyclase and 125I-iodohydroxybenzyl pindolol specific beta-receptor binding sites in 35,000 x g particulate cell fractions and phosphodiesterase activity in cell homogenates suggest that the decrease in the cells' ability to raise intracellular cyclic AMP concentration is mainly due to an initial "uncoupling" of the beta-receptor--adenylate cyclase system. During 16 hr exposure of cells to varying isoprenaline concentrations, the magnitude of the cells' ability to increase intracellular cyclic AMP and the concentration of beta-receptor binding sites were inversely related to the isoprenaline concentration to which they had been previously exposed. On removal of isoprenaline, both beta-receptor response and receptor concentration returned slowly towards control levels over the next 24 hr. These results suggest that loss of beta-receptor responsiveness of cardiac cells during prolonged exposure to isoprenaline involves both alterations in receptor number and alterations of the adenylate cyclase system distal to the receptor.
J Cardiovasc Pharmacol
PMID:Mechanism of isoprenaline-induced refractoriness of the beta-adrenoceptor--adenylate cyclase system in chick embryo cardiac cells. 616 35

MDL 17,043 (1,3-dihydro-4-methyl-5-[4-(methylthio)-benzoyl]-2H-imidazol-2-one) is a new drug with cardiotonic properties. Its effects on several biochemical systems considered to be important in myocardial contraction were investigated and compared with those produced by amrinone and theophylline. Dog cardiac phosphodiesterases (PDEs) were separated into three major forms and labeled PDE I, II, and III according to the order of elution during isolation by column chromatography. PDE I and II, considered to be "high-Km" enzymes for cyclic AMP, were not inhibited by MDL 17,043, amrinone, or theophylline in concentrations of 50 microM. PDE III, a "low-Km" enzyme, was strongly inhibited by MDL 17,043. Kinetic studies showed the inhibition to be characteristic of partial competitive inhibition. At 0.25 microM cyclic AMP, 1.3 microM MDL 17,043 caused 50% inhibition of PDE III (I50), while the I50 for amrinone and theophylline were estimated to be 19.5 microM and 119 microM, respectively. Dog kidney Na+, K+-ATPase was inhibited 54% by 100 microM MDL 17,043 while amrinone caused an 18% inhibition at the same concentration. Ca2+-ATPase and Ca2+ uptake by dog sarcoplasmic reticulum vesicles were unchanged by MDL 17,043 concentrations up to 300 microM and 100 microM, respectively. It is suggested that the inhibition of PDE III is related to the cardiotonic effects produced by MDL 17,043 and amrinone, although inhibition of Na+, K+-ATPase may also play a role at high concentrations of these drugs.
J Cardiovasc Pharmacol
PMID:Biochemical studies on the mechanism of cardiotonic activity of MDL 17,043. 617 50

Aprindine, an antiarrhythmic agent with structural similarities to lidocaine and procainamide, has proved effective in treatment of patients with ventricular premature depolarizations, ventricular tachycardia, and supraventricular arrhythmias. While its effects at an electrophysiologic level have been elucidated, its mechanism of action at a biochemical level has remained largely undefined. The data in this communication demonstrate that aprindine inhibits the activation of bovine brain cyclic 3':5'-nucleotide phosphodiesterase (EC 3.1.4.17) by calmodulin. This inhibition is specific for the calmodulin-stimulated enzyme, as no effect of aprindine is seen when phosphodiesterase is assayed in the absence of calmodulin. The inhibition is competitive with respect to substrate (cyclic AMP) and calmodulin concentrations. In the presence of 10 nM calmodulin, the ID50 for aprindine is 18 microM. This inhibition is not the result of aprindine acting as a calcium chelator because increasing the calcium concentration does not reverse the inhibitory effect. Aprindine also inhibits calmodulin-stimulated Ca-ATPase (ATP phosphohydrolase EC 3.6.1.3) activity, but again has no effect on the enzyme in the absence of calmodulin. Aprindine has hydrophobic properties which may be responsible for the inhibitory effect. Sufficient concentrations of aprindine are achieved in myocardial tissues to interfere with the ability of calmodulin to stimulate a number of enzymes present in the heart.
J Cardiovasc Pharmacol
PMID:Aprindine inhibits calmodulin-stimulated phosphodiesterase and Ca-ATPase activities. 618 51


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