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)

Anthopleurin-A (AP-A), a polypeptide with MW ca. 5500 (53 amino acids), isolated from the sea anemone, Anthopleura xanthogrammica (Brandt), elicited a potent positive inotropic effect but without an accompanying chronotropic effect on the isolated cardiac muscles of rat, rabbit, guinea pig and cat. Similarly in dogs and cats in situ, i.p. injections of AP-A increased the contractile force without effect on heart rate or blood pressure. The cardiotonic potency for AP-A was equivalent to that of isoproterenol but much greater than that for ouabain or glucagon on the isolated cardiac muscle. AP-A increased the contractile force (cardiac output) and decreased atrial pressure in dog heart during pentobarbital-induced failure. This inotropic effect was not inhibited by propranolol pretreatment. The Ca++ requirement to restore the contractile force was less in AP-A-treated than in ouabain or isoproterenol-treated tissues. After AP-A treatment, the cardiac contractility was more resistant to hypoxia and to low or high temperature stress than ouabain-treated or control preparations. AP-A at 5 10(-9) M increased the duration of the action potential, its mean rate of rise and conduction in the guinea-pig atria and ventricles. At the maximum effective concentration, AP-A did not inhibit Na+, K+-activated adenosine triphosphatase, phosphodiesterase (high Km and low Km) and cyclic 3',5'-adenosine monophosphate content of guinea-pig heart. AP-A (5 X 10(-8) to 5 X 10(-7) M) neither contracted nor relaxed the isolated vascular smooth muscle. The results suggest that AP-A may be useful in the clinical management of cardiac failure and as an experimental tool to study the pharmacology and physiology of cardiac muscle.
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PMID:A polypeptide (AP-A) from sea anemone (Anthopleura xanthogrammica) with potent positive inotropic action. 1 Apr 26

Cyclic AMP content, adenylate cyclase (EC 4.6.1.1) activity and phosphodiesterase I (EC 3.1.4.1) activity of the hind leg skeletal muscle and cardiac muscle in 60- and 150-day-old normal and myopathic (UM-X7.1) hamsters were examined. In 60-day-old myopathic animals, cardiac cyclic AMP levels were higher and phosphodiesterase I activity was lower, without any changes in the basal adenylate cyclase activity, whereas in 150-day-old myopathic hamsters, cardiac cyclic AMP and basal adenylate cyclase activity were lower, without any changes in the homogenate phosphodiesterase I activity. On the other hand, basal adenylate cyclase and phosphodiesterase I activities in the skeletal muscle homogenate from 60- and 150-day-old myopathic animals were not different from the normal values but the skeletal muscle cyclic AMP levels were significantly less in 60-day-old myopathic hamsters only. The plasma cyclic AMP levels in 60-day-old myopathic hamsters, unlike 150-day-old myopathic animals, were higher than the normal. Although these results reveal differences in myopathic cardiac and skeletal muscles, it is concluded that changes in adenylate cyclase-cyclic AMP system in myopathy are dependent upon the degree of disease.
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PMID:Studies on adenylate cyclase-cyclic AMP system of the myopathic hamster (UM-X7.1) skeletal and cardiac muscles. 17 52

Cyclic nucleotide phosphodiesterase activity of several tissues of rat is inhibited by an endogenous factor isolated from rat adipocytes following exposure of these cells to agents that raise intracellular cyclic AMP levels. The inhibitory action was demonstrated with varying cAMP concentrations from 0.1-400 muM. Enzyme from 10,000 X g supernatant of epididymal adipose tissue was inhibited approximately 2-3 fold more than the plasma membrane of adipocytes by a given concentration of the feedback regulator. Kinetic analysis of cAMP phosphodiesterase of plasma membrane showed that feedback regulator (8.8 U/ml) inhibited the Vmax 48%. The maximum inhibition of phosphodiesterase by feedback regulator (20 U/ml) was about 80%. The apparent Km for cAMP was increased. The ability of phosphodiesterase from several tissues of rat (10,000 X g supernatant) to hydrolyze cAMP and cGMP was tested. Feedback regulator inhibited cGMP hydrolysis in cardiac muscle and 5 other tissues 23-92% more than it inhibited the hydrolysis of cAMP. The physiological significance of this inhibitory effect can begin to be clarified when the feedback regulator is purified to homogeneity and characterized.
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PMID:Inhibition of cyclic nucleotide phosphodiesterase activity by an endogenous factor. 17 58

Utilization of 14C-prelabeled endogenous triglycerides was studied in isolated perfused working rat hearts. Lipolysis was estimated by the disappearance of 14C-labeled and total triglycerides. Metabolic 14CO2 production was continuously monitored to evaluate triglyceride fatty acid oxidation. Triglyceride utilization was enhanced by an increase in ventricular pressure development as evidenced by a faster rate of triglyceride mobilization and oxidation. Added catecholamines stimulated lipolysis in hearts perfused with glucose-containing buffer but were without effect in the presence of exogenous fatty acids; the latter were shown to be potent and, possibly, direct inhibitors of myocardial lipolysis. Mediation of catecholamine-induced lipolysis by cyclic AMP has not been settled. Dibutyryl cyclic AMP produced only a slight lipolytic effect, although theophylline, a known phosphodiesterase inhibitor, was a potent lipolytic agent. Theophylline may have exerted its lipolytic effect through an alternative mechanism. Hypoxia per se was a strong inhibitor of heart triglyceride utilization. Furthermore, added epinephrine was without effect on triglyceride lipolysis in hypoxic hearts. Thus, cardiac muscle triglyceride utilization is influenced by such factors as mechanical function, exogenous substrates, hormones, and oxygen availability. The mechanisms involved in these areas of regulation need to be resolved.
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PMID:Regulation of triglyceride metabolism in the isotopically prelabeled perfused heart. 19 38

Contractile responses of guinea-pig atria to papaverine were analyzed under different stimulation frequencies. Atria, driven at 2 Hz, showed positive inotropic responses to papaverine which were maximal within 10-15 min. These responses were maintained for 60 min in the presence of low concentrations of papaverine (up to 10(-5) M), but reversed into marked negative inotropic effects under the influence of higher concentrations. The well-known frequency-force relationship was reversed by papaverine. At low stimulation rates papaverine elicited positive inotropic responses, which gradually decreased with increasing frequencies until strong cardiodepression occurred. A frequency-force curve obtained in the presence of both the Ca2+-antagonistic drug D 600 and the inhibitor of the phosphodiesterase theophylline was similar to that obtained under the influence of papaverine. Theophylline alone evoked positive inotropic effects at all frequencies studied and left the character of the ascending staircase unchanged. In contrast, D 600 was ineffective at low, but cardiodepressive at high stimulation frequencies. In the presence of D 600 or papaverine high external Ca2+ could not restore a normal frequency-force relationship. The reversal of the frequency-force relationship as produced by D 600 and papaverine could not be obtained by lowering of the external Ca2+. The present results show that papaverine is able to evoke marked positive inotropic effects at low stimulation frequencies by inhibition of phosphodiesterase. At high frequencies, however, these effects are masked by negative inotropic responses due to the inhibitory action of papaverine on Ca2+-exchange of the cardiac muscle cell.
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PMID:Effect of papaverine on the frequency-force relationship in guinea-pig left atria. 83 71

Since the use of cardiac glycosides for heart failure therapy is limited by their narrow margin of safety, numerous efforts have been made to find and develop novel cardiotonic agents that are superior to the cardiotonic glycosides. Positive inotropic drugs acting on beta-adrenoceptors and inhibitors of cAMP phosphodiesterase have been extensively studied for the treatment of patients with heart failure. The main mechanism of these agents is elevation of cAMP tissue levels. Furthermore, Ca sensitizers such as sulmazol, pimobendan, MCI-154, END 53998 and DPI 201-106 are of interest, since such a mechanism of action may be beneficial for the failing heart. Recently, cardiotonic substances with a novel mechanism of action such as gingerol and xestoquinone have been isolated from natural sources. Natural products, purealin, goniodomin and okadaic acid, have proven to be valuable pharmacological tools for studies on cardiac muscle contraction.
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PMID:[Novel types of cardiotonic drugs]. 139 36

This study analyses the effects of Amrinone (bipyridine derivative with phosphodiesterase inhibitor properties) on the myofibrillar apparatus of rat myocardium. Thin trabeculae were isolated from the right ventricle and chemically demembranated. Force development and shortening velocity were measured during maximal calcium activations (pCa = 4.45) in control conditions and in the presence of 1-3 mM Amrinone. Maximum shortening velocity was obtained both from extrapolation of the force-velocity curve and with the slack test method. Amrinone was found to significantly reduce maximum shortening velocity and force development. Myofibrils and myosin were prepared from rat ventricular myocardium and their ATPase activity was assessed in control conditions and in the presence of Amrinone (0.3-6 mM). Ca-Mg dependent myofibrillar ATPase activity which was determined at low ionic strength was depressed by Amrinone in a dose-dependent way. Ca-stimulated ATPase activity determined at high ionic strength in myofibril or myosin preparations was not affected. Furthermore, Amrinone did not influence the pCa-ATPase activity curve of the myofibrillar preparations. A comparison between the inhibitory effects of Amrinone on myofibrils prepared from euthyroid rats and myofibrils prepared from hypothyroid rats was carried out. The ATPase activity was significantly less depressed in myofibrils prepared from hypothyroid rats than in those prepared from euthyroid rats. These results provide the first evidence of an effect of Amrinone on ATP splitting and force generation in the myofilament system of cardiac muscle.
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PMID:Effects of Amrinone on shortening velocity, force development and ATPase activity of demembranated preparations of rat ventricular myocardium. 144 24

Amrinone is the only phosphodiesterase fraction III inhibitor currently available in the USA for the treatment of perioperative biventricular failure. Patients with chronic congestive heart failure (CHF) show down-regulation of the beta 1-adrenergic receptor with a decrease in receptor density and altered responses to catecholamines. Intravenous administration of amrinone can transiently restore beta 1-adrenergic responses in patients who have CHF. Amrinone's mechanism of vasodilatation, independent of the beta 1-adrenergic receptor, nitrates, and calcium entry blockers, proves an important therapeutic option for pulmonary hypertension. The elimination half-life of amrinone in volunteers is 2.6-4.1 h, and 3.5 h when administered into the cardiopulmonary bypass (CPB) circuit. Different loading and infusion doses have been reported for amrinone. Investigators have demonstrated that increases in cardiac output following amrinone administration are directly related to plasma concentration. In cardiac surgical patients, following a dose of 0.75 mg kg-1 administered into the CPB circuit, plasma concentrations are subtherapeutic after 10 min. We believe that, when using amrinone to facilitate separation from CPB, a bolus dose of 1.5 mg kg-1 or more should be administered. If therapeutic levels need to be maintained in patients with biventricular failure, an infusion should also be administered after the bolus dose. Additive effects have been demonstrated when catecholamines are administered concomitantly with amrinone and other PDE III inhibitors to increase cyclic AMP in cardiac muscle and improve contractility. The use of amrinone with catecholamines is also important clinically, because together they attenuate the vasoconstrictive effects of catecholamines alone, while the catecholamines support perfusion pressure. Amrinone represents a novel drug for managing biventricular dysfunction in cardiac surgical patients.
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PMID:Perioperative experience with amrinone. 160 Sep 63

Canine cardiac muscle contains a type IV cyclic AMP (cAMP) phosphodiesterase (PDE) that is composed of two subtypes. One subtype is sensitive to rolipram inhibition (RSPDE), whereas the other is not inhibited significantly by rolipram (RIPDE). The RIPDE is inhibited by several cardiotonic agents operating by a PDE-inhibitory mechanism. Bemoradan [RWJ-22867; 7-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)-2H-1,4-benzoxazin -3(4H)-one], a novel, potent positive inotropic agent, demonstrated biphasic inhibition of the fraction III enzyme from canine cardiac muscle. Inhibition by rolipram of the RSPDE converted the IC50 curves of bemoradan, indolidan, pimobendan, and imazodan to sigmoidal, monophasic curves. Lineweaver-Burk analysis yielded competitive inhibition KI values of 0.023, 0.09, 0.065 and 0.60 microM, respectively, for these compounds. The cardiotonic compounds, however, were not potent inhibitors of the Type I and Type II cAMP PDEs found in canine ventricular muscle. The order of potency for inhibiting the RIPDE cAMP PDE subtype was bemoradan greater than pimobendan greater than indolidan greater than imazodan. Bemoradan is, therefore, a potent inhibitor of the cardiac muscle cAMP PDE which could, in part, be responsible for its cardiotonic activity.
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PMID:Bemoradan--a novel inhibitor of the rolipram-insensitive cyclic AMP phosphodiesterase from canine heart tissue. 165 Feb 19

Cyclic AMP appears to be involved in several excitatory actions of amines on neurones of the Limulus cardiac ganglion. Amines selectively increase levels of cardiac ganglion cyclic AMP with a magnitude and time course similar to that observed for amine-induced excitation of cardiac ganglion burst rate. With respect to either the physiological or biochemical effect, the apparent order of potency is octopamine greater than epinephrine approximately dopamine greater than norepinephrine. Elevation of cardiac ganglion cyclic AMP levels by octopamine or dopamine is dose-dependent and is potentiated by the phosphodiesterase inhibitor 3-isobutyl 1-methylxanthine (IBMX). Several pharmacological agents which influence cyclic nucleotide metabolism, including forskolin, IBMX and 8-substituted cyclic AMP analogues, have amine-like effects on the Limulus cardiac ganglion. These effects include increased burst rate of the isolated cardiac ganglion and decreased burst duration, interburst interval and number of spikes per burst in follower neurones. Forskolin and IBMX increase levels of cardiac ganglion cyclic AMP, and IBMX also increases cyclic GMP levels in this tissue. Amines, forskolin and IBMX have direct effects on follower neurones pharmacologically isolated from pacemaker cell input. Octopamine, forskolin and IBMX depolarize follower neurones, while dopamine hyperpolarizes these cells. Amines, forskolin and IBMX elicit burst-like potentials in follower neurones, and increase the size of evoked, unitary junction potentials recorded in cardiac muscle fibres. These pharmacological and biochemical data suggest that multiple, excitatory effects of biogenic amines on the Limulus cardiac ganglion are mediated by simultaneous increases in cyclic AMP at several loci within this neural network.
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PMID:Involvement of cyclic AMP in multiple, excitatory actions of biogenic amines on the cardiac ganglion of the horseshoe crab Limulus polyphemus. 170 51


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