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)

The role of guanosine 3',5'-cyclic monophosphate (cGMP) in the net K+ efflux following parasympathomimetic and sympathomimetic stimulation in dispersed rat submandibular cells was evaluated. In unstimulated cells, approx. 70 per cent of the total cGMP content was present in the incubation medium; the addition of 1-methyl-3-isobutylxanthine (MIX), a phosphodiesterase inhibitor, to the medium elevated both intracellular and extracellular levels of cGMP. Cholinergic receptor stimulation resulted in a rapid increase of the cGMP content in the cells and in the medium. Extracellular Ca2+ was necessary for an increased cGMP response and MIX potentiated the cGMP response. Adrenergic-receptor activation produced a slight increase in cGMP after 5 min of stimulation but only when MIX was present in the medium. cGMP analogues (8-Br-cGMP and Bt2cGMP) had no effect on the rate of maximal net K+ efflux, on submaximal net K+ efflux, or on K+ re-uptake following parasympathomimetic or sympathomimetic stimulation. The dose-response relationship for a cholinergic agonist, carbamylcholine, or an adrenergic agonist, norepinephrine, was unaffected by the presence of either 8-Br-cGMP or Bt2cGMP in the medium. MIX, at a concentration sufficient to increase intracellular and extracellular cGMP levels, had no effect on net K+ efflux. These data do not support a role for cGMP in modulating rat submandibular potassium release.
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PMID:Evidence against a role for guanosine 3',5'-cyclic monophosphate in rat submandibular salivary gland potassium release. 619 59

Since terbutaline treatment in premature labor has been shown to increase phosphodiesterase activity in the myometrium, the phosphodiesterase-inhibiting effect of theophylline and papaverine on myometrial preparations from pregnant women has been studied. The patients were either treated with terbutaline during the last 3 weeks of pregnancy or not treated. The results showed that papaverine is about 100 times more potent than theophylline in both phosphodiesterase-inhibiting effect and muscle-relaxing effect. No differences in effects were found in myometrial strips from terbutaline-treated or untreated women. A possible improvement in the tocolytic therapy with a combination of a beta-sympathomimetic and a phosphodiesterase-inhibiting drug is suggested.
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PMID:In vitro study of phosphodiesterase-inhibiting drugs: a complement to beta-sympathomimetic drug therapy in premature labor? 630 Dec 81

We studied the effect of posture on the sympathoadrenal response to intravenous theophylline in six normal subjects. On three separate occasions they received an intravenous infusion of either theophylline (6 mg/kg) while supine, theophylline (6 mg/kg) while standing or saline as placebo while standing. With the subjects standing theophylline caused tremor, a peak heart rate of 99 +/- 6 beats/min, and an elevation of plasma cyclic AMP from 9.3 +/- 0.7 to 15.1 +/- 1.7 nmol/1 (mean +/- s.e. mean). There was a small, but significant, elevation of plasma adrenaline, noradrenaline and glucose. The elevation in plasma catecholamines was insufficient to explain either the sympathomimetic effects of theophylline or the rise in plasma cyclic AMP. Theophylline had little or no effect with the subjects supine. The mean peak theophylline concentration following infusion was significantly higher with the subjects upright than when supine (18.3 c.f. 12.4 mg/l, P less than 0.025). However, adequate plasma levels of theophylline were obtained in all subjects when lying or supine. Analysis of individual data suggests that differences in plasma levels of theophylline are unlikely to account for the increased effects seen on standing. The mechanism of action of theophylline cannot be explained by increased secretion of catecholamines alone. Theophylline appears to amplify the increased sympathetic activity associated with standing and this is probably by phosphodiesterase inhibition.
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PMID:The effect of posture on the sympathoadrenal response to theophylline infusion. 631 28

It has been shown in experiments on conscious cats that nitroglycerin exerts a cardiostimulatory effect on the myocardium. The positive inotropic effect of nitroglycerin is associated with the two processes, catecholamine release from sympathetic nerve terminals and blockade of phosphodiesterase activity. The positive chronotropic effect arises from the indirect sympathomimetic properties of nitroglycerin. In addition to the effects listed, nitroglycerin reduces the intensity of the cardiac chronotropic reactions induced by isoproterenol and produces a direct inhibitory action on the myocardium. The implication of the nitroglycerin effects in the realization of its antianginal action is discussed.
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PMID:[Effect of nitroglycerin on the ino- and chronotropic function of the myocardium]. 679 60

Although prevention of heart failure recently has become a realistic issue, management of heart failure once the syndrome has developed, is mainly supportive, based on the various cardiac and peripheral changes which occur in the course of heart failure. Of these, abnormal neurohormonal activation is of major pathophysiologic and prognostic significance. Consequently, modulation of neuroendocrine activation is now recognized a prime target in the treatment of heart failure, besides diuretic therapy. In this respect, the value of converting enzyme inhibition is well established. Future developments in this area include dopaminergic agents, vasopressin antagonists, angiotensin II receptor antagonists, renin inhibitors, spironolactone and, possibly, ANF peptidase inhibitors. Besides diuretics, necessary when signs of fluid retention are present, the approach to heart failure management involves other pharmacologic issues. In view of abnormal vascular control with vasoconstriction prevailing during progressive heart failure, it clearly makes sense to vasodilate. However, of available vasodilators, only the combination of relatively high dose nitrates and hydralazine has proven to be of clinical significance, in terms of hemodynamics, exercise capacity and survival. It is possible, though, that novel generation dihydropyridine derivatives may prove beneficial as well. Thus far, there has been much debate concerning the usefulness and particularly the safety of positive inotrope therapy and inodilator treatment. Taken together, this concern relates to presence and predominance of cAMP-dependent mechanisms to induce these effects. Thus, sympathomimetic agents and phosphodiesterase inhibitors, such as milrinone or enoximone, are without beneficial effects, but instead shorten survival during long-term therapy. This may be different where compounds which act through cAMP-independent mechanisms, i.e., calcium sensitization or sodium channel stimulation, are concerned, but needs to be confirmed yet.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Congestive heart failure. Drug therapy: central or peripheral approach? 791 52

Milrinone (Inocor-Sanofi-Winthrop) represents a second generation phosphodiesterase inhibitor currently approved for intravenous administration in the treatment of decompensated congestive heart failure. By inhibiting Type III phosphodiesterase, milrinone increases intracellular cyclic adenosine monophosphate. This results in a positive inotropic effect on the heart and vasodilatation in the periphery. The hemodynamic consequences of this action produce left ventricular afterload reduction, with an increase in cardiac output and a reduction in total peripheral resistance. Unlike the sympathomimetic amines, milrinone produces no tolerance and possesses the distinct advantage of directly decreasing pulmonary vascular resistance. Short-term intermittent infusion by peripheral administration, continuous infusion, long-term therapy, and intermittent outpatient therapy was demonstrated to be safe, efficacious, and cost effective. It is hypothesized that intravenous milrinone, by producing biventricular afterload reduction, offers an efficacious, cost-effective tool for the treatment of decompensated heart failure.
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PMID:Milrinone: basic and clinical pharmacology and acute and chronic management. 865 56

Crataegus extract is used in cardiology for the treatment of mild to moderate heart failure (NYHA II) in Germany. However, little is known about the electrophysiological actions of Crataegus extract in the heart. Recently, it was shown that Crataegus extract prolongs the refractory period in isolated perfused hearts and increases action potential duration in guinea pig papillary muscle. It was the aim of this study to find out the mechanism of the increase in action potential duration caused by Crataegus extract. Using the patch-clamp technique, we measured the effects of Crataegus extract (10 mg/l; flavonoid content: 2.25%, total procyanidin content: 11.3 +/- 0.4%) on the inward rectifier and the delayed rectifier potassium current in isolated guinea pig ventricular myocytes. To get some insight into the mechanism underlying the positive inotropic effect of Crataegus extract, we also looked for effects on the L-type calcium current. Crataegus extract slightly blocked both the delayed and the inward rectifier potassium current. The inhibition amounted to 25% and about 15%, respectively. This amount of inhibition of these repolarising currents is sufficient to explain the prolongation of action potential duration caused by Crataegus extract. To our surprise we could not detect any influence of Crataegus extract on the L-type calcium current. In summary, our results show that Crataegus extract blocks repolarising potassium currents in ventricular myocytes. This effect is similar to the action of class III antiarrhythmic drugs and might be the basis of the antiarrhythmic effects described for Crataegus extract. Our measurements of the L-type calcium current indicate that Crataegus extract's positive inotropic effect is not caused by phosphodiesterase inhibition or a beta-sympathomimetic effect.
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PMID:Crataegus extract blocks potassium currents in guinea pig ventricular cardiac myocytes. 1036 39

Quantitative structure-activity relationships (QSARs) of different cardiotonic agents are presented. A critical analysis of all QSARs provides a very vivid picture of the mechanisms of varying cardiotonic agents. The cardiotonics can be broadly put into 2 categories: cardiac glycosides and nonglycoside cardiotonics, which include phosphodiesterase of type III (PDE III) inhibitors, sympathomimetic (adrenergic) stimulants, A1-selective adenosine antagonists, Ca2+ channel activators and vasopressin antagonists. For cardiac glycosides, QSARs reveal that the position of carbonyl oxygen in their lactone moiety and shifting of the lactone ring from its original position or its replacement by another group would be crucial for their activity. The carbonyl group or its isostere like CN is indicated to be the sole binding entity and the hydrogen bonding through this group is considered to be the most likely binding force. For nonglycoside cardiotonics that include PDE III inhibitors and A1-selective antagonists, a five-point model has been established for their activity, the salient features of which are: (1) the presence of a strong dipole, (2) an adjacent acidic proton, (3) a methyl-sized lipophilic space, (4) a relatively flat overall topography and (5) a basic or hydrogen-bond acceptor site opposite to the dipole. For Ca2+ channel activators, the importance of steric, electrostatic, lipophilic and hydrogen-bonding properties of molecules is indicated, while for vasopressin antagonists the lipophilic and electronic properties are suggested to be the most important.
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PMID:Quantitative structure-activity relationships of cardiotonic agents. 1112 65

1. We have already shown that the left ventricular (LV) end-systolic pressure-volume relationship (ESPVR) of rat hearts in situ is an upward convex curve and that LV end- systolic pressure (ESP(mLVV)) and the systolic pressure-volume area (PVA(mLVV)) at a mid-range LV volume (mLVV) sensitively reflect acute changes in LV contractility and work capability. Milrinone is a non-glycosidic, non-sympathomimetic drug that increases myocardial cAMP concentrations by selective inhibition of cardiac phosphodiesterase III. Therefore, milrinone could act on the entire cardiovascular system and cause an increase in inotropy, arterial vasodilatation and venodilatation. The aim of the present study was to investigate whether the approach we have recently instituted is able to detect the effects of milrinone on the entire cardiovascular system. 2. We measured simultaneously, in anaesthetized rats, continuous LV pressure using a catheter-tip micromanometer and LV volume by LV volumetry using a conductance catheter. We obtained steady state LV pressure-volume loops and intermittently obtained the LV ESPVR by gradual occlusion of the ascending aorta. We then evaluated LV function by assessing milrinone-induced changes in the ESPVR (i.e. ESP(mLVV) and PVA(mLVV)) and vasodilator actions by assessing milrinone-induced changes in ESP(ESV) and effective arterial elastance (Ea), defined as the ESP(ESV)/stroke volume ratio. 3. Milrinone (total dose 49.5 microg; infusion rate 3.3-6.7 microg/min, 7-10 microg/kg per min; blood concentration 53.9 ng/mL) largely shifted the ESPVR upwards and, thus, significantly increased end-systolic pressure (ESP(0.08)) and the systolic pressure-volume area (PVA(0.08)) at a mid-range LV volume (= 0.08 mL/g myocardium). Milrinone also significantly decreased LV ESP(ESV) and decreased Ea, although these decreases were not significant. 4. The results of the present study suggest that our own recently instituted approach to evaluate LV function by measuring LV pressure-volume loops and ESPVR succeeded in detecting a cardiotonic action of milrinone with arterial vasodilatation in normal rat hearts.
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PMID:Effects of milrinone on left ventricular end-systolic pressure-volume relationship of rat hearts in situ. 1155 33

Diazepam has phosphodiesterase (PDE) inhibitory activity and potentiates the effect of some 3',5'-cyclic adenosine monophosphate (cAMP)-dependent positive inotropic agents. The present study was undertaken to determine whether diazepam enhances the contractile responses and cAMP levels induced by endogenous catecholamines in electrically driven rat right ventricular strips, and the effects are compared with that of the PDE inhibitor 3-isobutylmethylxantine (IBMX). Noradrenaline (10 nM(-1) microM), adrenaline (50 nM-500 microM) and tyramine (5-100 microM) produced concentration-dependent positive inotropic effects that were potentiated by the presence of 10 microM diazepam or IBMX. The diazepam-induced potentiation of the contractile effect of the sympathomimetic agents was not mimicked by 100 microM GABA nor was it antagonized by a 5 microM concentration of the blockers of central and peripheral type benzodiazepine receptors, flumazenil and PK 11195. The beta(2)-adrenergic receptor agonist salbutamol (0.1-300 microM) also produced a concentration-dependent positive inotropic effect which was potentiated by the presence of 10 microM diazepam or 10 microM IBMX. However, the contractile effect of salbutamol, either alone or in the presence of diazepam or IBMX, was not affected by 50 nM ICI 118551, an antagonist of beta(2)-adrenergic receptors, but was virtually abolished by a 0.3 microM concentration of CGP 20712A, an antagonist of beta(1)-adrenergic receptors. Diazepam and IBMX also potentiated the increase in cAMP levels caused by these three sympathomimetic agents in this tissue. [(3)H]Noradrenaline release elicited by electrical stimulation or by tyramine was not affected by diazepam. The results demonstrate that diazepam, like the phosphodiesterase inhibitor IBMX, produces an inotropic and biochemical potentiation of the effects of endogenous catecholamines in rat myocardium. This effect is not due to the release of noradrenaline at the presynaptic level nor is it mediated by beta(2)-adrenergic receptors or benzodiazepine receptors of the central or peripheral type. The effect is probably consequential upon the phosphodiesterase inhibitory activity of diazepam.
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PMID:Diazepam potentiates the effects of endogenous catecholamines on contractility and cyclic AMP levels in rat ventricular myocardium. 1191 49


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