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)

During a 3-year period we administered enoximone, a phosphodiesterase inhibitor with positive inotropic and vasodilator properties, to 73 pretransplantation patients with end-stage heart failure who exhibited a clinical requirement for additional inotropic support. The clinical course and myocardial beta-adrenergic receptor status in the explanted hearts of these 73 patients was compared with results in 113 concurrently listed pretransplantation patients not requiring additional inotropic support. Only three patients required cessation of enoximone because of adverse effects, all from exacerbation of ventricular arrhythmias. Sixty-six of 73 (90.4%) enoximone-treated patients ultimately underwent cardiac transplantation a mean of 39.2 +/- 6.6 days (range 1 to 221 days) after starting enoximone, whereas seven patients (9.6%) died awaiting cardiac transplantation. The respective 1-, 3-, and 6-month pretransplantation survival rates of patients treated with enoximone calculated from their time on the waiting list for transplantation were 88.0%, 82.5%, and 82.5% compared with 92.1%, 83.8%, and 76.2% in control patients not receiving enoximone (all p = not significant). In 25 patients who received enoximone, ventricular myocardial beta-adrenergic receptors were measured at the time of transplantation and compared with values in failing ventricles from 52 pretransplantation patients not exposed to enoximone. Compared with ventricular myocardium of patients not given enoximone or intravenous beta-adrenergic agonists, total beta-adrenergic receptor (beta 1 plus beta 2) density was not decreased in patients treated with enoximone or enoximone plus intravenous beta-adrenergic agonists, but was decreased by 31% (p less than 0.05) in patients given intravenous beta-adrenergic agonists alone. Additionally, patients treated with enoximone had higher myocardial beta 2-adrenergic receptor densities than respective subgroups treated without (28% higher, p less than 0.01) or with (65% higher, p less than 0.01) intravenous beta-adrenergic agonists. Finally, isoproterenol- or calcium-mediated contractile responses in isolated right ventricular preparations from 14 patients treated with enoximone were similar to values in control patients not exposed to enoximone or intravenous beta-adrenergic agonists, suggesting that enoximone-related beta-adrenergic subsensitivity or damage to the contractile apparatus does not occur.
J Thorac Cardiovasc Surg 1991 Aug
PMID:Low-dose enoximone in subjects awaiting cardiac transplantation. Clinical results and effects on beta-adrenergic receptors. 165 Aug 67

The calcium channel blocker nifedipine and the new phosphodiesterase (PDE) inhibitor enoximone are used in the treatment of cardiovascular diseases. Since both substances are acting on slow calcium channels and because systemic elimination of these two agents is dependent on oxidative drug metabolizing enzyme activity, this study was performed in order to investigate hemodynamic changes and effects on plasma levels when both substances are given simultaneously. Forty-five patients undergoing aortocoronary bypass grafting were randomly subdivided into three groups: (a) group (n = 15) received 0.3 micrograms/kg/min of nifedipine as an infusion (N patients); (b) group (n = 15) received 0.5 mg/kg of enoximone as a bolus (E patients); and (c) group (n = 15) received nifedipine and enoximone in the same dosages (E + N patients). In addition to various hemodynamic variables, plasma levels of nifedipine, enoximone, and enoximone sulfoxide were measured until the end of the operation. Injection of enoximone was followed by an increase in cardiac index and right ventricular ejection fraction, decrease in pulmonary artery pressure, pulmonary capillary pressure, and systemic vascular resistance, whereas heart rate and mean arterial pressure remained almost unchanged. These changes were comparable for E and E + N patients. Plasma concentrations of enoximone and enoximone sulfoxide were not affected by nifedipine infusion and showed a comparable course in E and E + N patients. Nifedipine plasma level dropped to values less than 15 ng/ml at the end of extracorporeal circulation in N and E + N patients. It can be concluded that enoximone improved hemodynamics even in patients pretreated with nifedipine.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol 1990 Jan
PMID:Drug interactions: the new phosphodiesterase inhibitor enoximone and the calcium channel blocker nifedipine in coronary surgery patients--influence on hemodynamics and plasma concentrations. 168 80

We observed the intracellular localization of low-Km cyclic adenosine monophosphate (cAMP) phosphodiesterase (PDEIII) subclasses in human heart in comparison to that in human kidney by using comparable potencies of specific inhibitors. PDEIII was observed in not only soluble fraction but particulate fraction in human heart and kidney. Both soluble and particulate PDEIII from human heart selectively hydrolyzed cAMP with similar Km values of 0.36 and 0.40 microM, respectively. They were potently inhibited by amrinone, enoximone, and cyclic guanosine monophosphate (cGMP), but were weakly inhibited by rolipram with much the same IC50 values. Although several animals having soluble and particulate PDEIII possess two pharmacologically distinct subclasses of PDEIII, human heart has only one form, cGMP-sensitive PDEIII. In contrast to cardiac PDEIII, both soluble and particulate PDEIII from human kidney were not readily inhibited by amrinone, enoximone, and cGMP, but rather strongly inhibited by rolipram. Human kidney contains only cGMP-less sensitive form of PDEIII in soluble and particulate fractions. These results suggest that the intracellular distribution of PDEIII subclasses in human hearts are significantly different from those in the hearts of other animal species, and subclasses of PDEIII in humans hearts could not be distinguished by intracellular localization but by organ specificity.
J Cardiovasc Pharmacol 1990 Feb
PMID:Effects of amrinone and enoximone on the subclasses of cyclic AMP phosphodiesterase from human heart and kidney. 168 27

STUDY OBJECTIVE - The aim of the study was to measure variations in ATP synthase capacity in cultured cardiomyocytes under conditions of metabolic stimulation. DESIGN - ATP synthase activity was measured in cultured rat cardiomyocytes using a procedure which allowed rapid measurement of mitochondrial function during changes in metabolic state. EXPERIMENTAL MATERIAL - Calcium tolerant cardiomyocytes were prepared from male Wistar rats, weight 250-300 g, n = 6-22 per experiment. MEASUREMENTS AND MAIN RESULTS - Electrical stimulation of cardiomyocytes led to an approximate doubling of ATP synthase capacity within 1-2 min, and was rapidly reversible. Activation was reduced when extracellular calcium was lowered and abolished in presence of the calcium entry blocker ruthenium red. Exposure of cardiomyocytes to isoprenaline or to an inhibitor of phosphodiesterase III also led to a large increase in ATP synthase capacity, which was abolished in presence of ruthenium red. However, the response of cells to isoprenaline depended on their pretreatment: activation of ATP synthase was abolished after 20 min anoxia prior to isoprenaline treatment but regained after a subsequent 30 min reoxygenation. This may reflect down regulation of beta receptors on the cell surface during anoxia. CONCLUSIONS - ATP synthase is directly controlled in vivo by a non-allosteric mechanism. Activation of ATP synthase is a response to intramitochondrial Ca2+ concentration.
Cardiovasc Res 1990 May
PMID:Control of mitochondrial ATP synthase in heart cells: inactive to active transitions caused by beating or positive inotropic agents. 169 47

Although recent studies indicate that MCI-154 exerts novel positive inotropic actions in heart muscle, the chronotropic properties of this new drug remain undefined. The present study compared the inotropic/chronotropic profile of MCI-154 with those of a nonselective beta 1/beta 2-agonist (isoproterenol, Iso) and a type III phosphodiesterase inhibitor (imazodan, CI-914) in cardiac preparations isolated from guinea pigs. The inotropic efficacy of MCI-154 was approximately equal to that of Iso and CI-194 in electrically paced (1 Hz) atrial muscle, with each agent increasing isometric contractile tension approximately 170% above basal (predrug) values. The inotropic EC50 for Iso (2.9 +/- 0.7 x 10(-9) M) was several orders of magnitude less than that for MCI-154 (1.4 +/- 0.4 x 10(-4) M) and CI-914 (1.1 +/- 0.2 x 10(-4) M). The inotropic potency of MCI-154 was equivalent in atrial and left ventricular myocardium. Both Iso and CI-194 substantially increased spontaneous beating frequency of sinoatrial preparations, and the inotropic/chronotropic potency ratio for each was unity. In contrast, MCI-154 exerted a slight negative chronotropic action on basal sinoatrial rate. Moreover, the negative chronotropic influence of MCI-154 was increased several-fold in the presence of Iso-stimulated maximal increases in heart rate (HR), and this inhibitory chronotropic action of MCI-154 was not prevented by muscarinic receptor blockade with atropine. These findings indicate that MCI-154 has a unique inotropic/chronotropic profile in cardiac tissues of guinea pigs in that this drug (a) efficaciously increased myocardial contractility, (b) had minimal effect on basal sinoatrial automaticity and yet (c) markedly inhibited sympathetically mediated sinus tachycardia.
J Cardiovasc Pharmacol 1990 Jul
PMID:Inotropic and chronotropic profile of MCI-154: comparison with isoproterenol and imazodan in guinea pig cardiac preparations. 169 67

Forskolin, a diterpene derivative of the Indian plant Coleus forskhohlii, proved to be a marked positive inotropic and vasodilatory compound in animal experiments with a mechanism of action distinct from catecholamines, cardiac glycosides, and phosphodiesterase-inhibiting compounds. The cardiovascular effects of forskolin seem to be mediated by a direct stimulatory action at the catalytic unit of sarcolemmal adenylate cyclase. The aim of the present study was to clarify the cardiovascular profile of this compound in 12 patients with stage III (NYHA) congestive cardiomyopathy. The effects of forskolin were investigated by invasive techniques using the thermodilution catheter method and compared to the beta 1-receptor agonist dobutamine and the vasodilator sodium nitroprusside in an intraindividual comparison. Forskolin dose-dependently reduced cardiac pre- and afterload values, and led to a reduction in systolic, diastolic, and mean pulmonary artery pressure as well as pulmonary wedge pressure by greater than 50% concomitant with an increase in cardiac output. There was a slight increase in heart rate. Cardiac stroke volume and stroke volume index was increased by approximately 70%. The cardiovascular effects of dobutamine and nitroprusside were less pronounced; however, it seemed that a similar hemodynamic profile could be achieved by the combination of both dobutamine and sodium nitroprusside. In view of the rapid development of tolerance toward beta 1-receptor stimulation, forskolin, with its receptor-independent mechanism of action, may be advantageous for the treatment of severe heart failure, especially in patients with catecholamine-insensitive heart failure.
J Cardiovasc Pharmacol 1990 Jul
PMID:Cardiovascular effects of forskolin (HL 362) in patients with idiopathic congestive cardiomyopathy--a comparative study with dobutamine and sodium nitroprusside. 169 72

Peak III phosphodiesterase (PDE) inhibitors have combined positive inotropic and vasodilator effects. We studied 10 patients with chronic heart failure during and after infusion of intravenous (i.v.) ICI 153,110, an investigational peak III PDE inhibitor. Maximum hemodynamic response for the group occurred after cessation of infusion at a lower plasma drug concentration. At maximum hemodynamic response, cardiac index (CI) increased (2.4 +/- 0.5 vs. 3.2 +/- 0.37 L/min/m2, p less than 0.05) with a decrease in mean arterial pressure (MAP 91 +/- 5 vs. 80 +/- 3 mm Hg, p less than 0.05), pulmonary capillary wedge pressure (PCWP 25 +/- 2 vs. 17 +/- 3.1 mm Hg, p less than 0.01), systemic vascular resistance (SVR 1,422 +/- 106 vs. 983 +/- 97 dynes.s.cm-5, p less than 0.05) and pulmonary vascular resistance (PVR 227 +/- 39 vs. 16 +/- 31 dynes.s.cm-5, p less than 0.05). During the infusion, plasma renin activity (PRA) decreased from 6.34 +/- 2.53 to 3.6 +/- 3 ng/ml/h (NS). The five patients with high baseline PRA had a significant decrease (11.2 +/- 2.5 vs. 5.4 +/- 1.67 ng/ml/h, p less than 0.01) that preceded changes in CI and SVR by 1-2 h. These data suggest that reduction in PRA may have contributed to the hemodynamic effects of this peak III PDE inhibitor.
J Cardiovasc Pharmacol 1990 Sep
PMID:Acute neurohormonal and hemodynamic response to a new peak III phosphodiesterase inhibitor (ICI 153,110) in patients with chronic heart failure. 170 Feb 5

Cicletanine is an antihypertensive/vasorelaxant/natriuretic agent of unknown mechanism. We wished (a) to determine if cicletanine interacts with guanylate cyclase activators that modulate vasomotor tone and sodium balance [i.e., atriopeptin II (AP II), endothelium-derived relaxing factor (EDRF), and sodium nitroprusside (SNP)], and (b) to define the subcellular basis for this interaction by quantitating the effects of cicletanine on low Km cyclic GMP phosphodiesterase (PDE) activity. In phenylephrine-contracted rat aortic smooth muscle, the vasorelaxant potency of cicletanine was increased twofold in the presence of a threshold-relaxant concentration of AP II, and functional cyclic GMP PDE inhibition was also evident from the three- to sixfold potentiation by cicletanine of AP II- or SNP-induced vasorelaxation. Vasorelaxation produced by cicletanine was not endothelium dependent, however. In further studies, intravenous (i.v.) administration of cicletanine or the low Km cyclic GMP PDE inhibitor, zaprinast, decreased blood pressure (BP) greater than or equal to 20% in conscious spontaneously hypertensive rats (SHR). These results are consistent with the additional finding that cicletanine inhibited Ca2(+)-calmodulin (CaM) cyclic GMP PDE and zaprinast-sensitive cyclic GMP specific PDE over a concentration range (10-600 microM) similar to that for vasorelaxation. Thus, inhibition of low Km cyclic GMP PDEs by cicletanine may be partly responsible for the vasorelaxant effect of cicletanine as well as the potentiation by cicletanine of the vasorelaxant actions of guanylate cyclase activators. The extent to which this mechanism contributes to the antihypertensive efficacy of cicletanine has not yet been fully determined.
J Cardiovasc Pharmacol 1990 Sep
PMID:Inhibition of low Km cyclic GMP phosphodiesterases and potentiation of guanylate cyclase activators by cicletanine. 170 Feb 24

The involvement of rolipram-sensitive phosphodiesterase (PDE IV) in regulation of cardiac contraction was investigated by studying the effect of selective inhibitors (rolipram, denbufylline, Ro 20-1724) on guinea pig left atria contraction. In contrast to milrinone and SK&F 94120 (inhibitors of the cyclic GMP-inhibited PDE, PDE III), (+/-)-rolipram and denbufylline (0.1-30 microM) did not produce any positive inotropic effect in normal (2.5 mM) or elevated (3-3.2 mM) external CaCl2 concentration. In these conditions, Ro 20-1724 produced only a slight but significant increase of contraction over control levels. In the presence of forskolin (an adenylate cyclase activator) or SK&F 94120 (a PDE III inhibitor), which produced an increase of the response to electrical stimulation of approximately 10%, (+/-)-rolipram, denbufylline, and Ro 20-1724 all exerted concentration-dependent positive inotropic effects (mean EC50 values were 20, 25, and 125 nM, respectively, in the presence of forskolin). Rolipram exhibited stereospecificity: the (-)-enantiomer was 10 times more potent than the (+)-enantiomer. Neither preincubation of the atria with atenolol nor pretreatment of the guinea pigs with reserpine significantly modified the effect of PDE IV inhibitors obtained in the presence of forskolin. These data show that in the presence of cyclic AMP-dependent positive inotropic agents, PDE IV inhibitors exert a positive inotropic effect which probably does not involve enhanced catecholamine release from sympathetic nerve endings. This suggests that PDE IV may play a role in regulation of cardiac contraction in physiologic conditions in which the sympathetic outflow produces a stimulation of adenylate cyclase in cardiac cells.
J Cardiovasc Pharmacol 1990 Nov
PMID:Involvement of rolipram-sensitive cyclic AMP phosphodiesterase in the regulation of cardiac contraction. 170 3

The interactions between isoprenaline, sodium nitroprusside, and the isozyme-selective phosphodiesterase inhibitors OPC 3911 ("cAMP specific") and zaprinast ("cGMP specific") on platelet aggregation induced by adenosine diphosphate (ADP) and on levels of cAMP and cGMP were studied. Isoprenaline at 10(-6)M diminished aggregation by 28%, and this effect was enhanced by 10(-7)-10(-6)M OPC 3911. Neither 10(-6) M isoprenaline nor 10(-7)M OPC 3911 elevated cAMP, but in combination they caused a significant rise in cAMP (27% above the basal level), accompanying the synergistic functional inhibition, without affecting cGMP levels. Sodium nitroprusside at 10(-5) M diminished aggregation by 39%, elevated cGMP levels (81-110%), but also caused a statistically significant increase in cAMP (21-32%), and enhanced the effects of 10(-6)M isoprenaline on cAMP levels. Zaprinast at 10(-5) M caused a modest inhibition of aggregation by 20%, and a small increase in cGMP (20%), and it clearly enhanced the effects of 10(-5)M sodium nitroprusside on both cGMP and cAMP levels, but not on aggregation. The cAMP-increasing effect of sodium nitroprusside might be a consequence of a cGMP-mediated inhibition of the "low-Km cGMP-inhibited phosphodiesterase" that is also inhibited by OPC 3911. The effects of all of the drugs on ADP-induced aggregation seem to depend more on their effect on cAMP levels than on the levels on cGMP.
J Cardiovasc Pharmacol 1991 Aug
PMID:Interactions between isoprenaline, sodium nitroprusside, and isozyme-selective phosphodiesterase inhibitors on ADP-induced aggregation and cyclic nucleotide levels in human platelets. 171 85


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