Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to determine whether the selective type IV cAMP-phosphodiesterase inhibitor rolipram could reduce the reperfusion injury that occurs during myocardial infarction in the anesthetized dog. This question was tested in pentobarbital-anesthetized dogs subject to 90 min of regional myocardial ischemia and 5 h of reperfusion. Dogs were treated with 1 mg/kg of rolipram (i.v., 15 min before reperfusion) followed by a 1 mg/kg/h infusion over the duration of the 5 h of reperfusion. Rolipram was tested in vitro for efficacy in inhibition of isolated human neutrophil superoxide generation. Rolipram produced significant inhibition of superoxide production over the concentration range of 0.1-100 microM rolipram when neutrophils were stimulated with a 10(-7) M concentration of the chemotactic peptide f-Met-Leu-Phe. Rolipram significantly inhibited superoxide generation from human and canine granulocytes in whole blood stimulated by zymosan. Therapeutic concentrations of rolipram in the blood of dogs were achieved during the course of the experiments with a plasma concentration of 0.761 +/- 0.095 micrograms/ml (2.76 +/- 0.34 microM) at the time of reperfusion, and 0.574 +/- 0.098 micrograms/ml (2.08 +/- 0.36 microM) at the end of the reperfusion period. The relative severity of myocardial ischemia between the two treatment groups was similar as assessed with radiolabeled microsphere measurement of myocardial blood flow. Transmural myocardial blood flows were not significantly different between the two groups after coronary occlusion (control, 0.05 +/- 0.01 ml/min/g, n = 6, vs. rolipram, 0.18 +/- 0.07 ml/min/g, n = 6; p = 0.48).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Inhibition of granulocyte cAMP-phosphodiesterase by rolipram in vivo is not sufficient to protect the canine myocardium from reperfusion injury. 137 23

The antithrombotic activity of pelrinone, a phosphodiesterase III inhibitor was examined in a canine model of coronary thrombosis that uses electrical current to injure the coronary endothelium. Ninety percent of vehicle treated animals developed complete coronary occlusion and thrombus mass was 32.0 +/- 5.8 mg. In a group of animals treated with zomepirac, 10 mg/kg i.v., included as a positive control, thrombus mass was decreased to 10.3 +/- 3.3 mg and incidence of occlusion was reduced to 37.5%. Pelrinone, 5.0 mg/kg i.v. decreased the incidence of occlusion to 50%, thrombus mass to 21.3 +/- 8.3 mg and inhibited platelet aggregation to collagen, ADP and arachidonic acid by 80%, 54% and 87% of baseline, respectively. When yohimbine, an alpha 2-adrenergic antagonist, was co-administered (2.0 mg/kg at the beginning of the experiment +0.5 mg/kg halfway through the experiment) with the same dose of pelrinone, thrombus mass was decreased to 1.0 +/- 0.5 mg and none of the animals developed coronary occlusion. Yohimbine administration by itself at 2.0-3.0 mg/kg showed no evidence of antithrombotic activity (thrombus mass = 32.8 +/- 8.0 mg, incidence of occlusion = 100%). This dose of yohimbine inhibited significantly ADP-induced aggregation in the presence of epinephrine. These results demonstrate that, even though this dose of pelrinone elicited near maximal inhibition of platelet aggregation, the concurrent administration of an alpha 2-adrenergic antagonist was able to potentiate markedly the phosphodiesterase inhibitor antithrombotic activity.
 ...
PMID:Potentiation of phosphodiesterase inhibitor antithrombotic activity with alpha-2 adrenergic blockade. 167 Dec 93

The purpose of this study was to determine if idazoxan, an alpha 2-adrenergic antagonist, could enhance the antithrombotic activity of pelrinone, a PDE III inhibitor, in a canine model of coronary thrombosis that uses electrical current to injure the coronary endothelium. Thrombus mass in vehicle-treated animals was 37.9 +/- 8 mg. Pelrinone, 0.625 and 2.5 mg/kg decreased thrombus size by 46 and 21%, respectively, while idazoxan, 0.75 mg/kg decreased thrombus mass by 43%. When this dose of idazoxan was combined with pelrinone, 0.625 and 2.5 mg/kg, thrombus mass was decreased by 71 and 91%, respectively. Antithrombotic efficacy correlated with the ability of these treatments to inhibit epinephrine-sensitized, collagen-induced platelet aggregation. Sixty minutes following drug administration, idazoxan, 0.50 mg/kg inhibited aggregation by 50%, while pelrinone, 0.625 and 2.5 mg/kg inhibited aggregation by 55 and 68%, respectively. Combined administration of idazoxan with pelrinone, 0.625 and 2.5 mg/kg resulted in 80 and 95% inhibition of aggregation, respectively. Similar trends in inhibiting platelet aggregation to epinephrine-sensitized ADP and arachidonic acid were also observed. Experimental treatments did not affect hematocrit or circulating platelet count, although pelrinone was observed to prolong prothrombin time slightly. To examine the effect of drug-induced increases in coronary blood flow on thrombus formation, the potassium channel activator drug cromakalim was studied at a dose (0.1 mg/kg) that increased coronary blood flow by 25-35 ml/min above baseline in sham control animals. Animals treated with cromakalim showed a shorter time to coronary occlusion (103 +/- 11 min) vs. vehicle (173 +/- 24 min) and developed larger thrombi (53.7 +/- 19 mg). These results demonstrate that coronary vasodilation does not contribute to antithrombotic activity in this model. Results from the study also show that alpha-adrenergic inhibition of platelet function can potentiate phosphodiesterase inhibitor antiaggregatory and antithrombotic activity.
 ...
PMID:Antithrombotic activity of the phosphodiesterase III inhibitor pelrinone in a canine model of coronary artery thrombosis: enhancement of efficacy with concurrent alpha 2-adrenergic antagonism. 172 88

1. The aim of this study was to compare the effects of the non-selective phosphodiesterase (PDE) inhibitor, isobutylmethylxanthine (IBMX) and the selective PDE III inhibitor, milrinone, in a rabbit model of acute myocardial ischaemia. 2. Coronary artery occlusion caused changes in the ST-segment of the ECG and ectopic activity in all control rabbits. Ventricular fibrillation occurred in 10 out of 14 (71%) of these animals. Pretreatment with IBMX 100 micrograms kg-1 plus 10 micrograms kg-1 min-1, starting 10 min before coronary artery occlusion, reduced ischaemia-induced ST-segment changes and ventricular fibrillation occurred in only 10% of this group (n = 10). A similar dose of milrinone had no antiarrhythmic activity, whereas with a lower dose of milrinone, 30 micrograms kg-1 plus 3 micrograms kg-1 min-1 (n = 10), only 30% of rabbits fibrillated and ST-segment changes were attenuated. 3. Acute administration of both IBMX and milrinone reduced arterial blood pressure. With the higher dose of milrinone a significant effect was still present after 10 min of drug infusion. A greater hypotensive response to the higher dose of milrinone was observed in the rabbits which subsequently fibrillated during ischaemia. A marked tachycardia was also observed after administration of the higher dose of milrinone. 4. At the end of the experiment platelet aggregation was studied ex vivo. ADP-induced aggregation was reduced by pretreatment of the rabbits with milrinone but not IBMX. Both PDE inhibitors enhanced the ability of isoprenaline to inhibit ADP-induced platelet aggregation but milrinone was more effective, particularly at the higher dose. The results demonstrate that IBMX was antiarrhythmic but that this activity was not directly related to inhibition of platelet aggregation. Adverse haemodynamic effects may explain the failure of milrinone to have similar activity during myocardial ischaemia.
 ...
PMID:Comparison of the effects of isobutylmethylxanthine and milrinone on ischaemia-induced arrhythmias and platelet aggregation in anaesthetized rabbits. 247 45

Mild (not harmful) stress may initiate an adaptive mechanism, protecting the heart from harmful consequences of a more severe stress. There are at least three known types of cardiac adaptation to stress, such as: a) the gradually developing, long lasting adaptation to chronic mechanical overload, leading to cardiac hypertrophy, later to cardiomyopathy and heart failure, b) the rapidly developing adaptation to moderate stress initiated by 'preconditioning' brief coronary occlusion(s) or brief periods of rapid cardiac pacing, protecting for less than 1 h against consequences of a subsequent, severe stress, c) the later appearing, more prolonged cardio-protective adaptation, described by us in 1983, induced by various forms of more severe but not injurious stimuli, such as an optimal dose of prostacyclin or its stable analogues; or a series of brief periods of rapid pacings. This form of cardiac adaptation to stress protects for 24-48 h against consequences of a more severe stress such as: 1. myocardial ischaemia; 2. early and late postocclusion and reperfusion arrhythmias; 3. early morphologic changes secondary to ischaemia and reperfusion; 4. ischaemia induced myocardial loss of K+ and accumulation of Na+ and Ca++; 5. it may increase the tolerance to the toxic effects of cardiac glycosides. A reduced response to beta-adrenergic stimuli and a concomitant increase in activity and amount of PDE I and IV was shown by us earlier.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:On the mechanism and possible therapeutic application of delayed adaptation of the heart to stress situations. 749 39

We recently observed that dipyridamole pretreatment significantly enhanced the infarct size (IS)-limiting effect of preconditioning (PC), which was attenuated by adenosine receptor antagonist. This potentiation of PC was interpreted to result from inhibition of nucleoside transport by dipyridamole, but contribution of other pharmacologic actions of dipyridamole could not be excluded. To confirm that inhibition of nucleoside transport leads to PC enhancement, we assessed alteration of mild PC by two different nucleoside transport inhibitors, dilazep and R75231, which, unlike dipyridamole, lack action on phosphodiesterase (PDE) and prostacyclin. Myocardial infarction was induced in rabbits by 30-min coronary occlusion and 72-h reperfusion. IS and area at risk (AAR) were determined by histology and fluorescent particles, respectively. Rabbits either were untreated or received dilazep (0.34 mg/kg intravenously, i.v.) or R75231 (0.05 mg/kg i.v.) before coronary occlusion. In other groups of rabbits, PC was conducted with 2-min ischemia and 5-min reperfusion with or without injection of the nucleoside transport inhibitor (0.34 or 0.10 mg/kg dilazep or 0.05 mg/kg of R75231) before PC. IS expressed as percentage of AAR (%IS/AAR) was 43.9 +/- 2.3% (SE) in untreated controls; dilazep (0.34 mg/kg) and R75231 alone did not modify IS (%IS/AAR = 50.6 +/- 4.7 and 42.7 +/- 11.9%, respectively). PC tended to reduce IS (%IS/AAR = 33.3 +/- 3.5%), but the combination of dilazep or R75231 with PC significantly limited %IS/AAR (%IS/AAR = 22.5 +/- 5.0% after low-dose dilazep plus PC, 27.6 +/- 4.9% after high-dose dilazep plus PC, and 19.9 +/- 3.6%, after R75231 plus PC).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Nucleoside transport inhibitors enhance the infarct size-limiting effect of ischemic preconditioning. 753 64

Percutaneous transluminal coronary angioplasty (PTCA) is widely used to treat patients with ischemic heart disease, but the procedure involves a number of problems, including acute coronary occlusion and restenosis. Although stents have proved useful for preventing post-PTCA restenosis, especially elastic recoil during the acute phase, no method has yet been established to prevent restenosis caused by vascular smooth muscle cell proliferation in the late phase. Cilostazol selectively inhibits the 3'5'-cyclic-nucleotide phosphodiesterase (PDE) III (cyclic guanosine monophosphate-inhibited PDE) of the cyclic adenosine monophosphate PDE family; it also has antithrombotic and vasodilating effects, as well as an inhibitory effect on vascular smooth muscle cell proliferation through PDE III inhibition. From November 1995 to March 1997, the usefulness of cilostazol versus aspirin in preventing subacute thrombosis and restenosis was studied in 70 patients (55 men and 15 women; 82 total lesions) who had undergone successful elective Palmaz-Schatz stent implantation. Patients were randomly allocated to receive aspirin 81 mg/d (40 patients with 45 lesions) or cilostazol 200 mg/d (30 patients with 37 lesions) alone. There was no difference in patients or angiographic characteristics between these groups. No subacute thrombosis, acute complications (ie, death, emergent coronary artery bypass grafting, or hemorrhagic complications), or drug side effects were found in the cilostazol group. The minimal lumen diameter (mean +/- SD) at follow-up was 1.89 +/- 1.08 mm in the aspirin group (41 lesions, 5.63 +/- 1.74 months after stent implantation) and 2.34 +/- 0.74 mm in the cilostazol group (35 lesions, 5.14 +/- 1.91 months after stent implantation), revealing statistically significant dilatation in the cilostazol group. The restenosis rate was 26.8% in the aspirin group, compared with 8.6% in the cilostazol group; this difference was statistically significant. Administration of cilostazol alone after the implantation of intracoronary Palmaz-Schatz stents was useful for the prevention of subacute thrombosis and restenosis.
 ...
PMID:A randomized trial of aspirin versus cilostazol therapy after successful coronary stent implantation. 938 93

Sildenafil, a selective inhibitor of phosphodiesterase type 5, produces relaxation of isolated epicardial coronary artery segments by causing accumulation of cGMP. Because shear-induced nitric oxide-dependent vasodilation is mediated by cGMP, this study was performed to determine whether sildenafil would augment the coronary resistance vessel dilation that occurs during the high-flow states of exercise or reactive hyperemia. In chronically instrumented dogs, sildenafil (2 mg/kg per os) augmented the vasodilator response to acetylcholine, with a leftward shift of the dose-response curve relating coronary flow to acetylcholine dose. Sildenafil caused a 6. 7 +/- 2.1 mmHg decrease of mean aortic pressure, which was similar at rest and during treadmill exercise (P < 0.05), with no change of heart rate, left ventricular (LV) systolic pressure, or LV maximal first time derivative of LV pressure. Sildenafil tended to increase myocardial blood flow at rest and during exercise (mean increase = 14 +/- 3%; P < 0.05 by ANOVA), but this was associated with a significant decrease in hemoglobin, so that the relationship between myocardial oxygen consumption and oxygen delivery to the myocardium (myocardial blood flow x arterial O(2) content) was unchanged. Furthermore, sildenafil did not alter coronary venous PO(2), indicating that the coupling between myocardial blood flow and myocardial oxygen demands was not altered. In addition, sildenafil did not alter the peak coronary flow rate, debt repayment, or duration of reactive hyperemia that followed a 10-s coronary occlusion. The findings suggest that cGMP-mediated resistance vessel dilation contributes little to the increase in myocardial flow that occurs during exercise or reactive hyperemia.
 ...
PMID:Effect of sildenafil on coronary active and reactive hyperemia. 1104 68

Phosphodiesterase inhibitors as inodilators in heart failure are associated with promotion of arrhythmias. Calcium sensitizers have been proposed for the treatment of severe decompensated heart failure. The effect of levosimendan, a calcium sensitizer, and milrinone, a phosphodiesterase inhibitor, on ventricular arrhythmias was compared in a model of acute regional myocardial ischemia and reperfusion. The left anterior descending coronary artery in dogs was occluded for 25 minutes, followed by reperfusion. The 2 drugs were administered in a hemodynamically equieffective dose (0.1 micromol/kg) 10 minutes before coronary occlusion. Levosimendan, but not milrinone, significantly attenuated the pronounced increase in the number of ventricular premature beats (-63%), tachycardia (-50%), fibrillation (-70%), and inhomogeneity of ventricular electrical activation. Levosimendan significantly improved the overall survival rate. Levosimendan has a more beneficial profile than milrinone regarding the development of ventricular arrhythmias during and after regional myocardial ischemia.
 ...
PMID:Effect of levosimendan and milrinone on regional myocardial ischemia/reperfusion-induced arrhythmias in dogs. 1689 Dec 90

Antiplatelet agents, sarpogrelate (SAR), a 5-hydroxy tryptamine 2A receptor antagonist and cilostazol (CIL), a phosphodiesterase-III inhibitor, were observed to be beneficial in attenuating cardiac remodeling and improving cardiac function in congestive heart failure due to myocardial infarction in rats; however, CIL increased ventricular tachycardia and mortality. In order to study the effects of these antiplatelet agents on arrhythmias, Sprague-Dawley rats were pretreated with either SAR or CIL (5 mg/kg/day) for 2 weeks and were then either injected cumulative doses of epinephrine (Epi) or subjected to coronary occlusion. Saline-treated animals served as controls. Electrocardiographic analysis revealed that SAR pretreatment decreased the incidence and severity of ventricular arrhythmias (time of onset of arrhythmias as well as the occurrence of premature ventricular contractions, salvos, tachycardia, and fibrillations), whereas CIL treatment augmented the incidence of cardiac arrhythmias due to both Epi and coronary occlusion. None of the drugs affected the corrected QT interval significantly. Furthermore, the levels of cyclic adenosine monophosphate (cAMP) in left ventricle were markedly higher in CIL-pretreated rats when compared to SAR-pretreated or control rats. It is suggested that an excessive level of cAMP may contribute to increase incidence of ventricular arrhythmias and mortality in animals pretreated with CIL, unlike the SAR-pretreated rats.
 ...
PMID:Antiplatelet agents sarpogrelate and cilostazol affect experimentally-induced ventricular arrhythmias and mortality. 1875 28


1 2 Next >>