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 relation between myocardial tissue cyclic AMP (cAMP) and the vulnerability to ventricular fibrillation was assessed in the isolated perfused rat heart by measurement of ventricular fibrillation threshold (VFT) and vulnerable period duration (VP). Exogenous dibutyryl cyclic AMP (DBcAMP) reduced VFT and increased VP by a concentration-related action whereas exogenous cAMP did not. Theophylline (1.0 mmol/liter) increased the tissue content of cAMP by 58% (P < 0.001) and caused a leftward shift in the concentration-response curve to DBcAMP. An effect of cAMP on VFT and VP could be shown in the presence of phosphodiesterase inhibition by theophylline. beta-1-Adrenergic receptor blockade with atenolol did not alter the concentration-response curve for VFT when DBcAMP was administered. Epinephrine (100 nmol/liter to 1 mumol/liter) also increased vulnerability to VF; this effect was accompanied by a concentration-related increase in tissue cAMP, but inconsistent changes in tissue ATP, phosphocreatine and potassium. The concentration-response curve of VFT to epinephrine was shifted leftward by theophylline and rightward by atenolol. The increases in vulnerability to fibrillation in the isolated perfused rat heart, in response to DBcAMP, theophylline or epinephrine, could be related more closely to changes of tissue cAMP than to effects on tissue high energy phosphates or potassium. The effect of epinephrine and theophylline on vulnerability to ventricular fibrillation is mediated via alterations in the intracellular level of cAMP in the isolated perfused rat heart.
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PMID:The role of cyclic adenosine monophosphate in adrenergic effects on ventricular vulnerability to fibrillation in the isolated perfused rat heart. 20 34

Activation of the adrenergic nervous system appears to play a crucial role in the genesis of fatal arrhythmias associated with the very early stages of acute myocardial infarction. The second messenger of beta-adrenergic catecholamine stimulation, cyclic adenosine monophosphate (AMP), has established arrhythmogenic qualities, acting by an increase in cytosolic calcium, which potentially has three adverse electrophysiologic effects. First, stimulation of the transient inward current by excess oscillations of cytosolic calcium can invoke delayed afterdepolarizations, so that triggered automaticity can develop in otherwise quiescent ventricular muscle. Second, cyclic AMP can evoke calcium-dependent slow responses in depolarized fibers, so that conditions for reentry are favored. Third, excess cytosolic calcium can cause intercellular uncoupling with conduction slowing. Focal changes in cyclic AMP and cytosolic calcium promote the development of ventricular fibrillation. Beta-adrenergic blockade can limit the formation of cyclic AMP in ischemic tissue. Furthermore, by reducing sinus tachycardia it can lessen cytosolic calcium overload. Hence, beta-adrenergic blockade helps to prevent ventricular fibrillation in the early stages of acute myocardial infarction and protects from sudden death in the postinfarction phase. In congestive heart failure, abnormalities of cytosolic calcium patterns exist with cytosolic calcium overload. It is proposed that the adverse effects of phosphodiesterase inhibitors on the mortality rate in patients with congestive heart failure can be explained by increased rates of formation of cyclic AMP and the development of calcium-dependent arrhythmias. Because calcium is the ultimate messenger of cyclic AMP-induced arrhythmias and because cytosolic calcium is increased in heart failure, it will be difficult to develop positive inotropic agents that are free of the risk of sudden death.
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PMID:Potential arrhythmogenic role of cyclic adenosine monophosphate (AMP) and cytosolic calcium overload: implications for prophylactic effects of beta-blockers in myocardial infarction and proarrhythmic effects of phosphodiesterase inhibitors. 135 May 97

1. This study was designed to compare the effects of two selective inhibitors of certain phosphodiesterase (PDE) isoenzymes on arrhythmias induced by coronary artery occlusion and reperfusion. The drugs used were zaprinast which inhibits guanosine 3':5'-cyclic monophosphate (cyclic GMP)-specific PDE (PDE V) and rolipram which inhibits cyclic GMP-insensitive, adenosine 3':5'-cyclic monophosphate (cyclic AMP)-specific PDE (PDE IV). 2. Pretreatment of anaesthetized rabbits with zaprinast (300 micrograms kg-1 plus 30 micrograms kg-1 min-1) had no significant effect on ischaemia- or reperfusion-induced ST-segment changes, or arrhythmias. In contrast, rolipram (30 micrograms kg-1 plus 3 micrograms kg-1 min-1) and (100 micrograms kg-1 plus 10 micrograms kg-1 min-1) increased the severity of arrhythmias. With the higher dose of rolipram, ST-segment changes were increased in magnitude and mortality due to ventricular fibrillation during ischaemia or reperfusion was increased to 80% compared with 30% in controls (n = 10 per group). 3. Zaprinast caused small but significant increases in heart rate and arterial blood pressure whereas rolipram decreased diastolic arterial pressure, increased left ventricular (LV) dP/dtmax and substantially increased heart rate. 4. At the end of each experiment platelet aggregation was measured ex vivo. Pretreatment of rabbits with either dose of rolipram had no significant effect on platelet aggregation induced by adenosine diphosphate (ADP), collagen, arachidonic acid or thrombin or on isoprenaline- or prostacyclin-induced inhibition of aggregation. Aggregatory responses to ADP and collagen were increased in platelets obtained from rabbits which had received zaprinast. 5. These results indicate that in the dose used here, the PDE V inhibitor zaprinast had no significant effect on arrhythmias. The effects of the PDE IV inhibitor rolipram on haemodynamics, combined with its lack of antiplatelet activity, may have contributed to the exacerbation of arrhythmias observed during myocardial ischaemia and reperfusion.
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PMID:Effects of zaprinast and rolipram on platelet aggregation and arrhythmias following myocardial ischaemia and reperfusion in anaesthetized rabbits. 165 49

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.
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PMID:Comparison of the effects of isobutylmethylxanthine and milrinone on ischaemia-induced arrhythmias and platelet aggregation in anaesthetized rabbits. 247 45

Controversy exists about the role of an increased level of tissue cyclic adenosine 3'-5' monophosphate (cAMP) in the genesis of early ischemic ventricular arrhythmias. Evidence for an arrhythmogenic role for cAMP was proposed by Podzuweit et al. (1978) and Opie et al. (1979) who argued that ischemic ventricular fibrillation was associated with increased levels of tissue cAMP in the ischemic zone. Lubbe et al. (1978) found that infusion of dibutyryl (dBcAMP), or the beta-adrenergic stimulant epinephrine, or the phosphodiesterase inhibitor theophylline, all produced a marked fall in the ventricular fibrillation threshold and an increase in the duration of the vulnerable period of the isolated perfused rat heart. In contrast, Muller et al. (1986) recently showed that prevention of ventricular fibrillation by beta-adrenergic blockade is not directly associated with decreased levels of cAMP, while Manning et al. (1985) used forskolin to stimulate adenylate cyclase and found that the markedly elevated tissue cAMP levels in the rat heart did not promote ischemic or reperfusion arrhythmias. Some of these contradictions could be resolved if the electrophysiological mechanisms by which increased levels of cAMP might predispose to arrhythmias were better understood. It is known that intracellular injection of cAMP into cardiac myocytes can enhance delayed afterdepolarizations (DADs; Matsuda et al. 1982) and that DADs may explain certain arrhythmias such as those evoked by digitalis toxicity (Ferrier, 1977) or reperfusion (Ferrier et al. 1985).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition by simulated ischemia or hypoxia of delayed afterdepolarizations provoked by cyclic AMP: significance for ischemic and reperfusion arrhythmias. 284 May 14

In the isolated rat heart, changes in the ventricular fibrillation threshold (VFT) relate to the myocardial cyclic AMP content rather than to the high-energy phosphate content. After coronary ligation the reduction in VFT correlates with the increase in ischemic tissue cyclic AMP. Agents that reduce the myocardial cyclic AMP (propranolol, 16 microM in perfusate, or amiodarone, 42 microM/kg pretreatment) prevent the postligation fall of the VFT without altering high-energy phosphate depletion. Conversely, theophylline (500 microM), which increases cyclic AMP in ischemic myocardium, causes a greater reduction of VFT without increasing high-energy phosphate depletion. Spontaneous ventricular tachycardia and fibrillation are uncommon in coronary ligated hearts in the first 15 min after ligation (10-20%); these arrhythmias are greatly increased either by reducing the perfusate potassium from 5.9 to 3.0 mM or by pretreating hearts with 1-methyl-3-isobutyl xanthine (10 microM), a cyclic-AMP phosphodiesterase inhibitor. Adenosine (100 microM) antagonizes the increased arrhythmogenesis in both low perfusate potassium and cyclic-AMP phosphodiesterase-inhibited hearts, in the latter without reducing the ischemic tissue cyclic AMP levels. The antiarrhythmic action of adenosine in these hearts is independent of reducing tissue cyclic AMP. Adenosine generated in ischemic myocardium may serve as an endogenous antagonist to the arrhythmogenic action of cyclic AMP.
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PMID:Modulation of myocardial cyclic AMP and vulnerability to fibrillation in the rat heart. 630 87

Although the autonomic nervous system has been implicated in the formation of ventricular fibrillation, the precise mechanism by which this is mediated remains undetermined. In particular, the role of second messengers, generated by beta-adrenoceptor activation, has been postulated to mediate the pro-arrhythmic effects of the sympathetic nervous system. Thus, a 2 min occlusion of the left circumflex coronary artery was initiated during the last minute of exercise in canines with healed myocardial infarctions (produced by ligation of left anterior descending artery). Fifteen dogs were found to be susceptible to the formation of ventricular fibrillation while 17 animals were resistant. Nine resistant dogs were treated with the phosphodiesterase inhibitor isobutylmethyl xanthine (IBMX, 1 mg/kg) in combination with an infusion of 8-bromo-cAMP (100-150 micrograms/kg/min beginning 45 min prior to exercise). Heart rate and left ventricular dP/dtmax significantly increased, but failed to elicit, arrhythmias during the exercise and ischemia test. Nine resistant animals were also treated with the adenylate cyclase activator forskolin, (100 micrograms/kg), which provoked the same hemodynamic changes as the cyclic AMP infusion but also failed to induce ventricular fibrillation. Both forskolin (n = 3) and IBMX (n = 3) induced large increases in myocardial cAMP levels (control 5.2 +/- 0.5, forskolin 8.1 +/- 0.8 pmol/mg non-collagen protein; control 5.0 +/- 0.8, IBMX 6.8 +/- 0.3 pmol/mg non-collagen protein). Ten resistant animals were treated with the beta-adrenoceptor agonist isoproterenol (1-10 micrograms/kg/min), which failed to cause ventricular fibrillation despite significant increases in the hemodynamic parameters described above. Finally, experiments were repeated after 8-bromo-cAMP infusion and IBMX pretreatment in 8 susceptible animals with pharmacologic denervation (atropine+propranolol+prazosin). In spite of hemodynamic increases indicative of an increase in myocardial cyclic AMP levels, arrhythmias were not re-introduced. These data suggest that changes in cAMP may not be responsible for ventricular fibrillation in this model of sudden cardiac death.
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PMID:Effect of interventions that increase cyclic AMP levels on susceptibility to ventricular fibrillation in unanesthetized dogs. 751 86

The rat has been shown to be resistant to the inotropic action of milrinone. We compared in conscious rats, the effects of an i.v. infusion of milrinone (0.3 mg/kg/min), a phosphodiesterase (PDE) inhibitor to those of nitroprusside (50 micrograms/kg/min), a pure vasodilator, on blood pressure and dP/dtmax to determine whether or not an inherent positive inotropic effect of milrinone is offset by its powerful hypotensive action. For the first 10 min of infusion, we found no differences in dP/dtmax, (the first derivative of the left ventricular pressure (LVP), an index of contractility) for equihypotensive doses of milrinone or nitroprusside. A second objective of this study was to determine if milrinone-induced ventricular fibrillation (VF) is due to cardiac ischemia which could be associated with the profound hypotension induced by the drug. Milrinone infusion was accompanied by a significant QTc interval (QT corrected for heart rate) prolongation. VF and death occurred in 5/6 rats at total doses varying from 3.6 to 20.1 mg/kg infused over 12 to 67 min respectively. Premature ventricular contractions (PVCs) were noted in all 6 milrinone infused rats during the first min. of infusion. No arrhythmias were noted during the 2 hour i.v. infusion with nitroprusside. A direct action on the heart is postulated to explain, at least partially, the milrinone-induced VF since nitroprusside had a similar hypotensive action but no effect on the ECG. We conclude that the rat, in analogy to patients with severe cardiac failure, might be resistant to the inotropic action of milrinone but is sensitive to its vasodilatory and arrhythmogenic effects.
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PMID:Comparative cardiac effects of milrinone and sodium nitroprusside in conscious rats. 776 99

Induction of ventricular fibrillation (VF) is an important part of the process of inserting implantable cardioverter defibrillators (ICDs), allowing the measurement of defibrillation thresholds. However, animal studies have revealed that repeated cycles of VF and defibrillation result in depressed left ventricular (LV) function and reduced cardiac output. Short intervals of VF do not affect myocardial contractility but longer periods produce heart failure. Induced VF was used in a canine model to study profound myocardial stunning leading to heart failure, as well as the therapeutic potential of the phosphodiesterase inhibitor, amrinone (combined with epinephrine and norepinephrine). Amrinone was found to significantly (p < 0.05) increase contractility when added to a stable preparation supported by epinephrine and norepinephrine infusion; amrinone or catecholamines alone had no effect. In the clinical setting, the following factors may affect LV contractility during ICD surgery: catecholamines released as a result of hypotension; negative VF; ischemia; antiarrhythmic drugs; anesthetics; and bradycardia after device testing. Patients (n = 125) have tolerated ICD insertion well. Early data reveals no significant changes in ejection fraction. Though rare, death due to myocardial stunning and LV power failure can occur during ICD insertion. It may be possible to use arterial pressure monitoring to predict this event in vulnerable patients.
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PMID:Does ventricular fibrillation cause myocardial stunning during defibrillator implantation? 846 13

1. After a period of myocardial ischaemia, reperfusion of the myocardium can elicit cardiac arrhythmias. Susceptibility to these arrhythmias declines with time, such that a preceding period of more than approximately 40 min ischaemia is associated with few reperfusion-induced arrhythmias. We have tested the hypothesis that this decline in susceptibility occurs, in part, because of protection by endogenous guanosine 3':5'-cyclic monophosphate (cyclic GMP). 2. Rat isolated hearts were subjected to 60 min left regional ischaemia followed by reperfusion (n = 10 per group). Methylene blue (20 microM), a soluble guanylate cyclase inhibitor, raised the incidence of reperfusion-induced ventricular fibrillation (VF) from 10% in control hearts to 80% (P < 0.05). This effect of methylene blue was abolished by co-perfusion with zaprinast (100 microM), a phosphodiesterase inhibitor which, in the rat heart, is cyclic GMP-specific (specific for the type-V phosphodiesterase isozyme). 3. Methylene blue reduced cyclic GMP levels in the ischaemic, non-ischaemic and reperfused myocardium (P < 0.05) to 50 +/- 10, 52 +/- 12 and 70 +/- 7 fmol mg-1 tissue wet weight, respectively from control values of 143 +/- 38, 147 +/- 43 and 156 +/- 15 fmol mg-1. Co-perfusion with zaprinast prevented this effect, and cyclic GMP levels were actually elevated (P < 0.05) to 366 +/- 102, 396 +/- 130 and 293 +/- 22 fmol mg-1 in ischaemic, non-ischaemic and reperfused myocardium, respectively. Zaprinast by itself also elevated cyclic GMP content. Cyclic AMP levels were not affected by zaprinast or methylene blue. 4. In conclusion, when endogenous cardiac cyclic GMP synthesis is reduced, susceptibility to reperfusion-induced VF after sustained ischaemia is substantially increased. The effect is prevented by inhibiting cyclic GMP degradation. Therefore cyclic GMP appears to be an endogenous intracellular cardioprotectant, and its actions may account for the low susceptibility to VF normally encountered in hearts reperfused after sustained ischaemia.
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PMID:An endogenous protectant effect of cardiac cyclic GMP against reperfusion-induced ventricular fibrillation in the rat heart. 868 Jul 26


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