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 effects of toborinone ([(+/-)-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]-2 (1H)-quinolinone], OPC-18790), milrinone and E-4031 (1-(2-(6-methyl-2-pyridil)-1-ethyl)-4-(4-methanesulfonyl-amino-1-b enzoyl) piperidine dihydrochloride) on membrane potential were examined in isolated guinea pig sinoatrial node preparations. Toborinone, a new positive inotropic agent, prolonged cycle length (CL), depolarized maximum diastolic potential (MDP) and decreased maximum upstroke velocity (Vmax) and action potential amplitude (APA). On the other hand, milrinone, a peak III phosphodiesterase (PDE III) inhibitor, increased Vmax and APA and shortened CL and action potential duration. E-4031, an IK blocker, prolonged CL, depolarized MDP and decreased Vmax and APA. These results suggest that toborinone modulates the action potential like an IK blocker rather than a PDE III inhibitor in a sinoatrial node.
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PMID:Effects of toborinone (OPC-18790), a new positive inotropic agent, on action potential in guinea pig sinoatrial node: compared with milrinone and E-4031. 890 4

Toborinone ((+/-)-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]-2(1H)-qui nolinone, CAS 128667-95-8, OPC-18790), a novel cardiotonic agent with an inhibitory action on phosphodiesterase, is known to have a potent positive inotropic action with no positive chronotropic effect. The effectiveness of this drug in the treatment of heart failure occurring immediately after extracorporeal circulation (ECC) in cardiac surgery was investigated. The study was conducted in 12 patients with valvular heart disease showing a cardiac index (CI) of below 2.8 l/min/m2 and/or pulmonary capillary wedge pressure (PCWP) or pulmonary arterial diastolic pressure (PAD) of above 8 mmHg immediately after extracorporeal circulation. In group A (n = 6), toborinone was infused at a rate of 40 micrograms/kg/min for the first 5 min and then at 10 micrograms/kg/min for 85 min. In group B (n = 6), the drug was infused at a rate of 10 micrograms/kg/min for the entire 90 min. CI, mean systemic arterial pressure (mSAP), mean pulmonary artery pressure (mPAP), CVP, PCWP, and heart rate were measured at 5, 15, 30, 60, and 90 min after the start of infusion. The infusion volume required to maintain a constant PCWP was also estimated. In group A, CI increased rapidly and significantly from the baseline of 2.48 +/- 0.23 l/min/m2 to 3.57 +/- 1.07 l/min/m2 at 5 min after the start of infusion, and at that time mSAP was slightly decreased. In group B, CI increased gradually from the baseline of 2.53 +/- 0.18 l/min/m2 to 3.08 +/- 0.34 l/min/m2 at 15 min after the start of infusion, but almost no change was seen in mSAP. During the first 30 min, group A required a significantly larger infusion volume (983 +/- 395 ml) than group B (475 +/- 184 ml). From 30 to 90 min after the start of infusion, CI remained increased to similar levels in both groups and mSAP levels were also similar. There were no significant differences between the two groups in any other parameter. Continuous infusion of toborinone appears to be effective for treating heart failure occurring immediately after ECC in cardiac surgery. Initial loading at a rate of 40 micrograms/kg/min rapidly increased CI but was accompanied by mild hypotension. Constant infusion at 10 micrograms/kg/min brought about a more gradual effect that was similar to that of loading at 40 micrograms/kg/min, but without inducing hypotension. Thus, infusion at 10 micrograms/kg/min is considered preferable in order to avoid a larger-than-necessary infusion volume.
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PMID:Study on the effectiveness of toborinone (OPC-18790) in the treatment of heart failure in patients following cardiac surgery. 1041 65

Electropharmacologic effects of a new phosphodiesterase (PDE) III inhibitor toborinone (OPC-18790) were assessed in a halothane-anesthetized, closed-chest canine model. Toborinone, 0.03 mg/kg, increased ventricular contractility, decreased total peripheral resistance, and inhibited intraventricular conduction without changing other cardiovascular parameters. A clinically relevant dose of 0.3 mg/kg increased heart rate, systolic blood pressure, and cardiac output, decreased preload to the left ventricle, enhanced atrioventricular nodal conduction, and shortened repolarization and the vulnerable period of the ventricle, in addition to enhancing the effects observed after the low dose. A high dose of 3 mg/kg of toborinone decreased systolic, mean, and diastolic pressures and prolonged the effective refractory period (ERP) in addition to the effects observed after the middle dose. No further change was detected in ventricular repolarization. Most of the cardiohemodynamic effects can be explained by the PDE III inhibition by toborinone. With regard to electrophysiologic properties, the prolongation of intraventricular conduction time and ERP by toborinone suggests sodium channel inhibition. The lack of the prolongation of ventricular repolarization suggests that previously demonstrated inhibition of I(Kr) and I(K1) and increased I(Ca-L) by toborinone might be counteracted by factors such as the cyclic AMP-dependent outward currents, I(Ks) and I(C1).
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PMID:Electropharmacologic effects of a new phosphodiesterase III inhibitor, toborinone (OPC-18790), assessed in an in vivo canine model. 1148 77