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Research Area
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Description
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Cardiovascular Disease |
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Biological Activity
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Description
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Pimobendan is a selective inhibitor of PDE3 with IC50 of 0.32 μM. |
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Targets
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PDE3 |
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IC50 |
0.32 μM [1] |
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In Vitro
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Pimobendan exhibits selective inhibition of PDE III isolated from guinea pig cardiac muscle with IC50 of 0.32 uM compared to the inhibition of PDE I and PDE II (IC50s >30 μM). [1] Pimobendan inhibits the activity of cAMP-PDE III with IC50 of 2.4 μM. It also exerts concentration-dependent positive inotropic effects in isolated guinea-pig papillary muscles with a potency (EC50) of 6.0 μM, which is partly due to selective cardiac PDE III inhibition. [2] In human atrial cells, 100 μM pimobendan significantly increases the L-type calcium current (ICa(L)) (evoked by depolarization to +10 mV from a holding potential of -40 mV) by 250.4% with the half-maximal stimulation (EC50) of 1.13 μM. In rabbit atrial cells, Pimobendan increases ICa(L) at +10 mV by 67.4.%, which is significantly lower than that obtained in human atrial cells [3] |
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In Vivo
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Pimobendan shows a beneficial effect on survival in the murine model of EMC virus-induced myocarditis. Administration of Pimobendan significantly increases the final survival rate from 33.6% (control) to 53.3% (0.1 mg/kg) or 66.7% (1 mg/kg). Pimobendan (1 mg/kg) also significantly reduces myocardial cellular infiltration, the level of intracardiac tumor necrosis factor (TNF)-α and interleukin (IL)-1β compared with the control group, which shows no effect on myocardial necrosis, heart weight and body weight. Pimobendan suppresses expression of the intracardiac iNOS gene , causing reduction of intracardiac NO production. [4] |
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Clinical Trials
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Features
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Protocol
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Kinase Assay
[1]
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| Phosphodiesterase isoenzyme inhibition |
The isoenzymes PDE I, PDE II and PDE III are isolated from left ventricular guinea pig muscle. For determination of enzyme inhibition, Pimobendan is preincubated for 5 minutes with PDE in a buffer containing 40 mM Tris HCl, 50 mM MgCl2, and 10 mM EGTA (PH 8.0). The reaction is initiated at 37 °C by adding 0.3 μM [3H]cAMP (or 2.5 μM [3H]cGMP in the case of PDE II). The concentration of PDE is such that only 10% of the substrate is hydrolyzed during the reaction, which is stopped after 20 minutes by heating to 90 °C briefly. The reaction product [3H]AMP is split to [3H]adenosine by a phosphatase from king cobra venom. [3H]adenosine is separated from unhydrolyzed [3H]cAMP by chromatography and quantified in a scintillation counter. The concentration that produces 50% inhibition of hydrolysis (IC50) is determined from concentration-response curves. |
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Animal Study
[4]
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| Animal Models |
Male DBA/2 mice of viral myocarditis |
| Formulation |
Prepared as an oral suspension in 0.25% methylcellulose solution, in concentrations of 120 μg/mL and 12 μg/mL |
| Doses |
0.1 or 1 mg/kg |
| Administration |
Orally once daily |
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References |
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[1] Beier N, et al. J Cardiovasc Pharmacol, 1991, 18(1), 17-27.
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[2] Brunkhorst D, et al. Naunyn Schmiedebergs Arch Pharmacol, 1989, 339(5), 575-583.
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[3] Kajimoto K, et al. Br J Pharmacol, 1997, 121(8), 1549-1556.
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[4] Iwasaki A, J. Am Coll Cardiol, 1999, 33(5), 1400-1407.
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