HIGH SELECTIVITY FOR INHIBITION OF PHOSPHODIESTERASE-III AND POSITIVE INOTROPIC EFFECTS OF MCI-154 IN GUINEA-PIG MYOCARDIUM
HIGH SELECTIVITY FOR INHIBITION OF PHOSPHODIESTERASE-III AND POSITIVE INOTROPIC EFFECTS OF MCI-154 IN GUINEA-PIG MYOCARDIUM
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DOI：
10.1097/00005344-199306000-00001
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发表时间：
1993-06-01
影响因子：
3
通讯作者：
RAAP, A
中科院分区：
文献类型：
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作者：
BETHKE, T;MEYER, W;RAAP, A
MCI-154（0.3-100 μ M）在离体豚鼠乳头肌中发挥浓度依赖性正性肌力作用（EC 50 0.8 μ M）。MCI-154的疗效（给药前值的253%）是赛力农的1.7倍，但与米力农相当。卡巴胆碱显著降低MCI-154的收缩力（FOC）的增加。在完整的收缩乳头肌中，正性肌力作用伴随着环磷酸腺苷含量增加至0.78 +/- 0.09 pmol/mg湿重（n = 10），相当于基础值的150%（0.51 +/-0.05 pmol/mg湿重，n = 21）在次最大环AMP磷酸二酯酶（PDE）同工酶III抑制浓度的MCI-154（30 μ M）存在下。MCI-154（1- 1，000 μ M）浓度依赖性地抑制来自豚鼠心肌匀浆的PDE III的活性。IC 50为3.8 μ M。PDE I、II和IV在高达100 μ M（PDE I和IV）和高达1，000 μ M（PDE II）时不受显著影响。相比之下，米力农和赛力农是PDE III/IV选择性PDE抑制剂。咯利普兰仅抑制PDE IV。IBMX和茶碱是非选择性PDE抑制剂。MCI-154仅有轻微的正性变时作用。豚鼠心房自发搏动频率最多增加8.7%（n = 5）。MCI-154增加了化学去皮的猪心室肌纤维的Ca 2+敏感性。MCI-154（100 μ M）使FOC最大增强至对照值的129.3%。MCI-154的正性肌力作用可能主要是由于抑制PDE III。与PDE III/IV-选择性PDE抑制剂米力酮和赛替酮相反，MCI-154仅抑制PDE III。MCI-154增加收缩蛋白的Ca ~（2+）敏感性可能有助于正性肌力作用。
MCI-154 (0.3-100 muM) exerted a concentration-dependent positive inotropic effect in isolated guinea pig papillary muscles (EC50 0.8 muM). The efficacy of MCI-154 (253% of predrug value) was 1.7-fold higher than that of saterinone but comparable to that of milrinone. Carbachol markedly reduced the increase in force of contraction (FOC) of MCI-154. In intact contracting papillary muscles, the positive inotropic effect was accompanied by an increase in cyclicAMP content to 0.78 +/- 0.09 pmol/mg wet weight (n = 10), corresponding to 150% of the basal value (0.51 +/- 0.05 pmol/mg wet weight, n = 21) in the presence of submaximal cyclicAMP phosphodiesterase (PDE) isoenzyme III inhibiting concentrations of MCI-154 (30 muM). MCI-154 (1-1,000 muM) concentration-dependently inhibited the activity of PDE III from homogenates of guinea pig myocardium. The IC50 was 3.8 muM. PDE I, II, and IV were not significantly affected up to 100 muM (PDE I and IV) and up to 1,000 muM (PDE II). In comparison, milrinone and saterinone were PDE III/IV-selective PDE inhibitors. Rolipram inhibited PDE IV only. IBMX and theophylline were nonselective PDE inhibitors. MCI-154 had only a marginal positive chronotropic effect. The frequency of spontaneously beating fight auricles from guinea pig heart was increased by 8.7% at most (n = 5). MCI-154 increased Ca2+ sensitivity in chemically skinned porcine ventricular muscle fibers. FOC was maximally enhanced to 129.3% of control value by MCI-154 (100 muM). The positive inotropic effect of MCI-154 is probably due mainly to inhibition of PDE III. In contrast to the PDE III/IV-selective PDE inhibitors milrione and saterinone, MCI-154 inhibited PDE III only. The increase in Ca2+ sensitivity of the contractile proteins by MCI-154 may contribute to the positive inotropic effect.