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首页> 美国卫生研究院文献>Biochemical Journal >The identification of a new cyclic nucleotide phosphodiesterase activity in human and guinea-pig cardiac ventricle. Implications for the mechanism of action of selective phosphodiesterase inhibitors.
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The identification of a new cyclic nucleotide phosphodiesterase activity in human and guinea-pig cardiac ventricle. Implications for the mechanism of action of selective phosphodiesterase inhibitors.

机译：人和豚鼠心室中新的环状核苷酸磷酸二酯酶活性的鉴定。对选择性磷酸二酯酶抑制剂作用机制的影响。

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Four cyclic nucleotide phosphodiesterase (PDE) activities were separated from low-speed supernatants of homogenates of human cardiac ventricle by DEAE-Sepharose chromatography, and designated PDE I-PDE IV in order of elution with an increasing salt gradient. PDE I was a Ca2+/calmodulin-stimulated activity, and PDE II was an activity with a high Km for cyclic AMP which was stimulated by low concentrations of cyclic GMP. Human ventricle PDE III had Km values of 0.14 microM (cyclic AMP) and 4 microM (cyclic GMP), and showed simple Michaelis-Menten kinetics with both substrates. PDE IV is a previously unrecognized activity in cardiac muscle, the human enzyme having Km values of 2 microM (cyclic AMP) and 50 microM (cyclic GMP). PDE III and PDE IV were not activated by cyclic nucleotides or calmodulin. Four PDE activities were also isolated from guinea-pig ventricle, and had very similar kinetic properties. By gel filtration, the Mr of PDE III was 60,000, and that of PDE IV 45,000. The drug SK&F 94120 selectively and competitively inhibited PDE III with a Ki value of 0.8 microM (human), showing simple hyperbolic inhibition kinetics. Rolipram (Schering ZK 62711) and Ro 20-1724 (Roche), which have previously been reported to inhibit PDE III-like activities strongly, were shown to be weak inhibitors of human and guinea-pig PDE III enzymes (Ki values greater than 25 microM), but potent inhibitors of PDE IV [Ki values 2.4 microM (Rolipram) and 3.1 microM (Ro 20-1724) with human PDE IV]. The inhibition in all cases demonstrated simple hyperbolic competition. These observations suggest that the previously reported complex inhibition of PDE III-type activities from cardiac muscle was caused by incomplete separation of the PDE III from other enzymes, particularly PDE IV.
机译：通过DEAE-Sepharose色谱法从人心室匀浆的低速上清液中分离出四个环状核苷酸磷酸二酯酶（PDE）活性，并按照盐梯度递增的顺序命名为PDE I-PDE IV。 PDE I是Ca2 + /钙调蛋白刺激的活性，而PDE II是对环状AMP具有高Km的活性，而环AMP被低浓度的环状GMP刺激。人脑室PDE III的Km值为0.14 microM（循环AMP）和4 microM（循环GMP），并且在两种底物上均表现出简单的Michaelis-Menten动力学。 PDE IV是心肌中以前无法识别的活性，人类酶的Km值为2 microM（循环AMP）和50 microM（循环GMP）。 PDE III和PDE IV未被环状核苷酸或钙调蛋白激活。还从豚鼠心室中分离出四种PDE活性，并且具有非常相似的动力学特性。通过凝胶过滤，PDE III的先生为60,000，PDE IV的先生为45,000。药物SK＆F 94120选择性和竞争性抑制Ki值为0.8 microM（人）的PDE III，显示出简单的双曲线抑制动力学。 Rolipram（Schering ZK 62711）和Ro 20-1724（Roche）以前被报道强烈抑制PDE III样活性，但被证明是人和豚鼠PDE III酶的弱抑制剂（Ki值大于25）。 microM），但是有效的PDE IV抑制剂[Ki值是人类PDE IV的2.4 microM（Rolipram）和3.1 microM（Ro 20-1724）]。在所有情况下，抑制均表现为简单的双曲线竞争。这些观察结果表明，先前报道的对心肌中PDE III型活性的复杂抑制是由于PDE III与其他酶（尤其是PDE IV）的不完全分离引起的。

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