Weishaar R E, Kobylarz-Singer D C, Kaplan H R
Department of Pharmacology, Warner-Lambert/Parke-Davis Pharmaceutical Research, Ann Arbor, MI 48105.
J Mol Cell Cardiol. 1987 Oct;19(10):1025-36. doi: 10.1016/s0022-2828(87)80574-6.
Canine and guinea-pig left ventricular muscle contains multiple molecular forms of phosphodiesterase (PDE) which vary according to substrate specificity, stimulation by calmodulin and response to various selective and nonselective phosphodiesterase inhibitors. Both species possess a cyclic AMP-specific form of phosphodiesterase (PDE III). In the dog, both soluble and particulate forms of PDE III are present. The particulate form of PDE III is potently inhibited by cyclic GMP and the selective PDE III inhibitors imazodan (CI-914) and cilostamide, but is only weakly inhibited by the selective PDE III inhibitors Ro 20-1724 and rolipram. In contrast, the soluble form of PDE III in canine left ventricle is only weakly inhibited by cyclic GMP, imazodan and cilostamide, but is potently inhibited by Ro 20-1724 and rolipram. Guinea-pig left ventricle contains only one subclass of PDE III, which is potently inhibited by cyclic GMP, imazodan and cilostamide, but not by Ro 20-1724 or rolipram. However, whereas the imazodan-sensitive subclass of PDE III is a particulate enzyme in the canine left ventricle, in the guinea-pig this subclass of PDE III is a soluble enzyme. Both soluble and particulate PDE III's are (i) insensitive to calmodulin; (ii) possess comparable Km and Vmax values for hydrolysis of cyclic AMP; (iii) are equally inhibited by the nonselective PDE inhibitor theophylline, and (iv) are eluted from DEAE-cellulose anion-exchange resin by comparable concentrations of sodium acetate. The demonstration of distinct subclasses of the cyclic AMP-specific phosphodiesterase (PDE III) in canine left ventricular muscle associated with different domains of the cell suggests compartmentation of cyclic AMP. In addition, the observation that the imazodan-sensitive form of PDE III is a particulate enzyme in canine left ventricle and a soluble enzyme in guinea-pig left ventricle may explain the species differences which exist regarding the positive inotropic response to imazodan in these two species.
犬和豚鼠的左心室肌含有多种磷酸二酯酶（PDE）分子形式，这些形式根据底物特异性、钙调蛋白刺激以及对各种选择性和非选择性磷酸二酯酶抑制剂的反应而有所不同。这两个物种都拥有一种环磷酸腺苷特异性的磷酸二酯酶（PDE III）形式。在犬中，PDE III既有可溶性形式，也有颗粒性形式。PDE III的颗粒性形式受到环磷酸鸟苷以及选择性PDE III抑制剂咪唑旦（CI - 914）和西洛他唑的强烈抑制，但仅受到选择性PDE III抑制剂罗匹尼罗（Ro 20 - 1724）和咯利普兰的微弱抑制。相比之下，犬左心室中PDE III的可溶性形式仅受到环磷酸鸟苷、咪唑旦和西洛他唑的微弱抑制，但受到罗匹尼罗和咯利普兰的强烈抑制。豚鼠左心室仅含有一种PDE III亚类，它受到环磷酸鸟苷、咪唑旦和西洛他唑的强烈抑制，但不受罗匹尼罗或咯利普兰的抑制。然而，虽然犬左心室中对咪唑旦敏感的PDE III亚类是一种颗粒性酶，但在豚鼠中，该PDE III亚类是一种可溶性酶。可溶性和颗粒性PDE III均：（i）对钙调蛋白不敏感；（ii）对于环磷酸腺苷水解具有相当的值和值；（iii）受到非选择性PDE抑制剂茶碱的同等抑制；（iv）被相当浓度的醋酸钠从二乙氨基乙基纤维素阴离子交换树脂上洗脱下来。犬左心室肌中环磷酸腺苷特异性磷酸二酯酶（PDE III）的不同亚类与细胞的不同区域相关，这一发现表明环磷酸腺苷存在区室化。此外，观察到犬左心室中对咪唑旦敏感的PDE III形式是颗粒性酶，而在豚鼠左心室中是可溶性酶，这可能解释了这两个物种在对咪唑旦的正性肌力反应方面存在的种属差异。
