Shahid M, Nicholson C D
Department of Pharmacology, Organon Laboratories Ltd, Newhouse, Lanarkshire, Scotland.
Naunyn Schmiedebergs Arch Pharmacol. 1990 Dec;342(6):698-705. doi: 10.1007/BF00175715.
The species dependent variation in the cardiotonic activity of selective cyclic nucleotide phosphodiesterase (PDE) isoenzyme inhibitors was examined by comparing the inotropic and PDE inhibitory effects of Org 30029 (N-hydroxy-5,6-dimethoxy-benzo[b]thiophene-2-carboximidamide HCl), 3-isobutyl-1-methyl-xanthine (IBMX), milrinone and rolipram in rat and rabbit ventricular myocardium. The relative activities of PDE isoenzymes in rat and rabbit cardiac ventricle were also examined to assess the role of the different PDE subtypes in modulating contractile force in the two species. In rabbit papillary muscles, IBMX, Org 30029 and milrinone increased contractile force whilst rolipram was inactive. The rank order of potency of the active compounds was Org 30029 greater than IBMX greater than milrinone. Only Org 30029 and IBMX produced significant positive inotropic responses in rat papillary muscles, milrinone and rolipram being inactive. However, large positive inotropic responses were obtained in rat papillary muscles when milrinone and rolipram were tested in combination. In rabbit papillary muscles, the positive inotropic action of milrinone was markedly potentiated by rolipram. Four main types of PDE (I, II, III, IV) isoenzymes were resolved, by DEAE-sepharose or Mono-Q ion-exchange chromatography, from both rat and rabbit cardiac ventricular tissue. In rabbit, Ca2+/calmodulin dependent PDE (PDE I) and cyclic GMP inhibited PDE (PDE III) were the dominant cAMP activities. In contrast, cyclic GMP stimulated PDE (PDE II), PDE III and cGMP insensitive PDE (PDE IV) represented the main cAMP activities in rat cardiac ventricle. The inhibitory effects of Org 30029, IBMX, milrinone and rolipram on PDE isoenzymes from rat and rabbit cardiac ventricle were essentially similar.(ABSTRACT TRUNCATED AT 250 WORDS)
通过比较奥格30029（N-羟基-5,6-二甲氧基-苯并[b]噻吩-2-甲脒盐酸盐）、3-异丁基-1-甲基黄嘌呤（IBMX）、米力农和咯利普兰在大鼠和兔心室肌中的正性肌力作用及磷酸二酯酶（PDE）抑制作用，研究了选择性环核苷酸磷酸二酯酶（PDE）同工酶抑制剂强心活性的种属依赖性差异。还检测了大鼠和兔心室中PDE同工酶的相对活性，以评估不同PDE亚型在调节两种动物收缩力中的作用。在兔乳头肌中，IBMX、奥格30029和米力农增加收缩力，而咯利普兰无活性。活性化合物的效价顺序为奥格30029大于IBMX大于米力农。只有奥格30029和IBMX在大鼠乳头肌中产生显著的正性肌力反应，米力农和咯利普兰无活性。然而，当联合检测米力农和咯利普兰时，大鼠乳头肌中获得了较大的正性肌力反应。在兔乳头肌中，咯利普兰显著增强了米力农的正性肌力作用。通过DEAE-琼脂糖或Mono-Q离子交换色谱法，从大鼠和兔心室组织中分离出四种主要类型的PDE（I、II、III、IV）同工酶。在兔中，Ca2+/钙调蛋白依赖性PDE（PDE I）和环鸟苷酸抑制性PDE（PDE III）是主要的环磷酸腺苷活性。相反，环鸟苷酸刺激性PDE（PDE II）、PDE III和环鸟苷酸不敏感PDE（PDE IV）是大鼠心室中环磷酸腺苷的主要活性。奥格30029、IBMX、米力农和咯利普兰对大鼠和兔心室PDE同工酶的抑制作用基本相似。（摘要截短于250字）
