Korth M, Engels J, Schäfer-Korting M
Naunyn Schmiedebergs Arch Pharmacol. 1987 Feb;335(2):166-75. doi: 10.1007/BF00177719.
The influence of phosphodiesterase inhibitors and of carbachol on the positive inotropic effect of 8-substituted cyclic AMP analogues was studied on isometrically contracting guinea-pig papillary muscles driven at a rate of 0.2 Hz. In muscles from reserpine-pretreated animals, the phosphodiesterase inhibitors 3-isobutyl, 1-methyl xanthine (IBMX; 20 mumol/l) and papaverine (10 mumol/l) shifted the concentration-effect curves of 8-substituted cyclic AMP benzyl esters to the left, decreasing the EC50 by a factor of 10 to 25. In the presence of IBMX (5 and 20 mumol/l) or papaverine (10 mumol/l), the slopes of the concentration-effect curves of 8-substituted cyclic AMP benzyl esters became flatter. The positive inotropic effect and the increase in Vmax, overshoot and duration of slow action potentials induced by cyclic AMP analogues were not affected by carbachol (0.1-10 mumol/l). In the presence of IBMX (20 mumol/l), however, carbachol (3 mumol/l) antagonized the positive inotropic effect of 8-substituted cyclic AMP derivatives, shifting the EC50-values by a factor of 3 to the right. Cyclic AMP content determined by radioimmunoassay in individual papillary muscles was raised 1.22 and 1.63-fold in the presence of 3 and 20 mumol/l IBMX. Isoprenaline (0.1 mumol/l) induced an increase in cyclic AMP content which was not significantly different from that produced by 20 mumol/l IBMX, but in contrast to the phosphodiesterase inhibitor enhanced force of contraction by 17.7 mN as compared to 1.5 mN obtained with 20 mumol/l IBMX. The findings are consistent with a model that describes the interaction between IBMX and cyclic AMP analogues as an additive effect with only endogenously accumulated cyclic AMP (due to phosphodiesterase inhibition) being involved in the negative inotropic effect of carbachol. From the failure of carbachol to affect the positive inotropic effect of cyclic AMP analogues, it is concluded, that cyclic AMP derivatives do not act as phosphodiesterase inhibitors, and that the well-known negative inotropic effect of carbachol in the presence of cyclic AMP-elevating drugs does not occur at a step beyond cyclic AMP accumulation.
在以0.2Hz频率驱动的等长收缩豚鼠乳头肌上，研究了磷酸二酯酶抑制剂和卡巴胆碱对8-取代环磷酸腺苷类似物正性肌力作用的影响。在利血平预处理动物的肌肉中，磷酸二酯酶抑制剂3-异丁基-1-甲基黄嘌呤（IBMX；20μmol/L）和罂粟碱（10μmol/L）使8-取代环磷酸腺苷苄酯的浓度-效应曲线向左移动，将半数有效浓度（EC50）降低了10至25倍。在存在IBMX（5和20μmol/L）或罂粟碱（10μmol/L）的情况下，8-取代环磷酸腺苷苄酯的浓度-效应曲线斜率变得更平缓。卡巴胆碱（0.1 - 10μmol/L）不影响环磷酸腺苷类似物诱导的正性肌力作用以及最大反应速度（Vmax）、超射和慢动作电位持续时间的增加。然而，在存在IBMX（20μmol/L）的情况下，卡巴胆碱（3μmol/L）拮抗8-取代环磷酸腺苷衍生物的正性肌力作用，将EC50值向右移动了3倍。通过放射免疫测定法测定的单个乳头肌中环磷酸腺苷含量，在存在3和20μmol/L IBMX时分别升高了1.22倍和1.63倍。异丙肾上腺素（0.1μmol/L）诱导的环磷酸腺苷含量增加与20μmol/L IBMX产生的增加无显著差异，但与磷酸二酯酶抑制剂相比，异丙肾上腺素使收缩力增强了17.7mN，而20μmol/L IBMX仅使收缩力增强了1.5mN。这些发现与一个模型一致，该模型将IBMX与环磷酸腺苷类似物之间的相互作用描述为一种加和效应，只有内源性积累的环磷酸腺苷（由于磷酸二酯酶抑制）参与卡巴胆碱的负性肌力作用。从卡巴胆碱未能影响环磷酸腺苷类似物的正性肌力作用可以得出结论，环磷酸腺苷衍生物不作为磷酸二酯酶抑制剂起作用，并且在存在升高环磷酸腺苷的药物时，卡巴胆碱众所周知的负性肌力作用不会发生在环磷酸腺苷积累之后的步骤。
