Kenakin T P, Ambrose J R, Irving P E
Division of Pharmacology, Glaxo Research Institute, Glaxo Inc., Research Triangle Park, North Carolina.
J Pharmacol Exp Ther. 1991 Jun;257(3):1189-97.
The relative effects of drugs which elevate cytosolic cyclic AMP on inotropy and diastolic relaxation (lusitropy) of guinea pig atria were quantified in vitro. There was a temporal difference between these responses in that inotropy reached peak response considerably faster than lusitropy. Also, although the relaxation response was sustained to an elevated steady state, the inotropic responses to beta adrenoceptor agonists were transient and returned to base line over 90 min. However, the inotropic responses to forskolin and dibutyryl cyclic AMP (cAMP) were sustained. For all of the drugs tested, the lusitropic response was at least 4 times more sensitive than the inotropic response (i.e., the concentration response curve for relaxation was shifted to the left of the curve for inotropy). In the case of beta adrenoceptor agonists, these differences were greater, presumably because of the fading inotropic response over 90 min. It was found that although high efficacy beta adrenoceptor agonists such as isoproterenol (and the direct activator of adenylate cyclase forskolin) produced both inotropy and lusitropy, lower efficacy agonists produced predominant lusitropy. The low efficacy agonist prenalterol produced insignificant inotropy but 60% maximal lusitropy. These data were modeled mathematically by a "differential coupling model" which assumed that a uniform cytosolic level of elevated cAMP activated two biochemical processes of differing sensitivity. Thus, the lusitropic response (phosphorylation of phospholamban) was coupled more efficiently to the cAMP response than the inotropic response (phosphorylation of calcium channels). A second model ("differential messenger concentration model") which calculated the effects of a compartmentalization of cAMP concentration within the cardiac cell by restricted diffusion and/or selective degradation by phosphodiesterases also was used.(ABSTRACT TRUNCATED AT 250 WORDS)
在体外对提高胞质环磷酸腺苷（cAMP）水平的药物对豚鼠心房收缩性和舒张性松弛（舒张功能）的相对作用进行了定量研究。这些反应在时间上存在差异，即收缩性比舒张性松弛达到峰值反应的速度要快得多。此外，尽管舒张反应持续到升高的稳定状态，但β肾上腺素能受体激动剂的正性肌力反应是短暂的，并在90分钟内恢复到基线水平。然而，对福斯可林和二丁酰环磷酸腺苷（cAMP）的正性肌力反应是持续的。对于所有测试药物，舒张功能反应比对肌力反应至少敏感4倍（即舒张的浓度反应曲线向左移至肌力反应曲线的左侧）。就β肾上腺素能受体激动剂而言，这些差异更大，可能是因为90分钟内正性肌力反应逐渐减弱。研究发现，尽管高效β肾上腺素能受体激动剂如异丙肾上腺素（以及腺苷酸环化酶的直接激活剂福斯可林）既能产生正性肌力作用又能产生舒张功能作用，但低效激动剂主要产生舒张功能作用。低效激动剂普瑞特罗产生的正性肌力作用不明显，但能产生60%的最大舒张功能。这些数据通过“差异偶联模型”进行数学建模，该模型假设cAMP升高的均匀胞质水平激活了两个敏感性不同的生化过程。因此，舒张功能反应（受磷蛋白的磷酸化）比正性肌力反应（钙通道的磷酸化）与cAMP反应的偶联更有效。还使用了第二个模型（“差异信使浓度模型”），该模型通过限制扩散和/或磷酸二酯酶的选择性降解来计算心肌细胞内cAMP浓度的区室化效应。（摘要截短于250字）
