Wick P F, Keung A C, Bowler J J, Deth R C
J Pharmacol Exp Ther. 1987 May;241(2):458-64.
Differences in the ability of full vs. partial agonists to initiate alpha-1 adrenergic receptor-mediated coupling events were studied in isolated segments of rabbit aorta. Mono- and dimethoxysubstituted tolazolines produced contractile responses which, at their maximum, were 27 to 100% of the response produced by the full agonist phenylephrine. In addition to differences in maximum response, contraction kinetics varied between full and partial agonists. Responses to partial agonists displayed a slower approach to peak tension and loss of the rapid phase of tension development which is associated with release of intracellular Ca++. Among the tolazoline series 3,5 dimethoxy-, 3 methoxy-, and 2 methoxy derivatives were compared further with phenylephrine for their ability to cause phosphatidylinositol cycle turnover, intracellular Ca++ release and Ca++ influx. For each of these coupling events, a rank of phenylephrine greater than or equal to 3, 5 greater than 3 greater than 2 was observed. However, a higher percentage of Ca++ influx vs. Ca++ release was observed for the partial agonists, suggesting that their contractile responses may be more dependent upon extracellular Ca++ than intracellular Ca++. Our results indicate that partial agonists initiate the same coupling events as full agonists; however, the relative proportion of Ca++ release and influx may be different for partial agonists because of the reduced rate of second messenger production.
在兔主动脉离体节段中研究了完全激动剂与部分激动剂引发α-1肾上腺素能受体介导的偶联事件的能力差异。单甲氧基和二甲氧基取代的托拉唑啉产生收缩反应，其最大收缩反应为完全激动剂去氧肾上腺素产生反应的27%至100%。除最大反应存在差异外，完全激动剂和部分激动剂的收缩动力学也有所不同。对部分激动剂的反应显示达到峰值张力的过程较慢，且失去了与细胞内Ca++释放相关的快速张力发展阶段。在托拉唑啉系列中，进一步比较了3,5-二甲氧基、3-甲氧基和2-甲氧基衍生物与去氧肾上腺素引起磷脂酰肌醇循环周转、细胞内Ca++释放和Ca++内流的能力。对于这些偶联事件中的每一个，观察到去氧肾上腺素的排名大于或等于3,5大于3大于2。然而，部分激动剂的Ca++内流与Ca++释放的百分比更高，这表明它们的收缩反应可能比细胞内Ca++更依赖细胞外Ca++。我们的结果表明，部分激动剂与完全激动剂引发相同的偶联事件；然而，由于第二信使产生速率降低，部分激动剂的Ca++释放和内流的相对比例可能不同。
