Department of Pharmacology, College of Medicine, Chosun University, Gwangju 501-759, Korea.
Korean J Physiol Pharmacol. 2008 Feb;12(1):13-23. doi: 10.4196/kjpp.2008.12.1.13. Epub 2008 Feb 28.
The aim of the present study was designed to establish comparatively the inhibitory effects of D(1)-like and D(2)-like dopaminergic receptor agonists, SKF81297 and R(-)-TNPA on the release of catecholamines (CA) evoked by cholinergic stimulation and membrane depolarization from the isolated perfused model of the rat adrenal medulla. SKF81297 (30microM) and R-(-)-TNPA (30microM) perfused into an adrenal vein for 60 min, produced great inhibition in the CA secretory responses evoked by ACh (5.32x10(- 3) M), DMPP (10(-4) M), McN-A-343 (10(-4) M), high K(+) (5.6x10(-2) M), Bay-K-8644 (10microM), and cyclopiazonic acid (10microM), respectively. For the release of CA evoked by ACh, high K(+), DMPP, McN-A-343, Bay-K-8644 and cyclopiazonic acid, the following rank order of inhibitory potency was obtained: SKF81297>R-(-)-TNPA. However, R(+)-SCH23390, a selectve D(1)-like dopaminergic receptor antagonist, and S(-)-raclopride, a selectve D(2)-like dopaminergic receptor antagonist, enhanced the CA secretory responses evoked by ACh, high K(+), DMPP, McN-A-343, Bay-K-8644 and cyclopiazonic acid only for 0~4 min. The rank order for the enhancement of CA release evoked by high K(+), McN-A-343 and cyclopiazonic acid was R(+)-SCH23390>S(-)-raclopride. Also, the rank order for ACh, DMPP and Bay-K-8644 was S(-)-raclopride > R(+)-SCH23390. Taken together, these results demonstrate that both SKF81297 and R-(-)-TNPA inhibit the CA release evoked by stimulation of cholinergic (both nicotinic and muscarinic) receptors and the membrane depolarization from the isolated perfused rat adrenal gland without affecting the basal release, respectively, but both R(+)-SCH23390 and S(-)-raclopride facilitate the CA release evoked by them. It seems likely that the inhibitory effects of SKF81297 and R-(-)-TNPA are mediated by the activation of D(1)-like and D(2)-like dopaminergic receptors located on the rat adrenomedullary chromaffin cells, respectively, whereas the facilitatory effects of R(+)-SCH23390 and S(-)-raclopride are mediated by the blockade of D(1)-like and D(2)-like dopaminergic receptors, respectively: this action is possibly associated with extra- and intracellular calcium mobilization. Based on these results, it is thought that the presence of dopaminergic D(1) receptors may play an important role in regulation of the rat adrenomedullary CA secretion, in addition to well-known dopaminergic D(2) receptors.
本研究旨在建立比较 D（1）样和 D（2）样多巴胺能受体激动剂 SKF81297 和 R（-）-TNPA 对乙酰胆碱刺激和去极化膜诱发的大鼠肾上腺髓质分离灌注模型中儿茶酚胺（CA）释放的抑制作用。SKF81297（30μM）和 R-（-）-TNPA（30μM）分别灌流肾上腺静脉 60 分钟，对乙酰胆碱（5.32x10（-3）M）、DMPP（10（-4）M）、McN-A-343（10（-4）M）、高 K+（5.6x10（-2）M）、Bay-K-8644（10μM）和环匹阿尼酸（10μM）诱发的 CA 分泌反应产生强烈抑制。对于乙酰胆碱、高 K+、DMPP、McN-A-343、Bay-K-8644 和环匹阿尼酸诱发的 CA 释放，获得了以下抑制效力的顺序：SKF81297>R-（-）-TNPA。然而，选择性 D（1）样多巴胺能受体拮抗剂 R（+）-SCH23390 和选择性 D（2）样多巴胺能受体拮抗剂 S（-）-raclopride 仅在 0~4 分钟时增强乙酰胆碱、高 K+、DMPP、McN-A-343、Bay-K-8644 和环匹阿尼酸诱发的 CA 分泌反应。高 K+、McN-A-343 和环匹阿尼酸诱发的 CA 释放增强的顺序为 R（+）-SCH23390>S（-）-raclopride。此外，乙酰胆碱、DMPP 和 Bay-K-8644 的顺序为 S（-）-raclopride > R（+）-SCH23390。综上所述，这些结果表明，SKF81297 和 R-（-）-TNPA 均抑制刺激胆碱能（烟碱和毒蕈碱）受体和去极化膜从分离灌注大鼠肾上腺引起的 CA 释放，而不影响基础释放，而 R（+）-SCH23390 和 S（-）-raclopride 促进它们诱发的 CA 释放。似乎 SKF81297 和 R-（-）-TNPA 的抑制作用是通过位于大鼠肾上腺髓质嗜铬细胞上的 D（1）样和 D（2）样多巴胺能受体的激活来介导的，而 R（+）-SCH23390 和 S（-）-raclopride 的促进作用是通过 D（1）样和 D（2）样多巴胺能受体的阻断来介导的：这种作用可能与细胞外和细胞内钙动员有关。基于这些结果，认为除了众所周知的多巴胺 D（2）受体外，多巴胺 D（1）受体的存在可能在调节大鼠肾上腺髓质 CA 分泌中发挥重要作用。
