Rayment S J, Simpson J A D, Eames T, Acheson A G, Dashwood M R, Henry Y, Gruss H, Scholefield J H, Wilson V G
Division of GI Surgery, School of Medicine, University of Nottingham, Queen's Medical Centre, Nottingham, UK.
Neurogastroenterol Motil. 2014 Aug;26(8):1095-103. doi: 10.1111/nmo.12363. Epub 2014 Jun 6.
The role of α-adrenoceptors in promoting continence through modulation of sphincter tone has focused primarily on the effects of α1 -adrenoceptors. We have used three clinically available agents, which are selective for α2 -adrenoceptors, to investigate their role in contractile and neurogenic responses on the internal anal sphincter (IAS).
IAS strips, which had spontaneously generated tone, were used to investigate the contractile effect of lofexidine, brimonidine, and dexmedetomidine on muscle tone in the presence or absence of subtype selective antagonists. The effect of brimonidine on the magnitude and time course of neurogenic responses generated by electrical field stimulation (EFS) was also examined. The affinity of test compounds at α1 - and α2 -adrenoceptors was established by competition binding with [3H]-prazosin and [3H]-RX821002.
All agonists caused concentration-dependent contraction of the IAS and lofexidine demonstrated an enantiomeric difference in potency with a 10-fold difference between the (-) and (+) isomers. Responses to lofexidine and dexmedetomidine were inhibited in the presence of the α1 -adrenoceptor selective antagonist prazosin, but not in the presence of RX811059 (α2 -adrenoceptor selective antagonist); brimonidine responses were inhibited by RX811059 and, to a lesser extent, by prazosin. Brimonidine affected both magnitude and duration of neurogenic responses, which was reversed in the presence of RX811059.
CONCLUSIONS & INFERENCES: We conclude that α2 -adrenoceptors can mediate contraction of IAS, although this effect is most evident with efficacious imidazoline agonists rather than the most selective ligand. In addition, this receptor subtype can directly inhibit noradrenergic contractile responses to EFS and, indirectly, enhance nitrergic relaxatory responses.
α-肾上腺素能受体通过调节括约肌张力促进控尿的作用主要集中在α1-肾上腺素能受体的效应上。我们使用了三种临床可用的对α2-肾上腺素能受体具有选择性的药物，来研究它们在肛管内括约肌（IAS）的收缩和神经源性反应中的作用。
使用具有自发产生张力的IAS条带，在存在或不存在亚型选择性拮抗剂的情况下，研究洛非西定、溴莫尼定和右美托咪定对肌张力的收缩作用。还研究了溴莫尼定对电场刺激（EFS）产生的神经源性反应的幅度和时间进程的影响。通过与[3H]-哌唑嗪和[3H]-RX821002竞争结合来确定测试化合物对α1-和α2-肾上腺素能受体的亲和力。
所有激动剂均引起IAS的浓度依赖性收缩，洛非西定表现出对映体效力差异，（-）和（+）异构体之间相差10倍。在α1-肾上腺素能受体选择性拮抗剂哌唑嗪存在下，对洛非西定和右美托咪定的反应受到抑制，但在RX811059（α2-肾上腺素能受体选择性拮抗剂）存在下则不受抑制；溴莫尼定的反应受到RX811059的抑制，且在较小程度上受到哌唑嗪的抑制。溴莫尼定影响神经源性反应的幅度和持续时间，在RX811059存在下这种影响被逆转。
我们得出结论，α2-肾上腺素能受体可介导IAS的收缩，尽管这种效应在有效的咪唑啉激动剂而非最具选择性的配体中最为明显。此外，该受体亚型可直接抑制对EFS的去甲肾上腺素能收缩反应，并间接增强一氧化氮能舒张反应。
