Malmström Rickard E, Lundberg Jon O N, Weitzberg Eddie
Department of Physiology and Pharmacology, Karolinska Institutet, S-17177, Stockholm, Sweden.
Eur J Pharmacol. 2002 Mar 29;439(1-3):113-9. doi: 10.1016/s0014-2999(02)01371-7.
The significance of neuropeptide Y Y(2) receptors in sympathetic nonadrenergic transmission was investigated using the novel selective antagonist BIIE0246 ((S)-N2-[[1-[2-[4-[(R,S)-5,11-dihydro-6(6h)-oxodibenz[b,e]azepin-11-yl]-1-piperazinyl]-2-oxoethyl]cyclopentyl]acetyl]-N-[2-[1,2-dihydro-3,5 (4H)-dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl]ethyl]-argininamide). In anaesthetized pigs pretreated with reserpine, and after transection of sympathetic nerves (depleted of noradrenaline), electrical stimulation of renal and splanchnic sympathetic nerves evoked vasoconstriction in, and overflow of neuropeptide Y-like immunoreactivity from, kidney and spleen, respectively. In the presence of BIIE0246, the nerve-evoked overflows of neuropeptide Y-like immunoreactivity were markedly increased and the splenic vasoconstrictor response prolonged. In addition, BIIE0246 caused splenic vasodilatation per se in this model where basal levels of circulating neuropeptide Y exceed 40 pM. It is concluded that endogenous neurogenical neuropeptide Y regulates its own release via activation of sympathetic prejunctional inhibitory neuropeptide Y Y(2) receptors in both spleen and kidney in the reserpinized pig. Moreover, when circulating levels of neuropeptide Y are moderately increased, activation of neuropeptide Y Y(2) receptors seems to contribute to basal splenic vascular tone.
使用新型选择性拮抗剂BIIE0246（(S)-N2-[[1-[2-[4-[(R,S)-5,11-二氢-6(6H)-氧代二苯并[b,e]氮杂卓-11-基]-1-哌嗪基]-2-氧代乙基]环戊基]乙酰基]-N-[2-[1,2-二氢-3,5(4H)-二氧代-1,2-二苯基-3H-1,2,4-三唑-4-基]乙基]-精氨酰胺）研究了神经肽YY(2)受体在交感神经非肾上腺素能传递中的意义。在用利血平预处理的麻醉猪中，在切断交感神经（去甲肾上腺素耗竭）后，电刺激肾和内脏交感神经分别引起肾脏血管收缩和脾脏中神经肽Y样免疫反应性物质的溢出。在存在BIIE0246的情况下，神经诱发的神经肽Y样免疫反应性物质的溢出明显增加，脾脏血管收缩反应延长。此外，在这个循环神经肽Y基础水平超过40 pM的模型中，BIIE0246本身引起脾脏血管舒张。结论是，内源性神经源性神经肽Y通过激活利血平化猪脾脏和肾脏中交感神经节前抑制性神经肽YY(2)受体来调节其自身释放。此外，当神经肽Y的循环水平适度增加时，神经肽YY(2)受体的激活似乎有助于基础脾脏血管张力。
