血管活性肠肽拮抗剂在血管活性肠肽和胰高血糖素样肽对大鼠促肾上腺皮质激素及皮质酮分泌的刺激和抑制作用中表现出差异。

VIP antagonist demonstrates differences in VIP- and PHI-mediated stimulation and inhibition of ACTH and corticosterone secretion in rats.

作者信息

Alexander L D, Sander L D

机构信息

Department of Physiology, Meharry Medical College, School of Graduate Studies and Research, Nashville, TN 37208, USA.

出版信息

Regul Pept. 1995 Nov 10;59(3):321-33. doi: 10.1016/0167-0115(95)00087-r.

DOI:10.1016/0167-0115(95)00087-r

PMID:8577937

Abstract

Previous studies in our laboratory have demonstrated that PVN administration of equimolar doses of VIP and PHI induce similar increases in plasma ACTH and CORT concentrations via the release of CRF and vasopressin in fasted, freely moving rats studied during the early light cycle. The purpose of these investigations was to determine whether VIP and PHI act via the same receptor and/or mechanism. Individual studies involving the PVN administration of either VIP or PHI in doses ranging from 0.3 to 30.0 nmol/rat demonstrated that VIP increases both ACTH and CORT secretion throughout the administered range. In contrast, PHI was an effective stimulant in doses up to 15 nmol/rat but had no effect on either ACTH or CORT at a dose of 30 nmol/rat thus yielding a bell-shaped dose-response curve. When increasing doses of PHI (0.15-3.0 nmol/rat) were administered against a background of VIP (3.0 nmol/rat) predictably additive responses were observed; however, when increasing doses of VIP (0.15-3.0 nmol/rat) were administered with PHI (3.0 nmol/rat) only the higher doses of VIP facilitated the PHI-induced secretion while the lower doses of VIP actually reduced the PHI-induced ACTH secretion. Finally, pretreatment with [Lys1, Pro2,5, Arg3,4, Tyr6]-VIP, anVIP (1.5 nmol/rat) totally suppressed VIP-induced ACTH secretion but had no effect on PHI-induced secretion. These studies collectively suggest that VIP and PHI utilize different receptors/mechanisms to regulate HPA secretion. Furthermore, when a range of doses of anVIP (1.5-30.0 nmol/rat) was tested against VIP (3.0 nmol/rat), ACTH secretion was totally suppressed at all doses of the antagonist. However, the maximal reduction of CORT secretion occurred at the lowest dose of anVIP and increasing doses were less and less effective, suggesting that not only PHI but VIP may also stimulate and inhibit HPA secretion. While both the stimulatory and the inhibitory actions of PHI appear to involve ACTH, only the stimulatory action of VIP is ACTH-dependent.

摘要

我们实验室之前的研究表明，在光周期早期对自由活动的禁食大鼠进行研究时，向室旁核（PVN）注射等摩尔剂量的血管活性肠肽（VIP）和胰高血糖素样肽（PHI），会通过释放促肾上腺皮质激素释放因子（CRF）和血管加压素，使血浆促肾上腺皮质激素（ACTH）和皮质酮（CORT）浓度出现类似的升高。这些研究的目的是确定VIP和PHI是否通过相同的受体和/或机制发挥作用。对每只大鼠注射剂量范围为0.3至30.0纳摩尔的VIP或PHI的个体研究表明，在整个给药范围内，VIP都会增加ACTH和CORT的分泌。相比之下，PHI在剂量高达15纳摩尔/大鼠时是一种有效的刺激物，但在30纳摩尔/大鼠的剂量下对ACTH或CORT均无影响，从而产生钟形剂量反应曲线。当在VIP（3.0纳摩尔/大鼠）的背景下注射递增剂量的PHI（0.15 - 3.0纳摩尔/大鼠）时，可观察到可预测的相加反应；然而，当将递增剂量的VIP（0.15 - 3.0纳摩尔/大鼠）与PHI（3.0纳摩尔/大鼠）一起注射时，只有较高剂量的VIP促进了PHI诱导的分泌，而较低剂量的VIP实际上降低了PHI诱导的ACTH分泌。最后，用[赖氨酸1，脯氨酸2,5，精氨酸3,4，酪氨酸6]-VIP进行预处理，即一种VIP拮抗剂（1.5纳摩尔/大鼠），完全抑制了VIP诱导的ACTH分泌，但对PHI诱导的分泌没有影响。这些研究共同表明，VIP和PHI利用不同的受体/机制来调节下丘脑-垂体-肾上腺（HPA）轴的分泌。此外，当针对VIP（3.0纳摩尔/大鼠）测试一系列剂量的VIP拮抗剂（1.5 - 30.0纳摩尔/大鼠）时，所有剂量的拮抗剂都完全抑制了ACTH分泌。然而，CORT分泌的最大减少发生在拮抗剂的最低剂量时，并且随着剂量增加，效果越来越差，这表明不仅PHI而且VIP也可能刺激和抑制HPA轴的分泌。虽然PHI的刺激和抑制作用似乎都涉及ACTH，但只有VIP的刺激作用依赖于ACTH。