PACAP-38 infusion causes sustained vasodilation of the middle meningeal artery in the rat: Possible involvement of mast cells
PACAP-38 infusion causes sustained vasodilation of the middle meningeal artery in the rat: Possible involvement of mast cells
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DOI：
10.1177/0333102414523846
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发表时间：
2014-10-01
期刊：
影响因子：
4.9
通讯作者：
Jansen-Olesen, Inger
中科院分区：
文献类型：
--
作者：
Bhatt, Deepak K.;Gupta, Saurabh;Jansen-Olesen, Inger
背景资料：在健康志愿者和偏头痛患者中，垂体腺苷酸环化酶激活多肽-38（PACAP-38）输注引起脑膜中动脉（MMA）持续血管舒张，并立即和延迟头痛。所有研究受试者均发生面部潮红。肥大细胞（MC）可能在PACAP-38输注的持久效应中发挥作用。我们假设，在肥大细胞耗尽（MCD）大鼠的血管反应PACAP-38将小于对照大鼠，因为缺乏MC脱颗粒过程中释放的血管舒张产物。方法：MCs耗尽化合物48/80的慢性治疗。20分钟静脉注射（i. v.）采用真闭颅窗（CCW）模型，观察降钙素基因相关肽（CGRP）、PACAP-38、PACAP（6-38）（PAC-1受体拮抗剂）和PACAP-27对正常和MCD大鼠MMA直径和平均动脉压（MABP）的影响。对照组仅给予血管活性肠肽（VIP）输注。组胺H1受体拮抗剂美托咪胺（4 mg/kg，i. v.）和H-2受体拮抗剂法莫替丁（1 mg kg（-1）i. v.）在PACAP-38输注前10分钟给予。通过颈动脉内（i.c.）结果：CGRP引起的MMA直径增加在对照组和MCD大鼠中没有显著变化，并且在停止输注后立即恢复到基线水平。在MCD和抗组胺药（AH）预处理的大鼠中，PACAP-38诱导的延迟MMA扩张被消除。与PACAP-38相比，PACAP-27静脉输注在对照大鼠中产生较小的MMA峰扩张。在MCD大鼠中，PACAP-27未诱导任何显著扩张。VIP静脉输注降低了MABP，但没有显著扩张MMA。PACAP（6-38）是一种有效的MC去极化剂，也可显著延迟MMA的扩张。PACAP-38 i.c.反应（直接受体介导的反应）不受MC耗竭的影响。仅PACAP-27（i.c.）的最大响应（%E-max）值结论：PACAP-38诱导的MA延迟性舒张反应在MCD和AH预处理的大鼠中减弱，提示MC介导剂组胺在PACAP-38诱导的MA延迟性舒张中起作用。
Background: In healthy human volunteers and in migraineurs, pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) infusion caused sustained vasodilation of the middle meningeal artery (MMA) and an immediate as well as a delayed headache. All the study subjects experienced facial flushing. Mast cells (MCs) might have a role in the longlasting effect of PACAP-38 infusion. We hypothesized that in mast cell-depleted (MCD) rats the vascular responses to PACAP-38 would be lesser than in control rats because of a lack of vasodilatory products released during MC degranulation.Methods: MCs were depleted by chronic treatment with compound 48/80. The effect of 20 minutes' intravenous (i.v.) infusion of calcitonin gene-related peptide (CGRP), PACAP-38, PACAP(6-38) (PAC-1 receptor antagonist) and PACAP-27 on the diameter of the MMA and on mean arterial blood pressure (MABP) in control and MCD rats was recorded by using the genuine closed-cranial window (CCW) model. Vasoactive intestinal polypeptide (VIP) infusion was given only in control rats. A combination of the histamine H1 receptor antagonist mepyramine (4 mg kg(-1) i.v.) and the H-2 receptor antagonist famotidine (1 mg kg(-1) i.v.) was given 10 minutes prior to PACAP-38 infusion. Increasing doses of PACAP-38, PACAP-27 and VIP were infused through the intracarotid artery (i.c.) in control and MCD rats to see the direct effects of these peptides on MMA diameter change.Results: There was no significant change in CGRP-induced MMA diameter increase in control and MCD rats, and the dilated MMA immediately returned back to baseline after stopping the infusion. The delayed MMA dilation induced by PACAP-38 was abolished in MCD and antihistamine (AH)-pretreated rats. Compared to PACAP-38, the PACAP-27 i.v. infusion gave smaller peak dilation of MMA in control rats. In MCD rats, PACAP-27 did not induce any significant dilation. VIP i.v. infusion reduced MABP but did not dilate MMA significantly. PACAP(6-38), which is a potent MC degranulator, also gave a significant delayed dilation of MMA. PACAP-38 i.c. responses (direct receptor mediated response) were not affected by MC depletion. Only the maximum response (% E-max) value of PACAP-27 (i.c.) was significantly lower in MCD rats compared to control rats.Conclusions: The delayed MMA dilatory responses to PACAP-38 infusion were attenuated in MCD and AH-pretreated rats, indicating a role of the MC mediator-histamine in PACAP-38-induced delayed dilation of MA.