静脉注射PACAP38对健康志愿者脑血流动力学的影响。

The effect of intravenous PACAP38 on cerebral hemodynamics in healthy volunteers.

作者信息

Birk Steffen, Sitarz John Thomas, Petersen Kenneth Ahrend, Oturai Peter Sandor, Kruuse Christina, Fahrenkrug Jan, Olesen Jes

机构信息

Danish Headache Center, Department of Neurology, Glostrup Hospital, University of Copenhagen, Denmark.

出版信息

Regul Pept. 2007 May 3;140(3):185-91. doi: 10.1016/j.regpep.2006.12.010. Epub 2007 Jan 3.

DOI:10.1016/j.regpep.2006.12.010

PMID:17320198

Abstract

PACAP38 is an endogenous peptide located in trigeminal perivascular nerve fibers in the brain. It reduces neuronal loss and infarct size in animal stroke models and has been proposed a candidate substance for human clinical studies of stroke. The effect on systemic hemodynamics and regional cerebral blood flow (rCBF) is not well understood. We here present the first study of the effect of PACAP38 on cerebral hemodynamics in humans. PACAP (10 pmol kg(-1) min(-1)) or placebo (0.9% saline) was infused for 20 min into 12 healthy young volunteers in a cross over, double blind study. rCBF was measured with SPECT and (133)Xe inhalation and mean blood flow velocity in the middle cerebral artery was measured with transcranial Doppler ultrasonography. End tidal partial pressure of CO(2) (P(et)CO(2)) and vital parameters were recorded throughout the 2 hour study period. PACAP38 decreased rCBF in all regions of interest (ROIs) by approximately 3-10%, though not uniformly significant. P(et)CO(2) decreased significantly during PACAP38 infusion compared to placebo (P=0.032), peak decrease was 8.9+/-3.8%. After correction for P(et)CO(2), rCBF remained unchanged in most ROIs. Heart rate increased 61.9+/-22.4% (P<0.0001 vs. placebo). These findings suggest that PACAP38 has no major direct effect on rCBF in healthy volunteers. The marked increase in heart rate and the reduction in rCBF caused by decreased P(et)CO(2) are important dose-limiting factors to consider in future clinical studies.

摘要

垂体腺苷酸环化酶激活肽38（PACAP38）是一种内源性肽，存在于脑内三叉神经血管周围神经纤维中。在动物中风模型中，它可减少神经元损失和梗死面积，并且已被提议作为人类中风临床研究的候选物质。其对全身血流动力学和局部脑血流量（rCBF）的影响尚不清楚。我们在此展示了第一项关于PACAP38对人类脑血流动力学影响的研究。在一项交叉、双盲研究中，将PACAP（10 pmol kg⁻¹ min⁻¹）或安慰剂（0.9%生理盐水）输注给12名健康年轻志愿者，持续20分钟。用单光子发射计算机断层扫描（SPECT）和吸入¹³³氙测量rCBF，用经颅多普勒超声测量大脑中动脉的平均血流速度。在整个2小时的研究期间记录呼气末二氧化碳分压（P（et）CO₂）和生命体征参数。PACAP38使所有感兴趣区域（ROIs）的rCBF降低了约3 - 10%，尽管并非均具有统计学显著性。与安慰剂相比，输注PACAP38期间P（et）CO₂显著降低（P = 0.032），最大降幅为8.9±3.8%。校正P（et）CO₂后，大多数ROIs的rCBF保持不变。心率增加了61.9±22.4%（与安慰剂相比，P < 0.0001）。这些发现表明，PACAP38对健康志愿者的rCBF没有主要直接影响。心率的显著增加以及P（et）CO₂降低导致的rCBF减少是未来临床研究中需要考虑的重要剂量限制因素。