Gene Transfer of Calcitonin Gene–Related Peptide Prevents Vasoconstriction After Subarachnoid Hemorrhage
作者:
Kazunori Toyoda,
Frank Faraci,
Yoshimasa Watanabe,
Toshihiro Ueda,
Jon Andresen,
Yi Chu,
Shoichiro Otake,
Donald Heistad,
期刊:
Circulation Research: Journal of the American Heart Association
(OVID Available online 2000)
卷期:
Volume 87,
issue 9
页码: 818-824
ISSN:0009-7330
年代: 2000
出版商: OVID
关键词: gene therapy;cerebral vasospasm;vasodilation;neuropeptide;rabbit
数据来源: OVID
摘要:
Abstract—We sought to determine whether adenovirus-mediated gene transfer in vivo of calcitonin gene–related peptide (CGRP), a potent vasodilator, ameliorates cerebral vasoconstriction after experimental subarachnoid hemorrhage (SAH). Arterial blood was injected into the cisterna magna of rabbits to mimic SAH 5 days after injection of AdRSVCGRP (8×108pfu), AdRSV&bgr;gal (control virus), or vehicle. After injection of AdRSVCGRP, there was a 400-fold increase in CGRP in cerebrospinal fluid. Contraction of the basilar artery to serotonin in vitro was greater in rabbits after SAH than after injection of artificial cerebrospinal fluid (P<0.001). Contraction to serotonin was less in rabbits with SAH after AdRSVCGRP than after AdRSV&bgr;gal or vehicle (P<0.02). Basal diameter of the basilar artery before SAH (measured with digital subtraction angiogram) was 13% greater in rabbits treated with AdRSVCGRP than in rabbits treated with vehicle or AdRSV&bgr;gal (P<0.005). In rabbits treated with vehicle or AdRSV&bgr;gal, arterial diameter after SAH was 25±3% smaller than before SAH (P<0.0005). In rabbits treated with AdRSVCGRP, arterial diameter was similar before and after SAH and was reduced by 19±3% (P<0.01) after intracisternal injection of CGRP-(8-37) (0.5 nmol/kg), a CGRP1receptor antagonist. To determine whether gene transfer of CGRP after SAH may prevent cerebral vasoconstriction, we constructed a virus with a cytomegalovirus (CMV) promoter, which results in rapid expression of the transgene product. Treatment of rabbits with AdCMVCGRP after experimental SAH prevented constriction of the basilar artery 2 days after SAH. Thus, gene transfer of CGRP prevents cerebral vasoconstriction in vivo after experimental SAH.
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