Gene transfer of calcitonin gene-related peptide prevents vasoconstriction after subarachnoid hemorrhage.
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 (8x10(8) pfu), AdRSVbetagal (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 AdRSVbetagal 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 AdRSVbetagal (P:<0.005). In rabbits treated with vehicle or AdRSVbetagal, 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 CGRP(1) receptor 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.
Toyoda
K
K
Faraci
F M
FM
Watanabe
Y
Y
Ueda
T
T
Andresen
J J
JJ
Chu
Y
Y
Otake
S
S
Heistad
D D
DD
D000256:Adenoviridae / Q000235:genetics; D000792:Angiography; D000818:Animals; D001488:Basilar Artery / Q000187:drug effects* / Q000473:pathology; D015740:Calcitonin Gene-Related Peptide / Q000134:cerebrospinal fluid / Q000235:genetics / Q000627:therapeutic use*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006632:Histamine; D007276:Injections, Intraventricular; D011817:Rabbits; D012701:Serotonin; D013345:Subarachnoid Hemorrhage / Q000134:cerebrospinal fluid / Q000628:therapy*; D013997:Time Factors; D014665:Vasodilator Agents / Q000627:therapeutic use*; D020301:Vasospasm, Intracranial / Q000139:chemically induced / Q000517:prevention & control
D014665:Vasodilator Agents; D012701:Serotonin; D006632:Histamine; D015740:Calcitonin Gene-Related Peptide