Gene transfer of calcitonin gene-related peptide prevents vasoconstrictionafter 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 SA H 5 days after injection of AdRSVCCRP (8x10(8) pfu), AdRSV beta gal (contro l virus), or vehicle. After injection of AdRSVCCRP, there was a 400-fold in crease in CGRP in cerebrospinal fluid. Contraction of the basilar artery to serotonin in vitro was greater in rabbits after SAH than after injection o f artificial cerebrospinal fluid (P<0.001). Contraction to serotonin was le ss in rabbits with SAH after AdRSVCGRP than after AdRSV<beta>gal or vehicle (P<0.02). Basal diameter of the basilar artery before SAH (measured with d igital subtraction angiogram) was 13% greater in rabbits treated with AdRSV CGRP than in rabbits treated with vehicle or AdRSV<beta>gal (P<0.005). In r abbits treated with vehicle or AdRSV<beta>gal, arterial diameter after SAH was 25+/-3% smaller than before SAH (P<0.0005). In rabbits treated with AdR SVCGRP, 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 viru s with a cytomegalovirus (CMV) promoter, which results in rapid expression of the transgene product. Treatment of rabbits with AdCMVCGRP after experim ental SAH prevented constriction of the basilar artery 2 days after SAH. Th us, gene transfer of CGRP prevents cerebral vasoconstriction in vivo after experimental SAH.