J Neurosurg 72:917-925, 1990 Prevention of cerebral vasospasm in the rat by depletion or inhibition of substance P in conducting vessels TIA JUANA DELGADO-ZYGMUNT, M.D., PH.D., MOHAMMED ABDUL-RAHMAN ARBAB, M.D., PH.D., LARS EDVINSSON, M.D., PH.D., INGER JANSEN, M.D., AND NIELS AAGE SVENDGAARD, M.D., PH.D. Neurosurgical Research Department, Department of lnternal Medicine, University Hospital, and Department of Experimental Research, University of Lund, Malmb General Hospital, Lund, Sweden ~," Cisternal blood injection in the rat induces a biphasic angiographic vasospasm, with a maximal acute spasm at I0 minutes and a maximal late spasm at 2 days after the subarachnoid hemorrhage (SAH). Depletion of substance P-containing sensory nerves to the cerebral arteries with capsaicin prior to SAH prevents the development of both acute and late spasm. Intrathecal administration of the substance P antagonist spantide 2 hours prior to SAH also prevents the development of vasospasm, while spantide administration I hour before SAH only hinders the occurrence of late vasospasm. Intracisternal administration of spantide 2 hours post-SAH prevents the development of late vasospasm. This antagonist per se can induce a short-lasting dose- dependent angiographic vasoconstriction. Substance P-containing nerve fibers on the cerebral arteries could constitute the sensory link in a reflex arc system involved in the development of vasospasm in which the presence of blood in the subarachnoid space stimulates sensory substance P-containing nerve fibers on the cerebral arteries inducing a centripetal impulse to the Az-nucleus tractus solitarius and setting into motion the events in the brain stem leading to acute and late vasospasm. KEY WORDS subaraehnoid hemorrhage 9 vasospasm substance P 9 capsaicin rat C EREBRALvasospasm remains an important cause of morbidity and mortality following aneurys- mal subarachnoid hemorrhage (SAH), despite recent encouraging advances made in the management of delayed cerebral ischemia using prophylactic treat- ment with nimodipine. 2'49,5~Lack of knowledge con- cerning the pathogenesis of vasospasm has, however, prevented the development of a successful mode of therapy. Investigations of vasospasm in an SAH model in the rat ~ have suggested that the A2 (nomenclature accord- ing to Dahlstr6m and Fuxe 9) and nucleus tractus soli- tarius (A2-NTS) in the medulla oblongata and its pro- jection site, the median eminence hypothalamus, are involved in the development of vasospasm. 62-64The A2- NTS receives interoceptive sensory signals for trans- mission to the hypothalamus, where coordination of autonomic and endocrine responses takes place. 23,3~176 Signals induced by blood in the subarachnoid space could be transmitted to the A2 by sensory nerve fibers on the cerebral arteries. The anatomical prerequisites exist for the transmission of "information" from the cerebral arteries to the A2-NTS. The cerebral arteries have a substance P-containing trigeminovascular sen- sory innervation, 37"38'48'69and connections between the A2-NTS and substance P neurons innervating the ce- rebral arteries from the trigeminal ganglia have recently been identified. 3 Furthermore, clinical and experimen- tal studies indicate that the trigeminovascular sensory innervation can convey nociceptive information to the brain stem and that this innervation is involved in reflex v a s o m o t o r f u n c t i o n . 7"25'26'53"56"61"68 The aim of the present study was to investigate the role of the sensory innervation in the development of vasospasm. The effect of lesioning substance P sensory fibers with capsaicin and the therapeutic effect of a substance P antagonist on vasospasm were evaluated in a rat SAH model. Materials and Methods Animal Preparation Male Sprague-Dawley rats (SPF strain),* each weigh- ing 240 to 320 gm, were used in this study. The surgical * Rats obtained from Mollegaards Avelslaboratorium, K0ge, Denmark. J. Neurosurg. / Volume 72/June, 1990 917