Neurokinin-1 receptor antagonism in a rat model of subarachnoid hemorrhage: prevention of upregulation of contractile ETB and 5-HT1B receptors and cerebral blood flow reduction

Object. Cerebral vasospasm following subarachnoid hemorrhage (SAH) leads to reduced cerebral blood flow (CBF) and to cerebral ischemia, in some cases even producing infarction and long-term disability. The goal of the present study was to investigate the hypothesis that inhibition of neurokinin-1 receptors (NK1Rs) by administration of L-822429 blunts the decrease in CBF as well as cerebrovascular receptor upregulation in an animal model of SAH. Methods. Subarachnoid hemorrhage was induced in rats by injection of 250 mu l of blood into the prechiasmatic cistern. The NK1R inhibitor L-822429 was injected intracisternally 30 minutes and 24 hours after the induction of SAH. Two days after SAH induction, the basilar arteries were harvested, and contractile responses to endothelin-1 (ET-1, an ETA- and ETB-receptor agonist) and 5-carboxamidotryptamine (a 5-hydroxytryptamine-1 [5-HT1]-receptor agonist) were investigated using sensitive myographs. To determine whether NK1R inhibition had an influence on local CBF after post-SAH, a quantitative autoradiographic technique was used. After SAH, the vascular receptor phenotype was changed in cerebral arteries through upregulation of contractile ET, and 5-HT1B receptors, while regional and total CBF were markedly reduced. Treatment with the selective NK1R inhibitor L-822429 prevented both the receptor upregulation and the reduction in regional and global CBF. Conclusions. The data reveal the coregulation of vascular receptor changes and blood flow effects, and also show that interaction with a small-molecule NK1R antagonist is a promising area Of focus for the development of specific treatments for SAH

Ultrastructural cerebrovascular changes in a model of subarachnoid hemorrhage in baboon based on triple cisternal blood injection

In a subarachnoid hemorrhage model in the baboon, achieved through three cisternal blood injections with 1-day intervals, the cerebral arteries were dissected out 7 days after the first blood injection for electron microscopy All the animals showed ultrastructural changes in the cerebral arteries: two with severe, one with moderate, and three with mild alterations in the vessel walls. The most constant findings were seen in the muscle cells of the media layer. Fragmentation of the nuclei was frequently observed together with cytoplasmic vacuoles. Scattered groups or single degenerated muscle cells were also noted. In the intima the changes included rounding of the nuclei along with the appearance of cytoplasmic vacuoles. Desquamation or flattening of the endothelium and loss of tight junctions were encountered in some vessel areas. Degenerating mitochondria were a common finding