Prevention of vasospasm in penetrating arteries with MAPK inhibitors in dog double-hemorrhage model

BACKGROUND Vasospasm in the penetrating arteries contributes to ischemic neurological deficit. It may be as important as angiographic vasospasm because it would explain the discrepancies between angiographic vasospasm and clinical sympt oms in some patients. It may also underlie the different effects of vasodil ators. The present study examined this hypothesis by looking at the effect of the inhibitors of mitogen-activated protein kinase (MAPK) on vasospasm o f the penetrating arteries. METHODS Twenty-two adult mongrel dogs of either sex were used for the dog double-he morrhage model. The dogs were randomly divided into four groups: control-he morrhage, vehicle-treated PD98059-treated, and U0126-treated groups. The dr ug injections were started on Day 3 after the first subarachnoid hemorrhage (SAH). The clinical status of the dogs was studied, based on their activit y, appetite, and focal neurological symptoms. On Day 7, all the dogs were s acrificed, and the penetrating arteries from the brain stem were prepared f or transmission electron microscopy. RESULTS (1) Severe vasospasm developed in the basilar arteries in the SAH-without-t reatment group (control), in the DMSO-treated group (DMSO), and in the U012 6 treatment group with mean reduction of the basilar artery diameter of 46. 57%, 49.3%, and 39.6%, respectively. In the PD98059-reatment group only a m ild vasospasm was observed and the mean reduction of the basilar artery dia meter was 18.9%. (2) All the dogs in the control SAH and vehicle-treated gr oups developed severe angiographic and clinical vasospasm. The penetrating arteries were contracted, and the endothelial and smooth muscle cells were dystrophic. (3) The dogs in the U0126-treated group developed severe angiog raphic, but not clinical, vasospasm. The penetrating arteries were not cont racted, and the endothelial and smooth muscle cells were not dystrophic. (4 ) The dogs in the PD98059 group developed mild angiographic vasospasm. No d og developed clinical symptoms that could be attributed to vasospasm. In mo rphological studies, the penetrating arteries were slightly contracted, but the cells were not dystrophic. CONCLUSIONS Vasospasm of the penetrating arteries, but not angiographic vasospasm, is c onsistent with the clinical symptoms and signs of vasospasm. MAPK may be im portant in maintaining vasospasm of both major and penetrating cerebral art eries. The correlation of the improvement in the clinical score with the re duction of vasospasm in the penetrating arteries demonstrated an important role of penetrating arteries in the morbidity and mortality caused by SAH. (C) 2000 by Elsevier Science Inc.