Endothelin-1 initiates the development of vasospasm after subarachnoid haemorrhage through protein kinase C activation, but does not contribute to prolonged vasospasm

Endothelium plays a role in the regulation of vascular tone. Endothelin is a family of potent vasoconstrictive peptides, and endothelin-l (ET-I) produced in the endothelium induces a tonic contraction via specific receptor ETA. ET-I has been postulated as an important factor in the development of vasospasm after subarachnoid haemorrhage (SAH), We have previously shown that protein kinase C (PKC) of the cerebral artery plays a pivotal role in the pathogenesis of vasospasm. The purpose of this study is to clarify the relationship between ET-I and PKC in the development and maintenance of vasospasm. Using a "two-haemorrhage" canine model. chronological changes of angiographic progression of vasospasm. PKC activation, and ET-1 level of the basilar artery were assessed. In an isometric tension study with a control artery, the effects of ETA- and ETA/ETB antagonists on the tonic contraction induced by ET-I were examined. The effects of ET-I. ET-1 and an ETA-antagonist, and ET-I and an ETA/ETB-antagonist on PKC activation were also evaluated. ET-1 level temporarily increased. then decreased to the control level in a later stage of vasospasm. ET-1 induced a tonic contraction and enhancement of PKC activation, but both were inhibited either by an ETA- or an ETA/ETB-antagonist. These results indicate that ET-I initiates the development of vasospasm through PKC activation, but does not contribute to prolonged vasospasm.