Endothelin-1 Initiates the Development of Vasospasm after Subarachnoid Haemorrhage Through Protein Kinase C Activation, but does not Contribute to Prolonged Vasospasm

Summary

 Endothelium plays a role in the regulation of vascular tone. Endothelin is a family of potent vasoconstrictive peptides, and endothelin-1 (ET-1) produced in the endothelium induces a tonic contraction via specific receptor ETa. ET-1 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-1 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-1 were examined. The effects of ET-1, ET-1 and an ETa-antagonist, and ET-1 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-1 initiates the development of vasospasm through PKC activation, but does not contribute to prolonged vasospasm.