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-1 (ET-1) produced in the endothelium induces a tonic contraction via specific receptor ET(A). 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 ET(A)- and ET(A)/ET(B)-antagonists on the tonic contraction induced by ET-1 were examined. The effects of ET-1, ET-1 and an ET(A)-antagonist, and ET-1 and an ET(A)/ET(B)-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 ET(A)- or an ET(A)/ET(B)-antagonist. These results indicate that ET-1 initiates the development of vasospasm through PKC activation, but does not contribute to prolonged vasospasm.
Nishizawa
S
S
Department of Neurosurgery, Hamamatsu University School of Medicine, Shizuoka, Japan.
Chen
D
D
Yokoyama
T
T
Yokota
N
N
Otha
S
S
D000818:Animals; D001488:Basilar Artery / Q000000981:diagnostic imaging / Q000503:physiopathology; D002533:Cerebral Angiography; D004285:Dogs; D019332:Endothelin-1 / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D008297:Male; D011493:Protein Kinase C / Q000378:metabolism*; D013345:Subarachnoid Hemorrhage / Q000150:complications*; D013997:Time Factors; D014661:Vasoconstriction; D020301:Vasospasm, Intracranial / Q000209:etiology* / Q000503:physiopathology
D019332:Endothelin-1; D011493:Protein Kinase C