Novel mechanism of endothelin-1-induced vasospasm after subarachnoid hemorrhage.
Cerebral vasospasm is a major cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage (SAH). It is a sustained constriction of the cerebral arteries that can be reduced by endothelin (ET) receptor antagonists. Voltage-gated Ca(2+) channel antagonists such as nimodipine are relatively less effective. Endothelin-1 is not increased enough after SAH to directly cause the constriction, so we sought alternate mechanisms by which ET-1 might mediate vasospasm. Vasospasm was created in dogs, and the smooth muscle cells were studied molecularly, electrophysiologically, and by isometric tension. During vasospasm, ET-1, 10 nmol/L, induced a nonselective cation current carried by Ca(2+) in 64% of cells compared with in only 7% of control cells. Nimodipine and 2-aminoethoxydiphenylborate (a specific antagonist of store-operated channels) had no effect, whereas SKF96365 (a nonspecific antagonist of nonselective cation channels) decreased this current in vasospastic smooth muscle cells. Transient receptor potential (TRP) proteins may mediate entry of Ca(2+) through nonselective cationic pathways. We tested their role by incubating smooth muscle cells with anti-TRPC1 or TRPC4, both of which blocked ET-1-induced currents in SAH cells. Anti-TRPC5 had no effect. Anti-TRPC1 also inhibited ET-1 contraction of SAH arteries in vitro. Quantitative polymerase chain reaction and Western blotting of seven TRPC isoforms found increased expression of TRPC4 and a novel splice variant of TRPC1 and increased protein expression of TRPC4 and TRPC1. Taken together, the results support a novel mechanism whereby ET-1 significantly increases Ca(2+) influx mediated by TRPC1 and TRPC4 or their heteromers in smooth muscle cells, which promotes development of vasospasm after SAH.
Xie
An
A
Section of Neurosurgery, Department of Surgery, University of Chicago Medical Center and Pritzker School of Medicine, Chicago, Illinois, USA.
Aihara
Yasuo
Y
Bouryi
Vitali A
VA
Nikitina
Elena
E
Jahromi
Babak S
BS
Zhang
Zhen-Du
ZD
Takahashi
Masataka
M
Macdonald
R Loch
RL
D000595:Amino Acid Sequence; D000792:Angiography; D000818:Animals; D001483:Base Sequence; D004195:Disease Models, Animal; D004285:Dogs; D004594:Electrophysiology; D019332:Endothelin-1 / Q000494:pharmacology*; D005786:Gene Expression Regulation; D008969:Molecular Sequence Data; D009130:Muscle, Smooth / Q000187:drug effects; D018408:Patch-Clamp Techniques; D012333:RNA, Messenger / Q000235:genetics; D012680:Sensitivity and Specificity; D013345:Subarachnoid Hemorrhage / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D050052:TRPC Cation Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020301:Vasospasm, Intracranial / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
D019332:Endothelin-1; D012333:RNA, Messenger; D050052:TRPC Cation Channels