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Attenuation of pressure‐induced myogenic contraction and tyrosine phosphorylation by fasudil, a cerebral vasodilator, in rat cerebral artery
Author(s) -
Masumoto Naohiro,
Tanabe Yoshiyuki,
Saito Maki,
Nakayama Koichi
Publication year - 2000
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0703292
Subject(s) - fasudil , tyrosine phosphorylation , phosphorylation , chemistry , tyrosine , protein tyrosine phosphatase , medicine , contraction (grammar) , endocrinology , vasoconstriction , pharmacology , biochemistry , biology , rho associated protein kinase
The mechanism by which fasudil inhibits pressure‐induced myogenic contraction was studied with regard to tyrosine phosphorylation in rat cerebral artery. Intracellular Ca 2+ concentration ([Ca 2+ ] i ) and vessel diameter were simultaneously measured. Total tyrosine phosphorylation level and phosphorylation of tyrosine 419 on pp60 src required for its full catalytic activity were immunocytochemically detected in situ . Fasudil (1–100 μ M ) partially suppressed the increase in [Ca 2+ ] i , and totally attenuated contraction elicited by pressurization from 10 to 60 mmHg. Furthermore, fasudil (100 μ M ) significantly attenuated tyrosine phosphorylation and the activity of pp60 src augmented in situ by pressure. Herbimycin A (1–100 n M ) and genistein (3–30 μ M ), tyrosine kinase inhibitors, effectively attenuated the pressure‐induced increase in [Ca 2+ ] i , contraction, tyrosine phosphorylation, and activation of pp60 src . Both fasudil and herbimycin A directly inhibited the pp60 src activity in a cell free system. Orthovanadate (100 μ M ), a tyrosine phosphatase inhibitor, significantly potentiated the pressure‐induced increase in [Ca 2+ ] i and contraction. Nicardipine (100 n M ), a Ca 2+ antagonist, completely inhibited pressure‐induced increase in [Ca 2+ ] i and contraction, but affected neither tyrosine phosphorylation nor activity of pp60 src in the pressurized arteries. Arginine‐glycine‐aspartic acid‐serine peptide (1–100 μ M ) concentration‐dependently reduced the pressure‐induced contraction. In addition to the hitherto reported vasodilatory actions of fasudil, the present results suggest the inhibition by fasudil of pressure‐induced tyrosine phosphorylation and pp60 src activation. The wide spectrum of inhibitory actions of fasudil may contribute to the effective attenuation of the pressure‐induced contraction in the cerebral artery.British Journal of Pharmacology (2000) 130 , 219–230; doi: 10.1038/sj.bjp.0703292