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Effect of tyrosine kinase and tyrosine phosphatase inhibitors on aortic contraction and induction of nitric oxide synthase.

Abstract：

:We studied the effects of the tyrosine kinase inhibitors genistein and tyrphostin and the tyrosine phosphatase inhibitors sodium orthovanadate and phenylarsine oxide on endotoxin-mediated induction of nitric oxide (NO) synthase in rat aorta and its effects on vascular contractility. Genistein (i.p. 10 mg/kg) inhibited the ex vivo vascular hyporesponsiveness to noradrenaline and the aminoguanidine-sensitive nitrite accumulation induced by endotoxin (i.p. 5 mg/kg) in aortic rings. Low concentrations of genistein (10(-6) M) and tyrphostin (3 x 10(-6) M) inhibited both endotoxin-induced hyporesponsiveness and nitrite and NOx accumulation in vitro in rat aorta without affecting control nitrite or NOx accumulation or contraction. Higher concentrations of genistein (10(-5) and 5.5 x 10(-5) M), sodium orthovanadate (10(-4) M) and phenylarsine oxide (10(-6) M) produced an irreversible depression of noradrenaline-induced contractions. In the presence of these drugs, endotoxin did not induce further depression of vascular contractility and did not increase nitrite or NOx production. In conclusion, there is a dissociation between the effects of these drugs on vascular smooth muscle contraction and NO synthase induction, the latter being more sensitive to inhibition by these drugs. Surprisingly, tyrosine phosphatase inhibitors produced similar effects to those of tyrosine kinase inhibitors, suggesting that there is a complex relationship between tyrosine kinases and phosphatases in the signalling pathway of agonist-induced vascular smooth muscle contraction and NO synthase induction.

journal_name

Eur J Pharmacol

journal_title

European journal of pharmacology

authors

Duarte J,Ocete MA,Pérez-Vizcaino F,Zarzuelo A,Tamargo J

doi

10.1016/s0014-2999(97)01311-3

subject

Has Abstract

pub_date

1997-10-29 00:00:00

pages

25-33

issue

1

eissn

0014-2999

issn

1879-0712

pii

S0014-2999(97)01311-3

journal_volume

338

pub_type

杂志文章

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