Nonspecific Inhibition of Myogenic Tone by PD98059, a MEK1 Inhibitor, in Rat Middle Cerebral Arteries

Activation of MAP kinase kinase, also called ERK kinase (MEK), may lead to desinhibition of thin filament regulatory proteins and we therefore investigated the acute effects of the potent MEK inhibitor, PD98059 on the contractile properties of pressurized rat middle cerebral arteries. Cerebral arter...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 1999-04, Vol.257 (2), p.523-527
Main Authors: Lagaud, Guy.J.L., Lam, Eugene, Lui, Amy, van Breemen, Cornelis, Laher, Ismail
Format: Article
Language:English
Subjects:
Animals
Arginine Vasopressin - antagonists & inhibitors
Arginine Vasopressin - pharmacology
Blood Pressure - drug effects
Calcium Chloride - antagonists & inhibitors
Calcium Chloride - pharmacology
Cerebral Arteries - drug effects
Cerebral Arteries - physiology
Flavonoids - pharmacology
Male
MAP Kinase Kinase 1
Mitogen-Activated Protein Kinase Kinases
Muscle Contraction - drug effects
Muscle Tonus - drug effects
Muscle, Smooth, Vascular - drug effects
Muscle, Smooth, Vascular - physiology
Myography
Potassium Chloride - antagonists & inhibitors
Potassium Chloride - pharmacology
Protein-Serine-Threonine Kinases - antagonists & inhibitors
Protein-Tyrosine Kinases - antagonists & inhibitors
Rats
Rats, Sprague-Dawley
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Summary:Activation of MAP kinase kinase, also called ERK kinase (MEK), may lead to desinhibition of thin filament regulatory proteins and we therefore investigated the acute effects of the potent MEK inhibitor, PD98059 on the contractile properties of pressurized rat middle cerebral arteries. Cerebral arteries (diameter 100-150 μm) were mounted on a pressure myograph and PD98059 (10 μM, 40 μM) significantly inhibited (15% and 64%) myogenic tone (P < 0.001). At these concentrations, PD98059 also significantly reduced the vasopressin (0.1 μM)- and KCl (60 mM)-induced tone. Cumulative addition of exogenous Ca2+(0.4-1.6 mM) increased myogenic tone to ∼50% of constriction at 80 mmHg. This effect was inhibited by PD98059 (P < 0.001). These results demonstrate that pressure-induced myogenic tone is inhibited by PD98059 at the concentrations that have been reported to be selective for inhibition of MEK and the MAP kinase cascade. However, our results also demonstrate that PD98059 may have nonspecific effects on voltage-sensitive Ca2+entry in vascular smooth muscle.
ISSN:0006-291X
1090-2104
DOI:10.1006/bbrc.1999.0350