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 arteries (diameter 100-150 microm) were mounted on a pressure myograph and PD98059 (10 microM, 40 microM) significantly inhibited (15% and 64%) myogenic tone (P < 0.001). At these concentrations, PD98059 also significantly reduced the vasopressin (0.1 microM)- and KCl (60 mM)-induced tone. Cumulative addition of exogenous Ca2+ (0.4-1.6 mM) increased myogenic tone to approximately 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.
Lagaud
G J
GJ
Department of Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada.
Lam
E
E
Lui
A
A
van Breemen
C
C
Laher
I
I
D000818:Animals; D001127:Arginine Vasopressin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002122:Calcium Chloride / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002536:Cerebral Arteries / Q000187:drug effects* / Q000502:physiology; D005419:Flavonoids / Q000494:pharmacology*; D048369:MAP Kinase Kinase 1; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases; D009119:Muscle Contraction / Q000187:drug effects; D009129:Muscle Tonus / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009213:Myography; D011189:Potassium Chloride / Q000037:antagonists & inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley
D005419:Flavonoids; D001127:Arginine Vasopressin; D011189:Potassium Chloride; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D002122:Calcium Chloride; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one