Selective inhibition of myosin phosphorylation and tension of hyperplastic arteries by the kinase inhibitor HA1077.
To examine possible alterations in myosin light chain phosphorylation in hyperplastic arteries, rabbit strips from right hyperplastic and left normal control carotid arteries were used for experiments 6 weeks after the ballooning procedure. When the hyperplastic artery was stimulated with various concentrations of K+ (10, 20, 30, 40 and 60 mM), the maximal tension in response to each concentration was significantly higher (P < 0.05) than that in the control artery. The maximal extent of myosin light chain phosphorylation induced by 60 mM K+ in the hyperplastic artery was also significantly higher than that in the control (55.1 +/- 4.1 vs. 45.1 +/- 3.2%, mean +/- S.D.). However, the [Ca2+]i response to elevated K+ in hyperplastic arteries was much the same as that in control arteries, when measured with fura-PE3. HA1077 (1-5-(isoquinolinesulfonyl)-homopiperazine), a protein kinase inhibitor, was about 3-5 times more effective in inhibiting the tension and myosin light chain phosphorylation induced by 60 mM K+ in the hyperplastic artery than in the control artery. Nifedipine inhibited the tension and myosin light chain phosphorylation to the same extent in control and hyperplastic arteries. Thus, an alteration of the myosin light chain phosphorylation system, but not an alteration of Ca2+ mobilization, may be involved in the enhanced contraction of the hyperplastic artery. The enhanced phosphorylation of myosin light chain may be sensitive to HA1077.
Seto
M
M
First Pharmacology Laboratory, Asahi Chemical Industry, Co., Ltd., Shizuoka, Japan.
Shindo
K
K
Ito
K
K
Sasaki
Y
Y
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006965:Hyperplasia; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology*; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors*; D009218:Myosins / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology; D010766:Phosphorylation; D011188:Potassium / Q000494:pharmacology; D011817:Rabbits; D014661:Vasoconstriction / Q000187:drug effects*
D007546:Isoquinolines; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D009219:Myosin-Light-Chain Kinase; D009218:Myosins; D009543:Nifedipine; C049347:fasudil; D011188:Potassium; D002118:Calcium