Modulatory role of protein tyrosine kinase activation in the receptor-induced contractions of the bovine cerebral artery.
Changes in contractile force were measured during isometric contraction of the bovine middle cerebral artery caused by stimulation of various receptors and by application of high K+, caffeine, and protein kinase C (PKC)-activators. The protein tyrosine kinase (PTK)-inhibitors, such as genistein and tyrphostin, were applied before testing the effect on the contractions or during the maximal plateau of the contraction. The contractions induced by serotonin, prostaglandin F2 alpha, endothelin-1, and thromboxane A2 were significantly and dose-dependently depressed by the PTK-inhibitors (IC50 2-15 microM). In contrast, contractions were significantly augmented by 1 microM pervanadate, an inhibitor of phosphoprotein tyrosine phosphatase. Lineweaver-Burk plotting of the dose-response curves with an increase in inhibitor concentration indicated that the receptor affinity for each agonist remained unchanged in spite of marked depression of the responses. Although the effect was not significant, contractions induced by both high K+ and caffeine were also depressed slightly by PTK-inhibitors in the same range of concentrations used for receptor-induced contractions. Contractions induced by PKC-activators, such as 1-oleoyl-2-acetyl-sn-glycerol and phorbol-12,13-diacetate, were significantly depressed by PTK-inhibitors at concentrations similar to those used for receptor-induced contractions. The results suggest that receptor stimulations which produce sequential activation of phospholipase C and PKC can activate PTK and trigger the so-called "PTK-cascade" causing a sustained or long-lasting contraction similar to the cerebral vasospasm observed clinically.
Watanabe
M
M
Department of Neurosurgery, School of Medicine, Iwate Medical University, Morioka.
Doi
M
M
Sasaki
K
K
Ogawa
A
A
D000818:Animals; D001921:Brain / Q000098:blood supply*; D002417:Cattle; D002536:Cerebral Arteries / Q000187:drug effects / Q000503:physiopathology; D046508:Culture Techniques; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004793:Enzyme Reactivators / Q000494:pharmacology*; D002546:Ischemic Attack, Transient / Q000503:physiopathology; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D010738:Type C Phospholipases / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology
D004791:Enzyme Inhibitors; D004793:Enzyme Reactivators; D011505:Protein-Tyrosine Kinases; D010738:Type C Phospholipases