Key result
Protein tyrosine kinase inhibitors significantly and dose-dependently depressed receptor-induced contractions of bovine cerebral arteries with IC50 values ranging from 2 to 15 µM.
Receptor stimulations that produce sequential activation of PLC and PKC can activate PTK, suggesting PTK inhibitors may be useful for preventing cerebral vasospasm.
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PTK inhibitors merit in vivo testing for cerebral vasospasm; leaves open any clinical role pending further study.
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.
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Watanabe et al. (1998) studied Cerebral vasospasm (in vitro model). Protein tyrosine kinase (PTK) inhibitors (genistein and tyrphostin) vs. Control responses without inhibitors was evaluated on Changes in contractile force during isometric contraction caused by receptor stimulation (IC50 2-15 µM, p=<0.01). Protein tyrosine kinase inhibitors significantly and dose-dependently depressed receptor-induced contractions of bovine cerebral arteries with IC50 values ranging from 2 to 15 µM.
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