Institut for Biomedicin

Christian Aalkjær

Effects of tyrosine kinase inhibitors on the contractility of rat mesenteric resistance arteries

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  • Institut for Fysiologi og Biofysik
  • Farmakologisk Institut
1. A pharmacological characterization of tyrosine kinase inhibitors (TKI) belonging to two distinct groups (competitors at the ATP-binding site and the substrate-binding site, respectively) was performed, based on their effects on the contractility of rat mesenteric arteries. 2. Both the ATP-site competitors (genistein and its inactive analogue, daidzein) and the substrate-site competitors (tyrphostins A-23, A-47 and the inactive analogue, A-1) reversibly inhibited noradrenaline (NA, (10 microM)) and KCl (125 mM) induced contractions, concentration-dependently. Genistein was slightly but significantly more potent than daidzein; the tyrphostins were all less potent than genistein, and there were no significant differences between the individual potencies. The tyrosine kinase substrate-site inhibitor bis-tyrphostin had no inhibitory effect. 3. Genistein, daidzein, A-23 and A-47 each suppressed the contraction induced by Ca2+ (1 microM) in alpha-toxin permeabilized arteries. A-1 and bis-tyrphostin had little or no effect on contraction of the permeabilized arteries. 4. Genistein was significantly more potent than daidzein with respect to inhibition of the contraction induced by 200 nM Ca2+ in the presence of NA (100 microM) and GTP (3 microM). The effect of A-23, A-47, A-1 and bis-tyrphostin was similar in permeabilized arteries activated with Ca2+ (200 nM) + NA (100 microM) + GTP (3 microM) and permeabilized arteries activated with 1 microM Ca2+. 5. Genistein (30 microM) reduced the fura-2 measured intracellular calcium activity ([Ca2+]j) in arteries stimulated with NA but had no effect on [Ca2+]i in arteries stimulated with KCl (125 mM).6. The potent effect of the TKIs in this study is consistent with a role for tyrosine kinases in the mechanisms which regulate both cytoplasmic Ca2+ levels and the effect of Ca2+ on the contractile apparatus in smooth muscle cells in resistance arteries. However, the results must be interpreted cautiously because the enzyme inhibitors may have a poor specificity in intact tissues and because the presumed inactive analogues had potent effects.
TidsskriftBritish Journal of Pharmacology
Sider (fra-til)1266-1272
Antal sider7
StatusUdgivet - 1 mar. 1995

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