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

摘要

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+.(ABSTRACT TRUNCATED AT 250 WORDS)