Tyrphostin attenuates platelet-derived growth factor-induced contraction in aortic smooth muscle through inhibition of protein tyrosine kinase(s).

The effect of protein tyrosine kinase (PTK) inhibition on spontaneously hypertensive rat vascular smooth muscle contraction was examined in this study. By using isolated aortic strips, it was found that platelet-derived growth factor (PDGF) (0.1-1 nM), an activator of PTKs, elicited contraction with an EC50 of 0.25 +/- 0.08 nM. Treatment with tyrphostin (0.02-200 microM), a selective inhibitor of PTKs, caused a significant rightward shift of the concentration-response curves (P < .05). The IC50 for tyrphostin in the spontaneously hypertensive rat was calculated to be 9.5 +/- 4.2 microM. Tyrphostin also inhibited contractile activity in normotensive control Wistar-Kyoto rat aorta with an IC50 of 0.24 +/- 0.09 microM. Tyrphostin inhibited PDGF-induced contraction over a range of calcium concentrations, suggesting that it may oppose contraction through inhibition of calcium influx via PDGF-induced receptor-operated channel. However, KCl-mediated voltage-operated calcium channels were largely unaffected by tyrphostin, because it was unable to relax aortae which had been partially depolarized. Tyrphostin also had no significant antagonistic effect on contraction induced by phenylephrine or phorbol-12,13-dibutyrate. For both of these agents, contraction is mediated through activation of protein kinase C, which further alludes to the specificity of tyrphostin for PTKs. Treatment with 1 nM PDGF caused a significant stimulation of particulate/membrane PTK activity in the aorta. Tyrphostin attenuated PDGF-induced PTK activity in a concentration-dependent manner. The data suggest that PTKs may play a role in vascular smooth muscle contraction and that specific inhibition of PTK activity results in vasorelaxation. Furthermore, the results suggest that vasoconstriction and vascular smooth muscle cell proliferation may share common biochemical signalling pathways.