Cellular and molecular pharmacological studies on a role of tyrosine kinase in the signal transduction system in cardiac cells.

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The effects of tyrosine kinase inhibitors on the positive inotropic effect of histamine via H_1-receptors in guinea-pig left atria were examined and histamine-induced changes in phosphorylation levels of the cardiac proteins on tyrosine residues were evaluated using a recombinant antiphosphotyrosine antibody. The positive inotropic effect of histamine was depressed by the tyrosine kinase inhibitors tyrphostin A25 and genistein but not by the inactive genistein analogue daidzein. At a concentration of 1 umol/l histamine produced a dual-component positive inotropic response composed of an initial increasing phase and a second and late developing, greater positive inotropic phase. Treatment with tyrphostin A25 and genistein, but not daidzein, significantly attenuated the two components of the inotropic response, although genistein suppressed the initial component more markedly than the late component. Histamine induced a rapid but transient increase in tyrosine phosphorylation in four main clusters of proteins with approximately molecular weights of 30,35,85 and 120 kDa. histamine-induced protein tyrosine phosphorylation was antagonized by the H_1-receptor antagonist chlorpheniramine. We conclude that increased protein tyrosine phosphorylation may play an important role in initiating the positive inotropic effect of H_1-receptor stimulation in guinea-pig left atria.