Role of tyrosine kinase activity in α‐adrenergic inhibition of the β‐adrenergically regulated L‐type Ca 2+ current in guinea‐pig ventricular myocytes

1 The purpose of this study was to investigate the hypothesis that tyrosine kinase activity contributes to α 1 ‐adrenergic inhibition of β‐adrenergic responses in cardiac myocytes. We addressed this question by studying the pharmacological regulation of the L‐type Ca 2+ current in acutely isolated adult guinea‐pig ventricular myocytes using the whole‐cell patch‐clamp technique. 2 The selective α 1 ‐adrenergic receptor agonist methoxamine had no effect on the basal L‐type Ca 2+ current. Methoxamine also had no effect on cAMP‐dependent stimulation of the Ca 2+ current mediated by H 2 histamine receptor activation. However, methoxamine did inhibit cAMP‐dependent stimulation of the Ca 2+ current mediated by β‐adrenergic receptor activation. The ability of methoxamine to inhibit β‐adrenergic regulation of the Ca 2+ current was significantly antagonized by the tyrosine kinase inhibitors genistein and lavendustin A. 3 The inhibitory effect of methoxamine was also mimicked by the phosphotyrosine phosphatase inhibitor pervanadate (PVN). PVN had no effect on basal Ca 2+ current or Ca 2+ current stimulated by histamine, but it did inhibit Ca 2+ current stimulated by β‐adrenergic receptor activation. Furthermore, the ability of PVN to inhibit β‐adrenergic stimulation of the Ca 2+ current was antagonized by lavendustin A. 4 These results are consistent with the conclusion that in guinea‐pig ventricular myocytes α‐adrenergic inhibition of β‐adrenergic responses involves a tyrosine kinase‐dependent signalling pathway. The fact that methoxamine and PVN antagonized cAMP‐dependent responses mediated by β‐adrenergic, but not H 2 histamine, receptor activation suggests that the inhibitory effect of α‐adrenergic stimulation and tyrosine kinase activity is at the level of the β‐adrenergic receptor.