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Role of tyrosine kinase activity in -adrenergic inhibition of the -adrenergically regulated L-type Ca²⁺ current in guinea-pig ventricular myocytes

Andriy E. Belevych, Amy Nulton-Persson, Carl Sims and Robert D. Harvey

1. The purpose of this study was to investigate the hypothesis that tyrosine kinase activity contributes to ₁-adrenergic inhibition of -adrenergic responses in cardiac myocytes. We addressed this question by studying the pharmacological regulation of the L-type Ca²⁺ current in acutely isolated adult guinea-pig ventricular myocytes using the whole-cell patch-clamp technique.
2. The selective ₁-adrenergic receptor agonist methoxamine had no effect on the basal L-type Ca²⁺ current. Methoxamine also had no effect on cAMP-dependent stimulation of the Ca²⁺ current mediated by H₂ histamine receptor activation. However, methoxamine did inhibit cAMP-dependent stimulation of the Ca²⁺ current mediated by -adrenergic receptor activation. The ability of methoxamine to inhibit -adrenergic regulation of the Ca²⁺ 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 Ca²⁺ current or Ca²⁺ current stimulated by histamine, but it did inhibit Ca²⁺ current stimulated by -adrenergic receptor activation. Furthermore, the ability of PVN to inhibit -adrenergic stimulation of the Ca²⁺ current was antagonized by lavendustin A.
4. These results are consistent with the conclusion that in guinea-pig ventricular myocytes -adrenergic inhibition of -adrenergic responses involves a tyrosine kinase-dependent signalling pathway. The fact that methoxamine and PVN antagonized cAMP-dependent responses mediated by -adrenergic, but not H₂ histamine, receptor activation suggests that the inhibitory effect of -adrenergic stimulation and tyrosine kinase activity is at the level of the -adrenergic receptor.

This article has been cited by other articles:

				A. E. Belevych, S. Warrier, and R. D. Harvey Genistein Inhibits Cardiac L-Type Ca2+ Channel Activity by a Tyrosine Kinase-Independent Mechanism Mol. Pharmacol., September 1, 2002; 62(3): 554 - 565. [Abstract] [Full Text] [PDF]