Activation of Calcium Currents in Cardiac Myocytes by Empt j-Adrenoceptors

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The cardiac calcium channel is known to be modulated by catecholamines via 1-adrenoceptors acting through intermediary GTP-binding regulatory proteins (G proteins). In biochemical studies on isolated membranes and reconstituted systems, it has been demonstrated that various G protein-coupled receptors, including 3-adrenoceptors, can activate G proteins and also intracellular second messengers like cyclic AMP (cAMP) even in the absence of an agonist and that antagonists can block this empty receptor action. We examined electrophysiologically whether agonist-free j-adrenoceptors can modulate L-type calcium currents (Ick) in intact cardiac myocytes.

Methods and Results

Cardiomyocytes were isolated from ventricles of guinea pig and human hearts and from human right atrial appendage. The patch-clamp technique was applied in the single electrode mode to measure whole-cell Ica. Modulation of calcium currents by 3-adrenoceptor antagonists, without addition of an agonist, was studied in the absence and presence of the direct adenylyl cyclase activator forskolin and the cAMP analog adenosine cyclic 3',5'-monophosphorothioate (Sp-cAMPS). In the presence of forskolin (0.5 gtmol/L), an agent known to sensitize the adenylyl cyclase signal transduction system for receptor regulation, addition of the p31-selective antagonist atenolol and the nonselective antagonist propranolol (but not of the f%-selective antagonist ICI 118,551) caused a marked reduction of lca in a concentration-dependent and stereoselective manner. The inhibitory effect of atenolol was reversible after washing out and was found to be half maximal and maximal (50%o reduction) at about 50 and 300 nmol/L, respectively. In the absence of forskolin, inhibition of Ica by atenolol was markedly less (18% at 10 pmol/L atenolol). Finally, in contrast to forskolin-stimulated currents, atenolol (1, mol/L) did not reduce calcium currents activated by the protein kinase A activator Sp-cAMPS (0.1 mmol/L), causing by itself a similar increase in calcium currents as forskolin.


In isolated guinea pig and human cardiomyocytes, agonist-free (3-adrenoceptors are functionally active and can stimulate L-type calcium currents, an effect blocked by receptor-specific antagonists.

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