Background. The cardiac calcium channel is known to be modulated by ca
techolamines via beta-adrenoceptors acting through intermediary GTP-bi
nding regulatory proteins (G proteins). In biochemical studies on isol
ated membranes and reconstituted systems, it has been demonstrated tha
t various G protein-coupled receptors, including beta-adrenoceptors, c
an activate G proteins and also intracellular second messengers like c
yclic AMP (cAMP) even in the absence of an agonist and that antagonist
s can block this empty receptor action. We examined electrophysiologic
ally whether agonist-free beta-adrenoceptors can modulate C-type calci
um currents (I-Ca) in intact cardiac myocytes. Methods and Results. Ca
rdiomyocytes were isolated from ventricles of guinea pig and human hea
rts and from human right atrial appendage. The patch-clamp technique w
as applied in the single electrode mode to measure whole-cell I-Ca. Mo
dulation of calcium currents by beta-adrenoceptor antagonists, without
addition of an agonist, was studied in the absence and presence of th
e direct adenylyl cyclase activator forskolin and the cAMP analog aden
osine cyclic 3',5'-monophosphorothioate (Sp-cAMPS). In the presence of
forskolin (0.5 mu mol/L), an agent known to sensitize the adenylyl cy
clase signal transduction system for receptor regulation, addition of
the beta(1)-selective antagonist atenolol and the nonselective antagon
ist propranolol (but not of the beta(2)-selective antagonist ICI 118,5
51) caused a marked reduction of I-Ca in a concentration-dependent and
stereoselective manner. The inhibitory effect of atenolol was reversi
ble after washing out and was found to be half maximal and maximal (50
% reduction) at about 50 and 300 nmol/L, respectively. In the absence
of forskolin, inhibition of I-Ca by atenolol was markedly less (18% at
10 mu mol/L atenolol). Finally, in contrast to forskolin-stimulated c
urrents, atenolol (1 mu mol/L) did not reduce calcium currents activat
ed by the protein kinase A activator Sp-cAMPS (0.1 mmol/L), causing by
itself a similar increase in calcium currents as forskolin. Conclusio
ns. In isolated guinea pig and human cardiomyocytes, agonist-free beta
-adrenoceptors are functionally active and can stimulate L-type calciu
m currents, an effect blocked by receptor-specific antagonists.