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Vol. 283, Issue 2, 452-461, 1997
ius2 and
Laboratoire de Cardiologie Cellulaire et Moléculaire, INSERM
U-446, Université de Paris-Sud, Faculté de Pharmacie,
F-92296 Châtenay-Malabry, France
The whole-cell patch-clamp and intracellular perfusion techniques were
used for studying the effects of a beta-2 adrenergic receptor activation on the L-type Ca current
(ICa) in frog ventricular myocytes. The
beta-2 adrenergic agonist zinterol increased
ICa in a concentration-dependent manner with
an EC50 (i.e., the concentration of zinterol
at which the response was 50% of the maximum) of 2.2 nM. The effect of
zinterol was essentially independent of the membrane potential. The
stimulatory effect of zinterol was competitively antagonized by ICI
118,551, a beta-2 adrenergic antagonist. The maximal
stimulatory effect of zinterol was comparable in amplitude to the
effect of a saturating concentration (1 or 10 µM) of isoprenaline, a
nonselective beta adrenergic agonist. Moreover,
3-isobutyl-1-methylxanthine (100 µM), a nonselective
phosphodiesterase inhibitor, or forskolin (10 µM), a direct activator
of adenylyl cyclase, had no additive effects in the presence of 0.1 µM zinterol. Zinterol had a long lasting action on frog
ICa because after washout of the drug, ICa returned to basal level with a time
constant of 17 min. An application of acetylcholine (1 µM) during
this recovery phase promptly reduced ICa
back to its basal level suggesting a persistent activation of adenylyl
cyclase due to a slow dissociation rate constant of zinterol from its
receptor. Zinterol also increased ICa in rat
ventricular and human atrial myocytes, and the maximal effect was
obtained at 10 and 1 µM, respectively. In all three preparations,
intracellular perfusion with 20 µM PKI(15-22), a highly selective
peptide inhibitor of cAMP-dependent protein kinase, completely
antagonized the stimulatory effect of zinterol on
ICa. We conclude that beta-2
adrenergic receptor activation produces a strong increase in
ICa in frog, rat and human cardiac myocytes which is due to stimulation of adenylyl cyclase and activation of
cAMP-dependent phosphorylation.
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