Va. Skeberdis et al., BETA-2-ADRENERGIC ACTIVATION OF L-TYPE CA++ CURRENT IN CARDIAC MYOCYTES, The Journal of pharmacology and experimental therapeutics, 283(2), 1997, pp. 452-461
The whole-cell patch-clamp and intracellular perfusion techniques were
used for studying the effects of a beta-2 adrenergic receptor activat
ion on the L-type Ca current (I-ca) in frog ventricular myocytes. The
beta-2 adrenergic agonist zinterol increased I-ca in a concentration-d
ependent manner with an EC50 (i.e., the concentration of zinterol at w
hich the response was 50% of the maximum) of 2.2 nM. The effect of zin
terol was essentially independent of the membrane potential. The stimu
latory effect of zinterol was competitively antagonized by ICI 118,551
, a beta-2 adrenergic antagonist. The maximal stimulatory effect of zi
nterol was comparable in amplitude to the effect of a saturating conce
ntration (1 or 10 mu M) of isoprenaline, a nonselective beta adrenergi
c agonist. Moreover, 3-isobutyl-1-methylxanthine (100 mu M), a nonsele
ctive phosphodiesterase inhibitor, or forskolin (10 mu M), a direct ac
tivator of adenylyl cyclase, had no additive effects in the presence o
f 0.1 mu M zinterol. Zinterol had a long lasting action on frog I-ca b
ecause after washout of the drug, I-ca returned to basal level with a
time constant of 17 min. An application of acetylcholine (1 mu M) duri
ng this recovery phase promptly reduced I-ca back to its basal level s
uggesting a persistent activation of adenylyl cyclase due to a slow di
ssociation rate constant of zinterol from its receptor. Zinterol also
increased I-ca in rat ventricular and human atrial myocytes, and the m
aximal effect was obtained at 10 and 1 mu M, respectively. In all thre
e preparations, intracellular perfusion with 20 mu M PKI(15-22), a hig
hly selective peptide inhibitor of cAMP-dependent protein kinase, comp
letely antagonized the stimulatory effect of zinterol on I-ca. We conc
lude that beta-2 adrenergic receptor activation produces a strong incr
ease in I-ca in frog, rat and human cardiac myocytes which is due to s
timulation of adenylyl cyclase and activation of cAMP-dependent phosph
orylation.