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Received April 14, 2003
Revised May 6, 2003
Accepted after revision June 2, 2003
2-
adrenergic stimulation of ICa,L in
frog ventricular myocytes
1 Institute of Cardiology, Kaunas University of Medicine, 3007 Kaunas, Lithuania
2 Institute for Biomedical Research, Kaunas University of Medicine, 3007 Kaunas, Lithuania
3 Universite de Paris Sud
* To whom correspondence should be addressed. E-mail: fisch{at}vjf.inserm.fr.
The role of cyclic nucleotide phosphodiesterase (PDE)
isoforms in the 
2-adrenergic
stimulation of the L-type Ca2+ current
(ICa,L) was investigated in frog
ventricular myocytes using double patch-clamp and double-
barrelled microperfusion techniques. Isoprenaline (ISO,
1 nM to 10 µM) was applied on one half of the cell,
either alone or in the presence of PDE inhibitors, and
the local and distant responses of
ICa,L were used to determine the
gradient of local vs. distant cAMP concentration (&
[alpha]). IBMX (100 µM), a non-selective PDE
inhibitor,
reduced 
from 40 to 4.4 indicating a 9-fold
reduction in intracellular cAMP compartmentation when
all PDE activity was blocked. While PDE1 and PDE2
inhibition had no effect, PDE3 inhibition by milrinone
(3 µM) or PDE4 inhibition by Ro 20-1724 (3 µM)
reduced by 6- and 4-fold, respectively. A
simultaneous application of milrinone and Ro 20-1724
produced a similar effect as IBMX, showing that PDE3 and
PDE4 were the major PDEs accounting for cAMP
compartmentation. Okadaic acid (3 µM), a non
selective phosphatase inhibitor, or H-89 (1 µM), an
inhibitor of cAMP-dependent protein kinase (PKA), had no
effect on the distant response of
ICa,L
to ISO indicating that PDE activation by PKA played a
minor role in cAMP compartmentation. Our results
demonstrate that PDE activity determines the degree of
cAMP compartmentation in frog ventricular cells upon
2-adrenergic stimulation. PDE3 and
PDE4 subtypes play a major role in this process, and
contribute equally to ensure a functional coupling of &
[beta]2-adrenergic receptors with nearby
Ca2+ channels via local elevations of cAMP.
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