M. Rivetbastide et al., CGMP-STIMULATED CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE REGULATES THE BASAL CALCIUM CURRENT IN HUMAN ATRIAL MYOCYTES, The Journal of clinical investigation, 99(11), 1997, pp. 2710-2718
EHNA (Erythro-9-[2-hydroxy-3-nonyl]adenine) is a well-known inhibitor
of adenosine deaminase. Recently, EHNA was shown to block the activity
of purified soluble cGMP-stimulated phosphodiesterase (PDE2) from fro
g, human, and porcine heart with an apparent K-i value of similar to 1
mu M and with negligible effects on Ca2+/calmodulin PDE (PDE1), cGMP-
inhibited PDE (PDE3), and low K-m cAMP-specific PDE (PDE4) (Mery, P.F.
, C. Pavoine, F. Pecker, and R. Fischmeister. 1995. Mel. Pharmacol. 48
:121-130; Podzuweit, T., P. Nennstiel, and A. Muller. 1995. Cell. Sign
alling. 7:733-738). To investigate the role of PDE2 in the regulation
of cardiac L-type Ca2+ current (I-Ca), we have examined the effect of
EHNA on I-Ca in freshly isolated human atrial myocytes. Extracellular
application of 0.1-10 mu M EHNA induced an increase in the amplitude o
f basal I-Ca (similar to 80% at 1 mu M) without modification of the cu
rrent-voltage or inactivation curves. The maximal stimulatory effect o
f EHNA on I-Ca was comparable in amplitude with the maximal effect of
isoprenaline (1 mu M), and the two effects were not additive. The effe
ct of EHNA was not a result of adenosine deaminase inhibition, since 2
'-deoxycoformycin (1-30 mu M), another adenosine deaminase inhibitor w
ith no effect on PDE2, or adenosine (1-10 mu M) did not increase I-Ca.
In the absence of intracellular GTP, the substrate of guanylyl cyclas
e, EHNA did not increase I-Ca. However, under similar conditions, intr
acellular perfusion with 0.5 mu M cGMP produced an 80% increase in I-C
a. As opposed to human cardiomyocytes, EHNA (1-10 mu M) did not modify
I-Ca in isolated rat ventricular and atrial myocytes. We conclude tha
t basal I-Ca is controlled by PDE2 activity in human atrial myocytes.
Both PDE2 and PDES may contribute to keep the cyclic nucleotides conce
ntrations at minimum in the absence of adenylyl and/or guanylyl cyclas
e stimulation.