N. Abigerges et al., A COMPARATIVE-STUDY OF THE EFFECTS OF 3 GUANYLYL CYCLASE INHIBITORS ON THE L-TYPE CA2+ AND MUSCARINIC K+ CURRENTS IN FROG CARDIAC MYOCYTES, British Journal of Pharmacology, 121(7), 1997, pp. 1369-1377
1 To investigate the participation of guanylyl cyclase in the muscarin
ic regulation of the cardiac L-type calcium current (I-Ca), we examine
d the effects of three guanylyl cyclase inhibitors, 1H-[1,2,4]oxidiazo
lo[4,3-a]quinoxaline-1-one (ODQ), 6-anilino-5,8-quinolinedione (LY 835
83), and methylene blue (MBlue), on the beta-adrenoceptor; muscarinic
receptor and nitric oxide (NO) regulation of I-Ca and on the muscarini
c activated potassium current I-K,I-ACh, in frog atrial and ventricula
r myocytes. 2 ODQ (10 mu M) and LY 83583 (30 mu M) antagonized the inh
ibitory effect of an NO-donor (S-nitroso-N-acetylpenicillamine, SNAP,
1 mu M) on the isoprenaline (Iso)-stimulated I-Ca which was consistent
with their inhibitory action on guanylyl cyclase. However, MBlue (30
mu M) had no effect under similar conditions. 3 In the absence of SNAP
, LY 83583 (30 mu M) potentiated the stimulations of I-Ca by either Is
o (20 nM), forskolin (0.2 mu M) or intracellular cyclic AMP (5-10 mu M
). ODQ (10 mu M) had no effect under these conditions, while MBlue (30
mu M) inhibited the Iso-stimulated I-Ca. 4 LY 83583 and MBlue, but no
t ODQ, reduced the inhibitory effect of up to 10 mu M acetylcholine (A
Ch) on I-Ca. 5 MBlue, but not LY 83583 and ODQ, antagonized the activa
tion of I-K,I-ACh by ACh in the presence of intracellular GTP, and thi
s inhibition was weakened when I-K,I-ACh was activated by intracellula
r GTP gamma S. 6 The potentiating effect of LY 83583 on Iso-stimulated
I-Ca was absent in the presence of either DL-dithiothreitol (DTT, 100
mu M) or a combination of superoxide dismutase (150 u ml(-1)) and cat
alase (100 u ml(-1)). 7 All together, our data demonstrate that, among
the three compounds tested, only ODQ acts in a manner which is consis
tent with its inhibitory action on the NO-sensitive guanylyl cyclase.
The two other compounds produced severe side effects which may involve
superoxide anion generation in the case of LY 83583 and alteration of
beta-adrenoceptor and muscarinic receptor-coupling mechanisms in the
case of MBlue.