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A comparative study of the effects of three guanylyl cyclase inhibitors on the L-type Ca 2+ and muscarinic K + currents in frog cardiac myocytes

Abstract : To investigate the participation of guanylyl cyclase in the muscarinic regulation of the cardiac L-type calcium current (I Ca), we examined the eects of three guanylyl cyclase inhibitors, 1H-[1,2,4]oxidiazolo[4,3-a]quinoxaline-1-one (ODQ), 6-anilino-5,8-quinolinedione (LY 83583), and methylene blue (MBlue), on the b-adrenoceptor; muscarinic receptor and nitric oxide (NO) regulation of I Ca and on the muscarinic activated potassium current I K,ACh , in frog atrial and ventricular myocytes. 2 ODQ (10 mM) and LY 83583 (30 mM) antagonized the inhibitory eect of an NO-donor (S-nitroso-Nacetylpenicillamine, SNAP, 1 mM) on the isoprenaline (Iso)-stimulated I Ca which was consistent with their inhibitory action on guanylyl cyclase. However, MBlue (30 mM) had no eect under similar conditions. 3 In the absence of SNAP, LY 83583 (30 mM) potentiated the stimulations of I Ca by either Iso (20 nM), forskolin (0.2 mM) or intracellular cyclic AMP (5 ± 10 mM). ODQ (10 mM) had no eect under these conditions, while MBlue (30 mM) inhibited the Iso-stimulated I Ca. 4 LY 83583 and MBlue, but not ODQ, reduced the inhibitory eect of up to 10 mM acetylcholine (ACh) on I Ca. 5 MBlue, but not LY 83583 and ODQ, antagonized the activation of I K,ACh by ACh in the presence of intracellular GTP, and this inhibition was weakened when I K,ACh was activated by intracellular GTPgS. 6 The potentiating eect of LY 83583 on Iso-stimulated I Ca was absent in the presence of either DLdithiothreitol (DTT, 100 mM) or a combination of superoxide dismutase (150 u ml 71) and catalase (100 u ml 71). 7 All together, our data demonstrate that, among the three compounds tested, only ODQ acts in a manner which is consistent with its inhibitory action on the NO-sensitive guanylyl cyclase. The two other compounds produced severe side eects which may involve superoxide anion generation in the case of LY 83583 and alteration of b-adrenoceptor and muscarinic receptor-coupling mechanisms in the case of MBlue.
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Najah Abi-Gerges, Leif Hove-Madsen, Rodolphe Fischmeister, Pierre-François Méry. A comparative study of the effects of three guanylyl cyclase inhibitors on the L-type Ca 2+ and muscarinic K + currents in frog cardiac myocytes. British Journal of Pharmacology, Wiley, 1997, 121 (7), pp.1369-1377. ⟨10.1038/sj.bjp.0701249⟩. ⟨hal-03617577⟩



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