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Role of the NO-cGMP pathway in the muscarinic regulation of the L-type Ca²⁺ current in human atrial myocytes

Grégoire Vandecasteele, Thomas Eschenhagen and Rodolphe Fischmeister

1. The whole-cell patch-clamp technique was used to examine the participation of nitric oxide synthase (NOS) and soluble guanylyl cyclase in the muscarinic regulation of the L-type Ca²⁺ current (I_Ca) in freshly isolated human atrial myocytes.

2. Acetylcholine (ACh, 1 µM) decreased basal I_Ca by 39·1 ± 5·5 % (n = 8) under control conditions, and by 38·0 ± 6·1 % (n = 6) in the presence of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ, 10 µM), a potent guanylyl cyclase inhibitor, and N^G-monomethyl-L-arginine (L-NMMA, 1 mM), a competitive NOS inhibitor. L-NMMA alone had no effect on I_Ca, whilst ODQ increased I_Ca in 50 % of the cells.

3. The accentuated antagonism of ACh on I_Ca, i.e. its ability to antagonize the stimulatory effect of -adrenergic agonists and, by extension, of other cAMP-elevating agents, was examined after the current was stimulated by either the -adrenergic agonist isoprenaline (Iso) or serotonin (5-HT). ACh (100 nM or 1 µM) completely blocked the stimulatory effects of 10 nM Iso or 10 nM 5-HT on I_Ca.

4. Extracellular application of Methylene Blue (MBlue, 10 µM), a guanylyl cyclase inhibitor, antagonized the inhibitory effect of 1 µM ACh on Iso- or 5-HT-stimulated I_Ca. However, this effect was overcome by a 100-fold higher ACh concentration and was not mimicked by an intracellular application of MBlue.

5. Inhibition of NOS and soluble guanylyl cyclase activities by addition of ODQ (10 µM) and L-NMMA (1 mM) to both extracellular and intracellular solutions, or by a 2 h pre-incubation of the cells with these inhibitors, modified neither the Iso (10 nM) response nor the inhibitory effect of ACh (100 nM or 1 µM) on Iso-stimulated I_Ca.

6. Extracellular application of the NO donor SNAP (S-nitroso-N-acetyl-D,L-penicillamine) at 100 nM produced a stimulatory effect on I_Ca in control conditions. This stimulatory effect was abolished by intracellular MBlue (20 µM) or by intracellular and extracellular application of ODQ (10 µM) in combination with L-NMMA (1 mM).

7. We conclude that the NO-cGMP pathway does not contribute significantly to the muscarinic regulation of I_Ca in human atrial myocytes.

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