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NO donors potentiate the -adrenergic stimulation of I_Ca,L and the muscarinic activation of I_K,ACh in rat cardiac myocytes

Najah Abi-Gerges, Gabor Szabo *, Angela S. Otero *, Rodolphe Fischmeister and Pierre-François Méry

The effects of nitric oxide (NO) donors on the L-type Ca²⁺ current (I_Ca,L) and the muscarinic activated K⁺ current (I_K,ACh) were studied in isolated rat cardiac myocytes. The nitrosothiol S-nitroso-N-acetyl-D,L-penicillamine (SNAP, 1 pM-1 µM) strongly potentiated the stimulation of the I_Ca,L elicited by subthreshold concentrations of isoprenaline (Iso, 0.1-0.5 nM) in ventricular myocytes. The effect of SNAP was mimicked by 2-(N,N-diethylamino)-diazenolate-2-oxide (DEANO, 1 pM-1 nM), a NONOate that spontaneously releases NO in a pH-controlled manner, and was blunted by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (100 µM), a NO trap. 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxaline-1-one (10 µM), a guanylyl cyclase inhibitor, did not alter the effect of SNAP. SNAP (1 pM-1 µM) did not modify the effect of L858051 (0.1-0.3 µM), a forskolin analogue that activates adenylyl cyclase, on I_Ca,L and did not enhance the basal I_Ca,L in the presence of rolipram (1 µM), a phosphodiesterase type 4 inhibitor. Superfusion with Rp-CPT-cAMPS (500 µM), or internal dialysis with cAMP-dependent protein kinase (cA-PK) inhibitory peptide (PKI; 20 µM), inhibitors of the cA-PK, blunted the effect of SNAP (1 nM and 1 µM) on the Iso-stimulated (1-100 pM) I_Ca,L. SNAP (1 nM and 1 µM) potentiated the threshold stimulation of I_Ca,L elicited by internal GTP-S (10 µM), a non-hydrolysable analogue of GTP. SNAP (1 pM-1 µM) and DEANO (1 µM) potentiated the stimulation of I_K,ACh elicited by low concentrations of ACh (1-2 nM) in rat atrial myocytes. The threshold stimulation of I_K,ACh elicited by internal 5'-guanylylimidodiphosphate (10 µM) was also potentiated by NO donors. SNAP (1 µM) did not modify I_K,ACh reconstituted in human embryonic kidney 293 cells, in the absence or in the presence of ACh (1 or 10 nM). Taken together, these data suggest that NO is a cGMP-independent modulator of G-protein-coupled muscarinic and -adrenergic receptor actions on cardiac ion channels. Although this action of NO seemed to occur at the level of G proteins, it appeared to require a component distinct from receptors, G proteins or their effectors.

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