NO donors potentiate the β‐adrenergic stimulation of ICa,L and the muscarinic activation of IK,ACh in rat cardiac myocytes

The effects of nitric oxide (NO) donors on the L‐type Ca2+ current (ICa,L) and the muscarinic activated K+ current (IK,ACh) were studied in isolated rat cardiac myocytes. The nitrosothiol S‐nitroso‐N‐acetyl‐d,d‐penicillamine (SNAP, 1 pm‐1 μm) strongly potentiated the stimulation of the ICa,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 ICa,L and did not enhance the basal ICa,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) ICa,L. SNAP (1 nm and 1 μm) potentiated the threshold stimulation of ICa,L elicited by internal GTP‐γS (10 μm), a non‐hydrolysable analogue of GTP. SNAP (1 pm‐1 μm) and DEANO (1 μm) potentiated the stimulation of IK,ACh elicited by low concentrations of ACh (1–2 nm) in rat atrial myocytes. The threshold stimulation of IK,ACh elicited by internal 5′‐guanylylimidodiphosphate (10 μm) was also potentiated by NO donors. SNAP (1 μm) did not modify IK,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 β‐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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