Journal
JOURNAL OF PHYSIOLOGY-LONDON
Volume 540, Issue 2, Pages 411-424Publisher
CAMBRIDGE UNIV PRESS
DOI: 10.1113/jphysiol.2001.012929
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The effects of nitric oxide (NO) donors on the L-type Ca2+ current (I-Ca,I-L) and the muscarinic activated K+ current (I-K,I-ACh) were studied in isolated rat cardiac myocytes. The nitrosothiol S-nitroso-N-acetyl-D,L-penicillamine (SNAP, I pM-1 muM) strongly potentiated the stimulation of the I-Ca,I-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, I 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 mum), a NO trap. 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxaline-1-one (10 muM), a guanylyl cyclase inhibitor, did not alter the effect of SNAP. SNAP (I pM-1 muM) did not modify the effect of L858051 (0.1-0.3 muM), a forskolin analogue that activates adenylyl cyclase, on I-Ca,I-L and did not enhance the basal I-Ca,I-L ill the presence of rolipram (1 muM), a phosphodiesterase type 4 inhibitor. Superfusion with Rp-CPT-cAMPS (500 muM), or internal dialysis with cAMP-dependent protein kinase (cA-PK) inhibitory peptide (PKI; 20 muM), inhibitors of the cA-PK, blunted the effect of SNAP (1 nM and 1 muM) on the Iso-stimulated (1-100 pM) I-Ca,I-L- SNAP (I nM and I muM) potentiated the threshold stimulation Of I-Ca,I-L elicited by internal GTP-gammaS (10 mum), a non-hydrolysable analogue of GTP. SNAP (I pm-1 muM) and DEANO (I muM) potentiated the stimulation of I-K,I-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 pm) was also potentiated by NO donors. SNAP (I muM) did not modify I-K,I-ACh reconstituted in human embryonic kidney 293 cells, in the absence or in the presence of ACh (I or 10 nM). Taken together, these data suggest that NO is a cGMP-independent modulator of G-protein-coupled muscarinic and beta-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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