Nitric oxide modulates cardiac Na(+) channel via protein kinase A and protein kinase G.
We directly tested the effects of nitric oxide (NO) on Na(+) channels in guinea pig and mouse ventricular myocytes using patch-clamp recordings. We have previously shown that NO donors have no observed effects on expressed Na(+) channels. In contrast, NO (half-blocking concentration of 523 nmol/L) significantly reduces peak whole-cell Na(+) current (I(Na)) in isolated ventricular myocytes. The inhibitory effect of NO on I(Na) was not associated with changes in activation, inactivation, or reactivation kinetics. At the single-channel level, the reduction in macroscopic current was mediated by a decrease in open probability and/or a decrease in the number of functional channels with no change in single-channel conductance. Application of cell permeable analogs of cGMP or cAMP mimics the inhibitory effects of NO. Furthermore, the effects of NO on I(Na) can only be blocked by inhibition of both cGMP and cAMP pathways. Sulfhydryl-reducing agent does not reverse the effect of NO. In summary, although NO exerts its action via the known guanylyl cyclase (GC)/cGMP pathway, our findings provide evidence that NO can mediate its function via a GC/cGMP-independent mechanism involving the activation of adynylyl cyclase (AC) and cAMP-dependent protein kinase.
Ahmmed
G U
GU
Divisions of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis, California, USA.
Xu
Y
Y
Hong Dong
P
P
Zhang
Z
Z
Eiserich
J
J
Chiamvimonvat
N
N
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000502:physiology*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D004553:Electric Conductivity; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006168:Guinea Pigs; D006321:Heart / Q000502:physiology*; D006352:Heart Ventricles / Q000187:drug effects; D007700:Kinetics; D051379:Mice; D008954:Models, Biological; D009206:Myocardium / Q000201:enzymology*; D009569:Nitric Oxide / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D015398:Signal Transduction / Q000187:drug effects; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000502:physiology*; D016276:Ventricular Function
D004791:Enzyme Inhibitors; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D009569:Nitric Oxide; D003994:Bucladesine; D017868:Cyclic AMP-Dependent Protein Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D006162:Guanylate Cyclase