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(Circulation Research. 2001;89:1005.)
© 2001 American Heart Association, Inc.

Cellular Biology

Nitric Oxide Modulates Cardiac Na⁺ Channel via Protein Kinase A and Protein Kinase G

Gias U. Ahmmed, Yanfang Xu, Pei Hong Dong, Zhao Zhang, Jason Eiserich, Nipavan Chiamvimonvat

From the Divisions of Cardiovascular Medicine (G.U.A., Y.X., P.H.D., Z.Z., N.C.) and Nephrology (J.E.), Department of Internal Medicine, University of California, Davis, Calif.

Correspondence to Nipavan Chiamvimonvat, Division of Cardiovascular Medicine, University of California, Davis, One Shields Ave, TB 172, Davis, CA 95616. E-mail nchiamvimonvat{at}ucdavis.edu

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.

Key Words: nitric oxide • cardiac Na⁺ current • protein kinase A • protein kinase G

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