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

Abstract

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.