Role of Nitric Oxide in Ca ²⁺ Sensitivity of the Slowly Activating Delayed Rectifier K ⁺ Current in Cardiac Myocytes

Abstract

Abstract-SarcolemmalIn a previous article, we showed that I Ks enhancement by elevation of [Ca 2ϩ ] i was inhibited by a calmodulin (CaM) inhibitor, but not by an inhibitor of CaM-dependent kinase II. 6 Although this finding suggests that the allosteric regulation of CaM is crucial for Ca 2ϩ -sensitive I Ks alterations, the detailed underlying mechanism remains unknown. Recently, we found that I Ks was enhanced by nitric oxide (NO) via a cGMP-independent mechanism. 7 Because allosteric interaction of Ca 2ϩ /CaM complex with NO synthase (NOS) is a major mechanism of NOS activation and NO release, 8,9 we tested in the present study if NO plays an important role in the Ca 2ϩ -sensitive modulation of I Ks in cardiac myocytes.

CAPON modulates cardiac repolarization via neuronal nitric oxide synthase signaling in the heart

“…The inhibition of I Ca,L by NO is caused by cGMP-dependent or cGMPindependent (direct S-nitrosylation/redox) pathways (17,19,20). Similarly, NO can modulate the delayed rectifier K ϩ currents by cGMP-dependent or -independent pathway (17,18,21). Interestingly, although CAPON overexpression activates NOS1-derived NO in our work, the electrophysiological changes mediated by this NO activation are comparable with those in previous reports (17)(18)(19)21).…”

“…Similarly, NO can modulate the delayed rectifier K ϩ currents by cGMP-dependent or -independent pathway (17,18,21). Interestingly, although CAPON overexpression activates NOS1-derived NO in our work, the electrophysiological changes mediated by this NO activation are comparable with those in previous reports (17)(18)(19)21). Recently, evidence emerged that NOS1 may play a critical role in the regulation of calcium handling and myocyte contraction in the heart (9,10,12,22).…”

“…In guinea pig ventricular myocytes, NO can shorten APD by suppression of I Ca,L and augmentation of I Ks (17,18). The inhibition of I Ca,L by NO is caused by cGMP-dependent or cGMPindependent (direct S-nitrosylation/redox) pathways (17,19,20).…”

Endothelial nitric oxide synthase decreases β-adrenergic responsiveness via inhibition of the L-type Ca2+ current

“…It has also been demonstrated that NOS3 is able to modulate K ϩ channels. Specifically, activation of NOS3 leads to an enhancement of slowdelayed rectifier K ϩ current and shortening of APD in guinea pig myocytes (2). However, in normal adult mouse ventricular myocytes, the expression of delayed-rectifier K ϩ channel is very low (22), and the functional effects of I Ks on AP waveform are still undetermined (36).…”

Cardiovascular Effects of Androgens

“…Moreover, testosterone increases by 30% the density of repolarizing potassium currents, which is due to changes in both gating kinetics of the delayed rectifier potassium currents (Ikr) and shortening the duration of the QT interval Testosterone has been shown to interact directly with the NO system. Activation of this pathway induces shortening in the duration of the action potential by activating the slow component of delayed rectifier potassium current (Iks) and inhibiting L-type calcium currents (Ica, L ) (Bai et al, 2004(Bai et al, , 2005.…”