INACTIVATION OF THE CARDIAC RYANODINE RECEPTOR CALCIUM-RELEASE CHANNEL BY NITRIC-OXIDE

We have recently reported [Meszaros L.G. Minarovic I., Zahradnikova A. Inhibition of the skeletal muscle ryanodine receptor calcium release channel by nitric oxide. FEES Lett 1996; 380: 49-52] that nitric oxide (NO) reduces the activity of the skeletal muscle ryanodine receptor C a2+ release channel (RyRC), a principal component of the excitation-co ntraction coupling machinery in striated muscles. Since (i) as shown h ere, we have obtained evidence which indicates that the NO synthase (e NOS) of cardiac muscle origin cc-purified with RyRC-containing sarcopl asmic reticulum (SR) fractions; and (ii) the effects of NO donors on t he release channel, as well as on cardiac function, appear somewhat co ntradictory, we have made an attempt to investigate the response of th e cardiac RyRC to NO that is generated in situ from L-arginine in the NOS reaction. We found that L-arginine-derived NO inactivates Ca2+ rel ease from cardiac SR and reduces the steady-state activity (i.e. open probability) of single RyRCs fused into a planar lipid bilayer. This r eduction was prevented by NOS inhibitors and the NO quencher hemoglobi n and was reversed by 2-mercaptoethanol. We thus conclude that: (i) in isolated SR preparations, it is possible to assess the effects of NO that is generated from L-arginine in the NOS reaction; and Iii) cardia c RyRc responds to NO in a manner which is identical to that we have p reviously found with the skeletal channel. These findings suggest that the direct modulation of the RyRC by NO is a signaling mechanism whic h likely participates in earlier demonstrated NO-induced myocardial co ntractility changes.