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Attenuated response of ICa,L to nitric oxide in atrial fibrillation

Item Type:Article
Title:Attenuated response of ICa,L to nitric oxide in atrial fibrillation
Creators Name:Rozmaritsa, N. and Christ, T. and Van Wagoner, D.R. and Haase, H. and Stasch, J.P. and Matschke, K. and Ravens, U.
Abstract:AIM: Nitric oxide (NO) synthesized by cardiomyocytes plays an important role in the regulation of cardiac function. Here we studied the impact of NO signalling on calcium influx in human right atrial myocytes and its relation to atrial fibrillation (AF). METHODS AND RESULTS: Right atrial appendages (RAA) were obtained from patients in sinus rhythm (SR) and AF. The biotin-switch technique was used to evaluate endogenous S-nitrosylation of the alpha1C subunit of L-type calcium channels. Comparing SR to AF, S-nitrosylation of Ca2+ channels was similar.Direct effects of the NO donor S-nitroso-N-acetylpenicillamine (SNAP) on L-type calcium current (ICa,L) were studied in cardiomyocytes with standard voltage-clamp techniques. In SR, ICa,L increased with SNAP (100 microM) by 48%, n/N=117/56, p<0.001). The SNAP effect on ICa,L involved activation of soluble guanylate cyclase and protein kinase A. Specific inhibition of PDE3 with cilostamide (1 microM) enhanced ICa,L to a similar extent as SNAP. However, when cAMP was elevated by PDE3 inhibition or beta-adrenoceptor stimulation, SNAP reduced ICa,L, pointing to cGMP-cAMP cross-regulation. In AF, the stimulatory effect of SNAP on ICa,L was attenuated, while its inhibitory effect on isoprenaline- or cilostamide-stimulated current was preserved. cGMP elevation with SNAP was comparable between SR and AF group. Moreover, expression of PDE3 and sGC was not reduced in AF. CONCLUSION: NO exerts dual effects on ICa,L in SR with increase of basal and inhibition of cAMP-stimulated current, and in AF NO only inhibits stimulated ICa,L. We conclude that in AF, cGMP regulation of PDE2 is preserved, but regulation of PDE3 is lost.
Keywords:Nitric Oxide, Atrial Fibrillation, L-Type Calcium Current, Cyclic Nucleotides, Phosphodiesterases
Source:Cardiovascular Research
ISSN:0008-6363
Publisher:Oxford University Press (U.K.)
Volume:101
Number:3
Page Range:533-542
Date:1 March 2014
Official Publication:https://doi.org/10.1093/cvr/cvt334
PubMed:View item in PubMed

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