title: Attenuated response of L-type calcium current to nitric oxide in atrial fibrillation.
abstract: OBJECTIVE
  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).
  
  
  RESULTS
  Right atrial appendages (RAAs) were obtained from patients in sinus rhythm (SR) and AF. The biotin-switch technique was used to evaluate endogenous S-nitrosylation of the α1C subunit of L-type calcium channels. Comparing SR to AF, S-nitrosylation of Ca(2+) channels was similar. Direct effects of the NO donor S-nitroso-N-acetyl-penicillamine (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 µM) 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 phosphodiesterase (PDE)3 with cilostamide (1 µM) enhanced ICa,L to a similar extent as SNAP. However, when cAMP was elevated by PDE3 inhibition or β-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 the SR and AF group. Moreover, the expression of PDE3 and soluble guanylate cyclase was not reduced in AF.
  
  
  CONCLUSIONS
  NO exerts dual effects on ICa,L in SR with an increase of basal and inhibition of cAMP-stimulated current, and in AF NO inhibits only stimulated ICa,L. We conclude that in AF, cGMP regulation of PDE2 is preserved, but regulation of PDE3 is lost.
authors: Department of Pharmacology and Toxicology, Dresden University of Technology, Dresden, Germany.
authors: Nadiia
authors: N
authors: Rozmaritsa
authors: Torsten
authors: T
authors: Christ
authors: David R
authors: DR
authors: Van Wagoner
authors: Hannelore
authors: H
authors: Haase
authors: Johannes-Peter
authors: JP
authors: Stasch
authors: Klaus
authors: K
authors: Matschke
authors: Ursula
authors: U
authors: Ravens
mesh_terms: D001281:Atrial Fibrillation / Q000188:drug therapy / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D006801:Humans; D009206:Myocardium / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D018408:Patch-Clamp Techniques / Q000379:methods; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology
chemical_list: D020746:Calcium Channels, L-Type; D058987:Phosphodiesterase 3 Inhibitors; D015363:Quinolones; D009569:Nitric Oxide; C021294:cilostamide; D000242:Cyclic AMP; D006152:Cyclic GMP; D002118:Calcium
keywords: Atrial fibrillation; Cyclic nucleotides; L-type calcium current; Nitric oxide; Phosphodiesterases