In permanent atrial fibrillation, PDE3 reduces force responses to 5-HT, but PDE3 and PDE4 do not cause the blunting of atrial arrhythmias

Abstract

Background and Purpose: 5-HT increases force and L-type Ca2+current (ICa,L) and causes arrhythmias through 5-HT4receptors in human atrium. In permanent atrial fibrillation (peAF), atrial force responses to 5-HT are blunted, arrhythmias abolished but ICa,Lresponses only moderately attenuated. We investigated whether, in peAF, this could be due to an increased function of PDE3 and/or PDE4, using the inhibitors cilostamide (300 nM) and rolipram (1 μM) respectively. Experimental Approach: Contractile force, arrhythmic contractions and ICa,Lwere assessed in right atrial trabeculae and myocytes, obtained from patients with sinus rhythm (SR), paroxysmal atrial fibrillation (pAF) and peAF. Key Results: Maximum force responses to 5-HT were reduced to 15% in peAF, but not in pAF. Cilostamide, but not rolipram, increased both the blunted force responses to 5-HT in peAF and the inotropic potency of 5-HT fourfold to sevenfold in trabeculae of patients with SR, pAF and peAF. Lusitropic responses to 5-HT were not decreased in peAF. Responses of ICa,Lto 5-HT did not differ and were unaffected by cilostamide or rolipram in myocytes from patients with SR or peAF. Concurrent cilostamide and rolipram increased 5-HT's propensity to elicit arrhythmias in trabeculae from patients with SR, but not with peAF. Conclusions and Implications: PDE3, but not PDE4, reduced inotropic responses to 5-HT in peAF, independently of lusitropy and ICa,L, but PDE3 activity was the same as that in patients with SR and pAF. Atrial remodelling in peAF abolished the facilitation of 5-HT to induce arrhythmias by inhibition of PDE3 plus PDE4.