In permanent atrial fibrillation, PDE3 reduces force responses to 5-HT, but PDE3 and PDE4 do not cause the blunting of atrial arrhythmias
Autor: | Torsten Christ, Simon Schwarz, Michael Knaut, Alberto J. Kaumann, Ursula Ravens, Emanuel Berk |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Pharmacology Inotrope medicine.medical_specialty Cilostamide Lusitropy Atrium (architecture) business.industry Phosphodiesterase 3 Atrial fibrillation medicine.disease 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology chemistry Internal medicine cardiovascular system Cardiology medicine Sinus rhythm business Rolipram medicine.drug |
Zdroj: | British Journal of Pharmacology. 173:2478-2489 |
ISSN: | 0007-1188 |
DOI: | 10.1111/bph.13525 |
Popis: | Background and purpose 5-HT increases force and L-type Ca(2) (+) current (ICa,L ) and causes arrhythmias through 5-HT4 receptors in human atrium. In permanent atrial fibrillation (peAF), atrial force responses to 5-HT are blunted, arrhythmias abolished but ICa,L responses 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,L were 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,L to 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. |
Databáze: | OpenAIRE |
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