title: Effects on atrial fibrillation in aged hypertensive rats by Ca(2+)-activated K(+) channel inhibition.
abstract: We have shown previously that inhibition of small conductance Ca(2+)-activated K(+) (SK) channels is antiarrhythmic in models of acutely induced atrial fibrillation (AF). These models, however, do not take into account that AF derives from a wide range of predisposing factors, the most prevalent being hypertension. In this study we assessed the effects of two different SK channel inhibitors, NS8593 and UCL1684, in aging, spontaneously hypertensive rats to examine their antiarrhythmic properties in a setting of hypertension-induced atrial remodeling. Male spontaneously hypertensive rats and the normotensive Wistar-Kyoto rat strain were divided in 2×3 groups of animals aged 3, 8, and 11 months, respectively. The animals were randomly assigned to treatment with NS8593, UCL1684, or vehicle, and open chest in vivo experiments including burst pacing-induced AF were performed. The aging spontaneously hypertensive rats were more vulnerable to AF induction both by S2 stimulation and burst pacing. Vehicle affected neither the atrial effective refractory period nor AF duration. SK channel inhibition with NS8593 and UCL1684 significantly increased the atrial effective refractory period and decreased AF duration in both the normotensive and hypertensive strains with no decline in efficacy as age increased. In conclusion, SK channel inhibition with NS8593 and UCL1684 possesses antiarrhythmic properties in a rat in vivo model of paroxysmal AF with hypertension-induced atrial remodeling. The present results support the notion that SK channels may offer a promising new therapeutic target in the treatment of AF.
authors.affiliation: NeuroSearch A/S, Pederstrupvej 93, 2750 Ballerup, Denmark.
authors.forename: Jonas G
authors.initials: JG
authors.lastname: Diness
authors.forename: Lasse
authors.initials: L
authors.lastname: Skibsbye
authors.forename: Thomas
authors.initials: T
authors.lastname: Jespersen
authors.forename: Emil D
authors.initials: ED
authors.lastname: Bartels
authors.forename: Ulrik S
authors.initials: US
authors.lastname: Sørensen
authors.forename: Rie S
authors.initials: RS
authors.lastname: Hansen
authors.forename: Morten
authors.initials: M
authors.lastname: Grunnet
mesh_terms: D015057:1-Naphthylamine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000367:Age Factors; D000473:Alkanes / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology; D001281:Atrial Fibrillation / Q000503:physiopathology / Q000517:prevention & control*; D002304:Cardiac Pacing, Artificial; D004195:Disease Models, Animal; D006801:Humans; D006973:Hypertension / Q000503:physiopathology*; D007275:Injections, Intravenous; D008297:Male; D026902:Potassium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors* / Q000502:physiology; D011806:Quinolinium Compounds / Q000008:administration & dosage / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013045:Species Specificity; D013997:Time Factors
chemical_list: C515166:(R)-N-(benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphthylamine; C110349:6,10-diaza-3(1,3),8(1,4)dibenzena-1,5(1,4)diquinolinacyclodecaphane; D000473:Alkanes; D000889:Anti-Arrhythmia Agents; D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; D011806:Quinolinium Compounds; D015057:1-Naphthylamine