Effects on atrial fibrillation in aged hypertensive rats by Ca(2+)-activated K(+) channel inhibition

TY - JOUR

T1 - Effects on atrial fibrillation in aged hypertensive rats by Ca(2+)-activated K(+) channel inhibition

AU - Diness, Jonas Goldin

AU - Skibsbye, Lasse

AU - Jespersen, Thomas

AU - Bartels, Emil D

AU - Sørensen, Ulrik S

AU - Hansen, Rie S

AU - Grunnet, Morten

PY - 2011/6

Y1 - 2011/6

N2 - 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.

AB - 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.

KW - 1-Naphthylamine

KW - Age Factors

KW - Alkanes

KW - Animals

KW - Anti-Arrhythmia Agents

KW - Atrial Fibrillation

KW - Cardiac Pacing, Artificial

KW - Disease Models, Animal

KW - Humans

KW - Hypertension

KW - Injections, Intravenous

KW - Male

KW - Potassium Channel Blockers

KW - Potassium Channels, Calcium-Activated

KW - Quinolinium Compounds

KW - Random Allocation

KW - Rats

KW - Rats, Inbred SHR

KW - Rats, Inbred WKY

KW - Species Specificity

KW - Time Factors

U2 - 10.1161/hypertensionaha.111.170613

DO - 10.1161/hypertensionaha.111.170613

M3 - Journal article

C2 - 21502564

SN - 0194-911X

VL - 57

SP - 1129

EP - 1135

JO - Hypertension

JF - Hypertension

IS - 6

ER -