Effects on Atrial Fibrillation in Aged Hypertensive Rats by Ca2+-Activated K+ Channel Inhibition

We have shown previously that inhibition of small conductance Ca2+-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.

[1]  U. Sørensen,et al.  Inhibition of Small-Conductance Ca2+-Activated K+ Channels Terminates and Protects Against Atrial Fibrillation , 2010, Circulation. Arrhythmia and electrophysiology.

[2]  Thomas Meitinger,et al.  Common Variants in KCNN3 are Associated with Lone Atrial Fibrillation , 2010, Nature Genetics.

[3]  Ling Lu,et al.  α-Actinin2 cytoskeletal protein is required for the functional membrane localization of a Ca2+-activated K+ channel (SK2 channel) , 2009, Proceedings of the National Academy of Sciences.

[4]  Zhao Zhang,et al.  Ablation of a Ca2+‐activated K+ channel (SK2 channel) results in action potential prolongation in atrial myocytes and atrial fibrillation , 2009, The Journal of physiology.

[5]  J. Adelman,et al.  Functional Roles of a Ca2+-Activated K+ Channel in Atrioventricular Nodes , 2008, Circulation research.

[6]  Masanori Hirose,et al.  Early electrical remodeling in rabbit pulmonary vein results from trafficking of intracellular SK2 channels to membrane sites. , 2007, Cardiovascular research.

[7]  J. Hancox,et al.  Increased Susceptibility to Atrial Tachyarrhythmia in Spontaneously Hypertensive Rat Hearts , 2007, Hypertension.

[8]  Ling Lu,et al.  Molecular Coupling of a Ca2+-Activated K+ Channel to L-Type Ca2+ Channels via α-Actinin2 , 2007 .

[9]  D. Strøbæk,et al.  Inhibitory Gating Modulation of Small Conductance Ca2+-Activated K+ Channels by the Synthetic Compound (R)-N-(Benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphtylamine (NS8593) Reduces Afterhyperpolarizing Current in Hippocampal CA1 Neurons , 2006, Molecular Pharmacology.

[10]  P. Bois,et al.  Functional Expression of the TRPM4 Cationic Current in Ventricular Cardiomyocytes From Spontaneously Hypertensive Rats , 2006, Hypertension.

[11]  D. Paterson,et al.  Remodeling of the Cardiac Pacemaker L-Type Calcium Current and Its β-Adrenergic Responsiveness in Hypertension After Neuronal NO Synthase Gene Transfer , 2006, Hypertension.

[12]  Ling Lu,et al.  Differential expression of small-conductance Ca2+-activated K+ channels SK1, SK2, and SK3 in mouse atrial and ventricular myocytes. , 2005, American journal of physiology. Heart and circulatory physiology.

[13]  Ming Lei,et al.  Specific pattern of ionic channel gene expression associated with pacemaker activity in the mouse heart , 2005, The Journal of physiology.

[14]  Yi Zhang,et al.  Molecular Identification and Functional Roles of a Ca2+-activated K+ Channel in Human and Mouse Hearts* , 2003, Journal of Biological Chemistry.

[15]  S. Nattel.  New ideas about atrial fibrillation 50 years on , 2002, Nature.

[16]  Michael R. Rosen,et al.  Pathophysiology and Prevention of Atrial Fibrillation , 2001, Circulation.

[17]  B. Gersh,et al.  Epidemiology and natural history of atrial fibrillation: clinical implications. , 2001, Journal of the American College of Cardiology.

[18]  D. Levy,et al.  Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. , 1998, Circulation.

[19]  S. Garrigue,et al.  Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. , 1998, The New England journal of medicine.

[20]  S. Lévy.  Factors Predisposing to the Development of Atrial Fibrillation , 1997, Pacing and clinical electrophysiology : PACE.

[21]  A Mugelli,et al.  Ionic basis of action potential prolongation of hypertrophied cardiac myocytes isolated from hypertensive rats of different ages. , 1994, Cardiovascular research.

[22]  Capelle,et al.  Slow conduction in the infarcted human heart. 'Zigzag' course of activation. , 1993, Circulation.

[23]  P. Wolf,et al.  Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. , 1991, Stroke.

[24]  S. Ricksten,et al.  Left atrial pressure in normotensive and spontaneously hypertensive rats. , 1979, Acta physiologica Scandinavica.

[25]  J A ABILDSKOV,et al.  Atrial fibrillation as a self-sustaining arrhythmia independent of focal discharge. , 1959, American heart journal.

[26]  P. Levesque,et al.  Antiarrhythmic drug therapy for atrial fibrillation: focus on atrial selectivity and safety. , 2009, Cardiovascular & hematological agents in medicinal chemistry.

[27]  C. H. Conrad,et al.  Myocardial fibrosis and stiffness with hypertrophy and heart failure in the spontaneously hypertensive rat. , 1995, Circulation.

[28]  C. H. Conrad,et al.  The spontaneously hypertensive rat as a model of the transition from compensated left ventricular hypertrophy to failure. , 1995, Journal of molecular and cellular cardiology.

[29]  M. Pfeffer,et al.  ECG alterations with progressive left ventricular hypertrophy in spontaneous hypertension. , 1978, Clinical and experimental hypertension.