Effects of selective mineralocorticoid receptor antagonism on atrial ion currents and early ionic tachycardia-induced electrical remodelling in rabbits.
Over the past years, the importance of the renin-angiotensin-aldosterone system in atrial fibrillation (AF) pathophysiology has been recognised. Lately, the role of aldosterone in AF pathophysiology and mineralocorticoid receptor (MR) antagonism in "upstream" AF treatment is discussed. Hypothesising that selective MR antagonism might also influence atrial ion currents (L-type calcium current [I (Ca,L)], transient outward potassium current [I (to)], sustained outward potassium current [I (sus)]) and their tachycardia-induced remodelling, the effects of an eplerenone treatment were studied in a rabbit model. Six groups each with four animals were built. Animals of the control group received atrial pacing leads, but in contrast to the pacing groups, no atrial tachypacing (600 per minute for 24 and 120 h immediately before heart removal) was applied. Animals of the eplerenone groups were instrumented/paced as the corresponding control/pacing groups, but were additionally treated with eplerenone (7 days before heart removal). Atrial tachypacing was associated with a reduction of I (Ca,L). I (to) was decreased after 24 h of tachypacing, but returned to control values after 120 h. In the absence of rapid atrial pacing, MR antagonism reduced I (Ca,L) to a similar extent as 120 h of tachypacing alone. Based on this lower "take-off level", I (Ca,L) was not further decreased by high-rate pacing. I (to) and its expected tachycardia-induced alterations were not influenced by MR antagonism. In our experiments, selective MR antagonism influenced atrial I (Ca,L) and its tachycardia-induced alterations. As changes of I (Ca,L) are closely linked with atrial calcium signalling, the relevance of these alterations in AF pathophysiology and, accordingly, AF treatment is likely and has to be further evaluated.
Laszlo
Roman
R
Kardiologie und Kreislauferkrankungen, Eberhard Karls Universität Tuebingen, Otfried-Mueller-Straße 10, 72076, Tuebingen, Germany. roman.laszlo@gmx.de
Bentz
Kerstin
K
Konior
Agnes
A
Eick
Christian
C
Schreiner
Birgit
B
Kettering
Klaus
K
Schreieck
Juergen
J
D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism* / Q000503:physiopathology; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002304:Cardiac Pacing, Artificial; D004195:Disease Models, Animal; D004553:Electric Conductivity; D000077545:Eplerenone; D005260:Female; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D006329:Heart Conduction System / Q000187:drug effects / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects; D000451:Mineralocorticoid Receptor Antagonists; D015221:Potassium Channels / Q000378:metabolism; D011817:Rabbits; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D013610:Tachycardia / Q000378:metabolism* / Q000503:physiopathology
D020746:Calcium Channels, L-Type; D000451:Mineralocorticoid Receptor Antagonists; D015221:Potassium Channels; D013148:Spironolactone; D000077545:Eplerenone
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