Abstract 17723: Effects of a Mutant Form of Atrial Natriuretic Peptide Associated With Atrial Fibrillation on Atrial Electrophysiology
Recently a familial mutation in the gene encoding the cardiac hormone atrial natriuretic peptide (ANP) was linked to atrial fibrillation (AF) in all affected family members. This mutation results in the production of a mutant ANP (mANP) with a twelve amino acid C-terminal extension. ANP and mANP can bind to two receptors denoted NPR-A (guanylyl cyclase-linked receptor) and NPR-C (activates inhibitory G proteins). The purpose of this study was to determine the effects of ANP and mANP in mice using patch-clamping of right atrial myocytes and high resolution optical mapping of the atria. In basal conditions neither peptide affected atrial myocyte electrophysiology, but in the presence of the β-adrenergic receptor agonist isoproterenol (ISO; 10 nM) important differences emerged. ANP (100 nM) increased ISO stimulated AP duration at 50% (APD50; 15.5±2.3 ms vs. 19.1±2.9 ms) and 90% (APD90; 58.3±4.3 ms vs. 71.5±4.9 ms) repolarization (P<0.05; n=5 myocytes). Peak ICa,L was increased from -2.5±0.4 to -6.7±0.3 pA/pF by ISO and was further increased to -7.9±0.3 pA/pF by ANP (P<0.05; n=9). ANP also shifted the V1/2 of ICa,L activation (V1/2(act)) from -16.6±0.1 mV to -18.3±1.3 mV (P<0.05). Conversely, mANP (100 nM) shortened ISO stimulated APD50 (15±0.9 to12.1±1.2 ms) and APD90 (60.8±2.1 to 54.1±1.9 ms; P<0.05; n=11). mANP reduced peak ICa,L (in ISO) from -7.6±0.5 to -6.1±0.2 pA/pF and shifted the V1/2(act) from -20±0.5 to -19±0.4 mV (P<0.05; n=11). The effects of ANP on ICa,L were preserved in myocytes from NPR-C knockout mice (NPR-C-/-) where ICa,L was increased from -6.8±0.7 to -8.2±0.7 pA/pF (P<0.05; n=8). Strikingly, the ability of mANP to reduce ICa,L was completely absent in NPR-C-/- myocytes where ISO stimulated ICa,L was not affected by mANP (-7.5±0.5 vs. -7.6±0.5 pA/pF; P=0.989; n=8). Optical mapping revealed that atrial conduction velocity (CV) was increased from 35±0.4 to 44.6±1.2 cm/s in ISO and further increased to 53.2±2.2 cm/s by ANP (P<0.05; n=5 hearts). In contrast, mANP reduced ISO stimulated atrial CV from 47.4±1.2 to 42.2±1.5 cm/s (P<0.05; n=5). These data demonstrate that ANP and mANP have opposing effects on atrial APD, ICa,L and CV. ANP primarily signals through NPR-A while mANP primarily signals through NPR-C which may explain how mANP causes AF.
- © 2013 by American Heart Association, Inc.