Effects of Autonomic Agents on Ca2+ Cycling in Canine Atrial Myocytes during Rapid Pacing

Abstract

Atrial fibrillation (AF), or conditions conducive to it, often occur(s) in conjunction with high and/or unbalanced sympathetic/parasympathetic (autonomic) activity, which has profound effects on myocyte Ca2+ cycling. Using confocal microscopy, we have begun scrutinizing the effects various autonomic agents–including but not limited to isoproterenol (ISO; ∗-adrenergic receptor (AR) agonist), phenylephrine (PE; ∗-AR agonist) norepinephrine (NE, ∗- and ∗-AR agonist), and carbachol (CCh; muscarinic cholinergic receptor agonist)–have on Ca2+ cycling in isolated canine atrial myocytes paced at cycle lengths (CLs) ranging from 5000-200ms. In general, Ca-transient amplitudes were increased by ISO and NE; decreased by CCh; and varying decreased, increased or unaffected by PE–although PE only increased Ca-transients after PTX-treatment. However, considerable cell-to-cell variability in magnitude/dose-response for such effects was notable. The effects these agents had on irregular Ca-release events (ICREs)–i.e., Ca-alternans triggered-Ca-waves occurring during pacing (t-CaWs), and spontaneous-Ca-waves occurring during a pause after pacing (s-CaWs)–consequent to rapid pacing (CLs≤300ms) were interestingly distinct. CCh significantly reduced the appearance of all ICREs, yet were often accentuated upon CCh withdrawal. ISO often induced s-CaWs, but suppressed t-CaWs–with Ca-alternans often appearing in their stead. NE mimicked ISO regarding ICREs in some cells, but in others did not suppress and sometimes accentuated t-CaWs. PE accentuating t-CaWs and/or subcellular Ca-alternans in some cells, while suppressing or having no apparent effect on them in others. However, after PTX-treatment, PE mimicked ISO regarding ICREs without s-CaWs induction. These findings not only underscore the complexity of atrial autonomic modulation and its differences with that in ventricle, but also particulars evident only during rapid pacing–i.e., that during or conducive to the onset of AF.