Reduced density and altered regulation of rat atrial L-type Ca2+ current in heart failure

Richard Bond, Simon Bryant, Judy Watson, Jules Hancox, Clive Orchard, Andrew James

Research output: Contribution to journalArticle (Academic Journal)

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Abstract

Atrial L-type Ca2+ current (ICaL) downregulation in heart failure contributes to the pathogenesis of atrial fibrillation and is proposed to involve reduction in channel phosphorylation by PKA. The regulation of atrial ICaL was examined in heart failure. Anesthetized adult male Wistar rats underwent surgical coronary artery ligation (CAL, N=10) or equivalent sham-operation (Sham, N=12). Left atrial myocytes were isolated ~18 weeks post-surgery and whole-cell currents recorded (holding potential=-80 mV). ICaL activated by depolarizing pulses to voltages from -40 to +50 mV were normalized to cell capacitance and current density-voltage relations plotted. CAL cells were larger than Sham (94.7±5.2 pF; n=63 vs 56.6±2.1 pF; n=47; P≤0.0001). Maximal ICaLconductance (Gmax) was downregulated in CAL (Gmax: 140.6±16.5 pS/pF, n/N=31/10; Sham 288.4±24.2 pS/pF, n/N=32/12; P<0.0001). Norepinephrine (NE; 1 μmol/L) increased Gmax >50% more effectively in CAL (2.72-fold) than in Sham (1.78-fold) so that differences in ICaL density were abolished. Calyculin A (100 nmol/L) increased basal ICaL similarly in both cell types, indicating significant regulation of ICaL by protein phosphatases but increased protein dephosphorylation did not account for ICaL downregulation in heart failure. Treatment with either H-89 (10 μmol/L) or AIP (5 μmol/L) had no effect on basal currents in Sham or CAL myocytes, indicating that, in contrast to ventricular myocytes, neither PKA nor CaMKII contributed to basal ICaL. Expression of the L-type α1C-subunit, protein phosphatases 1 and 2A and inhibitor-1 proteins was unchanged in heart failure. In conclusion, reduction in PKA-dependent regulation did not contribute to downregulation of atrial ICaL in heart failure.
Original languageEnglish
Pages (from-to)H384-H391
Number of pages8
JournalAJP - Heart and Circulatory Physiology
Volume312
Issue number3
Early online date6 Dec 2016
DOIs
Publication statusPublished - Mar 2017

Keywords

  • atrial remodelling
  • coronary artery ligation
  • voltage-gated calcium channel

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