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This Article Full Text Full Text (PDF) All Versions of this Article: 295/4/H1669    most recent 00010.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Said, M. Articles by Mattiazzi, A. PubMed PubMed Citation Articles by Said, M. Articles by Mattiazzi, A.

Increased intracellular Ca²⁺ and SR Ca²⁺ load contribute to arrhythmias after acidosis in rat heart. Role of Ca²⁺/calmodulin-dependent protein kinase II

¹Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Argentina; ²Department of Genome Science, University of Cincinnati College of Medicine, Cincinnati, Ohio; and ³Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, Illinois

Submitted 3 January 2008 ; accepted in final form 15 August 2008

Returning to normal pH after acidosis, similar to reperfusion after ischemia, is prone to arrhythmias. The type and mechanisms of these arrhythmias have never been explored and were the aim of the present work. Langendorff-perfused rat/mice hearts and rat-isolated myocytes were subjected to respiratory acidosis and then returned to normal pH. Monophasic action potentials and left ventricular developed pressure were recorded. The removal of acidosis provoked ectopic beats that were blunted by 1 µM of the CaMKII inhibitor KN-93, 1 µM thapsigargin, to inhibit sarcoplasmic reticulum (SR) Ca²⁺ uptake, and 30 nM ryanodine or 45 µM dantrolene, to inhibit SR Ca²⁺ release and were not observed in a transgenic mouse model with inhibition of CaMKII targeted to the SR. Acidosis increased the phosphorylation of Thr¹⁷ site of phospholamban (PT-PLN) and SR Ca²⁺ load. Both effects were precluded by KN-93. The return to normal pH was associated with an increase in SR Ca²⁺ leak, when compared with that of control or with acidosis at the same SR Ca²⁺ content. Ca²⁺ leak occurred without changes in the phosphorylation of ryanodine receptors type 2 (RyR2) and was blunted by KN-93. Experiments in planar lipid bilayers confirmed the reversible inhibitory effect of acidosis on RyR2. Ectopic activity was triggered by membrane depolarizations (delayed afterdepolarizations), primarily occurring in epicardium and were prevented by KN-93. The results reveal that arrhythmias after acidosis are dependent on CaMKII activation and are associated with an increase in SR Ca²⁺ load, which appears to be mainly due to the increase in PT-PLN.

sarcoplasmic reticulum; calcium/calmodulin-dependent protein kinase