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Catecholamines are known to provoke cardiac arrhythmias, but important aspects such as localization of the arrhythmia source in multicellular tissue and exact ionic mechanisms are not well-known. In this work, a multicellular model of arrhythmias caused by local epinephrine application was developed; V (m) and Ca(i)(2+) changes at the arrhythmia source were measured using fluorescent dyes and high-resolution optical mapping. Cultured strands of neonatal rat myocytes (width approximately 0.4 mm) were produced by patterned growth. Epinephrine (1 micromol/l) was applied over an area of 0.3-0.6 mm via two micropipettes, and strands were stimulated by burst pacing. Local epinephrine application caused triggered arrhythmias with cycle lengths of 202-379 ms and duration of >10 s in 9 out of 16 preparations. Optical V(m) mapping demonstrated that in 78% of cases, the source of arrhythmia was located at the boundary of the locally perfused area. Staining with Ca(i)(2+)-sensitive dye Fluo-4 prevented arrhythmia induction in most cases (85%) likely due to Ca(2+) buffering by the dye. Optical Ca(i)(2+) mapping revealed non-propagated Ca(i)(2+) oscillations at the boundary of the locally perfused area in 45% cases. In conclusion, we developed a new model of catecholamine-dependent arrhythmias allowing mapping of V(m) and Ca(i)(2+) at the arrhythmia source with microscopic resolution. The arrhythmias typically originated from the boundary of the epinephrine-perfused area. The location of the arrhythmia source correlated with localized Ca(i)(2+) oscillations suggesting that arrhythmias were caused by Ca(i)(2+) overload at these locations.

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