{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T18:15:44Z","timestamp":1761675344811},"reference-count":36,"publisher":"American Physiological Society","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2006,12]]},"abstract":"<jats:p> Overexpression of calcineurin in transgenic mouse heart results in massive cardiac hypertrophy followed by sudden death. Sudden deaths are caused by abrupt transitions from sinus rhythm to heart block (asystole) in calcineurin-overexpressing (CN) mice. Preliminary studies showed decreased maximum change in potential over time (d V\/d t<jats:sub>max<\/jats:sub>) of phase 0 of the action potential. Accordingly, the hypothesis was tested that decreased activity of the sodium channel contributes to heart block. Profound decreases in activity of sodium currents ( I<jats:sub>Na<\/jats:sub>) paralleled the changes in action potential characteristics. Progressive age-dependent decreases were observed such that at 42\u201350 days of life little sodium channel function existed. However, this was not paralleled by decreased protein expression as assessed by immunocytochemistry or by Western blot. Since calcineurin can interact with the ryanodine receptor, we assessed whether chronic in vitro treatment with BAPTA-AM, thapsigargin, and ryanodine could rescue the decrease of I<jats:sub>Na<\/jats:sub>. All of these treatments rescued I<jats:sub>Na<\/jats:sub> to levels indistinguishable from wild type. The nonspecific PKC inhibitor bisindolylmaleimide I also rescued the decrease of I<jats:sub>Na<\/jats:sub>. To assess whether decreased sodium channel activity contributes to sudden death in vivo, the response to encainide (20 mg\/kg) was assessed: 6 of 10 young CN mice died because of asystole, whereas 0 of 10 wild-type mice died ( P &lt; 0.01). Moreover, encainide produced exaggerated prolongation of the QRS width in sinus beats before the heart block. Catecholamine tone appears necessary to support life in older CN mice because propranolol (1 mg\/kg) triggered asystolic death in five of six CN mice. We conclude that decrease in sodium channel activity is in the common final pathway to asystole in CN mice. <\/jats:p>","DOI":"10.1152\/ajpheart.01247.2005","type":"journal-article","created":{"date-parts":[[2006,6,2]],"date-time":"2006-06-02T20:47:27Z","timestamp":1149281247000},"page":"H2669-H2679","source":"Crossref","is-referenced-by-count":12,"title":["Decrease in density of <i>I<\/i><sub>Na<\/sub> is in the common final pathway to heart block in murine hearts overexpressing calcineurin"],"prefix":"10.1152","volume":"291","author":[{"given":"J.","family":"Guo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S.","family":"Zhan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J.","family":"Somers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R. 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