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Ca2+ spark parameters were quantified with a detection/analysis computer algorithm. SR Ca2+ leak was measured as the tetracaine (RyR2 inhibitor)-induced shift in diastolic [Ca2+]i (Shannon et al. 2002; Knollmann et al. 2006; Picht et al. 2007). Myocytes were loaded at 22��C with Fluo-4 AM (10 ��m, Molecular Probes, Eugene, OR, USA) for 30 min, washed out, and then an additional 30 min was allowed for intracellular de-esterification. Then the cells were stimulated for 1 min in normal Tyrode solution. After reaching steady state, the solution was rapidly switched to 0 Na+, 0 Ca2+ Tyrode solution (Na+ was replaced by Li+) plus 1 mm tetracaine (Sigma) for https://en.wikipedia.org/wiki/Pentamorphone 30 s. Afterwards, the solution was rapidly switched to 0 Na+, 0 Ca2+ Tyrode solution for 20 s. Tetracaine, by blocking RyR2 and therefore SR Ca2+ leak, caused a decrease in diastolic [Ca2+]i. The shift in diastolic [Ca2+]i upon the removal of tetracaine was used as a measure of RyR2-dependent SR Ca2+ leak. Since SR Ca2+ leak is also dependent upon SR Ca2+ load, SR Ca2+ load of each cell was measured. Measurements were performed at room temperature. Normal Tyrode solution consisted of (in mm): 140 NaCl, http://www.selleckchem.com/products/Adriamycin.html 4 KCl, 1 MgCl2, 1 CaCl2, 10 glucose, 5 Hepes, 1 l-arginine, pH 7.4 adjusted with HCl. S-Methyl-l-thiocitrulline (SMLT, 10 ��m, Calbiochem, La Jolla, CA, USA), a specific NOS1 inhibitor (Narayanan & Griffith, 1994), and SNAP (1 and 10 ��m, Sigma), a NO donor and S-nitrosylating agent, were prepared fresh each experimental day. Myocytes were pre-incubated with SMLT (30 min) or SNAP (20 min). Results were expressed as means ��s.e.m. Statistical significance (P http://www.selleckchem.com/products/LBH-589.html observed a decreased SR Ca2+ fractional release (twitch Ca2+ transient amplitude/SR Ca2+ load) with NOS1 knockout (WT: 0.49 �� 0.02, NOS1?/?: 0.37 �� 0.03, P