Fig. 1.

S1P₁R activation provides anti-RAS IPC-like cardioprotection in an isolated guinea pig heart model of I/R. S1P₁R blockade, PKCε inhibition, and ALDH2 inactivation prevent IPC-like cardioprotection. All guinea pig hearts were subjected to 20 minutes of global ischemia followed by 30 minutes of reperfusion in either the absence (control, n = 8) or presence of W146 (S1P₁R antagonist, 1 μM; n = 15) and SEW2871 (S1P₁R agonist, 1 μM; n = 10). When necessary, W146 (S1P₁R antagonist, 1 μM; n = 15), εV_1–2 (PKCε inhibitor, 1 μM; n = 8), or GTN (ALDH2 inactivator, 2 μM; n = 8) were added in the presence of SEW2871 (S1P₁R agonist, 1 μM). Other hearts were subjected to I/R preceded by IPC alone (i.e., 2 × 5-minute cycles of ischemia, each followed by 5-minute reperfusion, n = 14) or in the presence of W146 (1 μM; n = 8). Bars indicate mean ± S.E.M. of independent experiments. (A) Duration of reperfusion arrhythmias (VT/VF). (B) Overflow of NE and (C) angiotensin I (Ang I)–forming activity collected over 6 minutes either before ischemia or at the start of reperfusion. *P < 0.05; **P < 0.01; ***P < 0.001, by unpaired t test. (D–F) Representative ECG recordings from guinea pig hearts before ischemia (control, D), at the start of reperfusion (E), and at the end of VT/VF (recovery, F).