OBJECTIVE Developed tension in guinea-pig papillary muscles is depressed by prolonged hypoxia; subsequent reoxygenation leads to a partial recovery that stabilizes after an early period of arrhythmia. We have investigated whether hypoxic preconditioning in these muscles (1) improves the recovery of developed tension, (2) protects against arrhythmia, and (3) causes other significant electromechanical changes. METHODS Papillary muscles stimulated at 1 Hz were superfused with oxygenated Krebs solution for 60 min and either preconditioned (5 min of 3 Hz pacing substrate-free hypoxic conditions, 10 min of normoxic recovery) or equilibrated for an extra 15 min. Muscles were subsequently challenged with substrate-free hypoxia (1 Hz), and reoxygenated (1 Hz) for 60 min. Contractile performance, action potential parameters, and indicators of arrhythmic activity were measured in 10 preconditioned and 10 non-preconditioned muscles. RESULTS Developed tension in preconditioned muscles declined to the same level (10-15% control) as in non-preconditioned muscles after 60 min hypoxia. A notable difference was that developed tension in the preconditioned muscles failed to rebound during mid-hypoxia, a hallmark feature in non-preconditioned muscles. The action potential duration and overshoot collapsed at a significantly faster rate in hypoxic preconditioned muscles. Action potential recovery during reoxygenation was similar in the two groups of muscles, but recovery of developed tension was significantly stronger in preconditioned (76.7 +/- 5.4%) than in non-preconditioned (42.9 +/- 1.7%) muscles (P < 0.001). Reoxygenation provoked arrhythmic activity in all muscles, but the summed average duration was shorter (5.5 +/- 1.0 vs. 9.4 +/- 1.5 min) (P < 0.05) in the preconditioned muscles. CONCLUSIONS Hypoxic preconditioning can significantly enhance post-hypoxia recovery of developed tension, and significantly attenuate arrhythmic activity, in guinea-pig papillary muscles.