In the guinea pig heart-lung preparation, the protective effects of nifedipine and R 58735 on cardiovascular alterations following mild (35 min) and severe (60 min) ischemia and reperfusion (30 min) were studied. Nifedipine and R 58735 were equi-protective against the effects of mild ischemia with respect to functional (LVP, dp/dt, and cardiac output) and biochemical (ATP, CrP, and adenylate charge) parameters. A clear difference, however, was observed between nifedipine and R 58735 upon severe ischemia, where R 58735 produced a significantly greater protection of functional, but not of biochemical parameters. Since no significant differences between the two compounds were found with respect to the concentrations of high energy phosphates after 35 and 60 min of ischemia before reperfusion, an energy sparing effect is not likely to be responsible for the difference between nifedipine and R 58735 in severe ischemia. An additional protective effect of R 58735 upon reperfusion in severe ischemia experiments may explain the difference between the two compounds.