The effects of a novel agent that is reported to selectively block Ca2+ influx by Na+/Ca2+ exchange (NCX), KB-R7943, on the reoxygenation-induced arrhythmias and the recovery of developed tension after reoxygenation, were investigated in guinea pig papillary muscles. KB-R7943 dose-dependently suppressed the contracture tension during low-sodium (21.9 mM) perfusion (23+/-8% of steady-state developed tension at 10 microM vs. 56+/-11% in control; n = 6, p<0.05), but did not change action potential and contractile parameters. During the reoxygenation period after 60-min substrate-free hypoxia, KB-R7943 (10 microM) significantly decreased the incidence of arrhythmias (44 vs. 100% in control; n = 9, p <0.05) and shortened the duration of arrhythmias (16+/-11 vs. 72+/-14 s; p<0.01). KB-R7943 (10 microM) significantly enhanced the recovery of developed tension after reoxygenation (83+/-4 vs. 69+/-3% in control; p<0.05). We conclude that KB-R7943 (10 microM) selectively inhibits the reverse mode of NCX, and that it attenuates reoxygenation-induced arrhythmic activity and prevents contractile dysfunction in guinea pig papillary muscles. These results suggest that Ca2+ influx by NCX may play a key role in reoxygenation injury.