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Resting membrane potential regulates Na⁺-Ca²⁺ exchange-mediated Ca²⁺ overload during hypoxia-reoxygenation in rat ventricular myocytes

István Baczkó, Wayne R. Giles*† and Peter E. Light

In the heart, reperfusion following an ischaemic episode can result in a marked increase in [Ca²⁺]_i and cause myocyte dysfunction and death. Although the Na⁺-Ca²⁺ exchanger has been implicated in this response, the ionic mechanisms that are responsible have not been identified. In this study, the hypothesis that the diastolic membrane potential can influence Na⁺-Ca²⁺ exchange and Ca²⁺ homeostasis during chemically induced hypoxia-reoxygenation has been tested using right ventricular myocytes isolated from adult rat hearts. Superfusion with selected [K⁺]_o of 0.5, 2.5, 5, 7, 10 and 15 mM yielded the following resting membrane potentials: -27.6 ± 1.63 mV, -102.2 ± 1.89, -86.5 ± 1.03, -80.1 ± 1.25, -73.6 ± 1.02 and -66.4 ± 1.03, respectively. In a second set of experiments myocytes were subjected to chemically induced hypoxia-reoxygenation at these different [K⁺]_o, while [Ca²⁺]_i was monitored using fura-2. These results demonstrated that after chemically induced hypoxia-reoxygenation had caused a marked increase in [Ca²⁺]_i, hyperpolarization of myocytes with 2.5 mM [K⁺]_o significantly reduced [Ca²⁺]_i (7.5 ± 0.32 vs. 16.9 ± 0.55 %); while depolarization (with either 0.5 or 15 mM [K⁺]_o) significantly increased [Ca²⁺]_i (31.8 ± 3.21 and 20.8 ± 0.36 vs. 16.9 ± 0.55 %, respectively). As expected, at depolarized membrane potentials myocyte hypercontracture and death increased in parallel with Ca²⁺ overload. The involvement of the Na⁺-Ca²⁺ exchanger in Ca²⁺ homeostasis was evaluated using the Na⁺-Ca²⁺ exchanger inhibitor KB-R7943. During reoxygenation KB-R7943 (5 µM) almost completely prevented the increase in [Ca²⁺]_i both in control conditions (in 5 mM [K⁺]_o: 2.2 ± 0.40 vs. 10.8 ± 0.14 %) and in depolarized myocytes (in 15 mM [K⁺]_o: -2.1 ± 0.51 vs. 11.3 ± 0.05 %). These findings demonstrate that the resting membrane potential of ventricular myocytes is a critical determinant of [Ca²⁺]_i during hypoxia-reoxygenation. This appears to be due mainly to an effect of diastolic membrane potential on the Na⁺-Ca²⁺ exchanger, since at depolarized potentials this exchanger mechanism operates in the reverse mode, causing a significant Ca²⁺ influx.

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