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Na⁺-Ca²⁺ exchange and sarcoplasmic reticular Ca²⁺ regulation in ventricular myocytes from transgenic mice overexpressing the Na⁺-Ca²⁺ exchanger

Cesare M. N. Terracciano, Ayesha I. De Souza, Kenneth D. Philipson * and Kenneth T. MacLeod

1. The contribution of the sarcoplasmic reticulum (SR) and Na⁺-Ca²⁺ exchanger to intracellular Ca²⁺ regulation in mouse cardiac myocytes was investigated by measuring contraction after variable rest intervals, rapid cooling contractures (RCCs) and fast application of caffeine. The results obtained showed differences from other species in the roles played by the SR and the Na⁺-Ca²⁺ exchanger. They suggest that in mouse ventricular myocytes there is significant Ca²⁺ entry via the exchanger during rest and during the latter part of the Ca²⁺ transient.

2. In cardiac myocytes isolated from transgenic mice overexpressing the cardiac Na⁺-Ca²⁺ exchanger the time to peak and relaxation of twitches and RCCs were faster than in control littermates. The decline of Ca²⁺, assessed by indo-1 fluorescence, was faster in transgenic myocytes even in the absence of Na⁺ and Ca²⁺ in the superfusing solution. This suggests that SR Ca²⁺ uptake is faster in these myocytes. However, no difference in the expression of SERCA2a, phospholamban or calsequestrin measured with Western blotting could be found in the two groups.

3. We measured SR Ca²⁺ content by integrating the caffeine-induced transient inward current. The amount of Ca²⁺ stored in the SR of transgenic mouse myocytes was 69 % greater than in non-transgenic littermates. The increased SR Ca²⁺ content may be responsible for the faster rate of SR Ca²⁺ release and uptake in cells from transgenic mice.

4. We performed experiments to assess whether the reversal potential of the Na⁺-Ca²⁺ exchanger (E_Na-Ca) was different in transgenic cardiac cells. We measured a Ni²⁺-sensitive current elicited by voltage ramps in non-dialysed myocytes. The current-voltage relationship showed no difference in the reversal potential of the Na⁺-Ca²⁺ exchanger in transgenic and control myocytes. This suggests that the effects on the SR Ca²⁺ content in transgenic cardiac myocytes can be ascribed to the overexpression of the exchanger and are not secondary to changes in intracellular diastolic Ca²⁺ and Na⁺.

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