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Enhanced L-type Ca²⁺ channel current density in coronary smooth muscle of exercise-trained pigs is compensated to limit myoplasmic free Ca²⁺ accumulation

Cristine L. Heaps*†, Douglas K. Bowles*‡, Michael Sturek*†, M. Harold Laughlin*†‡ and Janet L. Parker*†§

1. We hypothesized that enhanced voltage-gated Ca²⁺ channel current (VGCC) density in coronary smooth muscle cells of exercise-trained miniature Yucatan pigs is compensated by other cellular Ca²⁺ regulatory mechanisms to limit net myoplasmic free Ca²⁺ accumulation.

2. Whole-cell voltage clamp experiments demonstrated enhanced VGCC density in smooth muscle cells freshly dispersed from coronary arteries of exercise-trained vs. sedentary animals.

3. In separate experiments using fura-2 microfluorometry, we measured depolarization-induced (80 mM KCl) accumulation of myoplasmic free Ba²⁺ and free Ca²⁺. Both maximal rate and net accumulation of free Ba²⁺ in response to membrane depolarization were increased in smooth muscle cells isolated from exercise-trained pigs, consistent with an increased VGCC density. Depolarization also produced an enhanced maximal rate of free Ca²⁺ accumulation in cells of exercise-trained pigs; however, net accumulation of free Ca²⁺ was not significantly increased suggesting enhanced Ca²⁺ influx was compensated to limit net free Ca²⁺ accumulation.

4. Inhibition of sarco-endoplasmic reticulum Ca²⁺-transporting ATPase (SERCA; 10 µM cyclopiazonic acid) and/or sarcolemmal Na⁺-Ca²⁺ exchange (low extracellular Na⁺) suggested neither mechanism compensated the enhanced VGCC in cells of exercise-trained animals.

5. Local Ca²⁺-dependent inactivation of VGCC, assessed by buffering myoplasmic Ca²⁺ with EGTA in the pipette and using Ca²⁺ and Ba²⁺ as charge carriers, was not different between cells of sedentary and exercise-trained animals.

6. Our findings indicate that increased VGCC density is compensated by other cellular Ca²⁺ regulatory mechanisms to limit net myoplasmic free Ca²⁺ accumulation in smooth muscle cells of exercise-trained animals. Further, SERCA, Na⁺-Ca²⁺ exchange and local Ca²⁺-dependent inactivation of VGCC do not appear to function as compensatory mechanisms. Additional potential compensatory mechanisms include Ca²⁺ extrusion via plasma membrane Ca²⁺-ATPase, mitochondrial uptake, myoplasmic Ca²⁺-binding proteins and other sources of VGCC inactivation.

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