Sodium/calcium exchange regulates cytoplasmic calcium in smooth muscle

The sodium/calcium (Na⁺/Ca²⁺) exchanger is often considered to be a key regulator of the cytoplasmic calcium concentration (Ca²⁺]) in smooth muscle but neither its precise role in Ca²⁺ homeostasis nor even its existence in smooth muscle are generally agreed upon. Here we directly assessed the role Na⁺/Ca²⁺ exchange plays in regulating Ca²⁺] in single voltage-clamped smooth muscle cells. Following an elevation of Ca²⁺], its decline was found to have both voltage-dependent and voltage-independent components. The voltage-dependent component was abolished when Na⁺ was removed from the external bathing solution. During the fall of Ca²⁺] a small and declining Na⁺-dependent inward current was observed of a magnitude predicted by 31 Na⁺/Ca²⁺ exchange stoichiometry. At Ca²⁺] above 400 nM the principal efflux of Ca²⁺ above rest was attributed to this Na⁺-dependent removal mechanism. These results establish that a Na⁺/Ca²⁺ exchanger exists in smooth muscle and argue that it can regulate Ca²⁺] at physiological Ca²⁺ concentrations.