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 3:1 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.