Paradoxical decrease in cytosolic calcium with increasing depolarization by potassium in guinea-pig mesotubarium smooth muscle

The free intracellular Ca²⁺ concentration ([Ca²⁺]_i) was measured simultaneously with isometric force in strips of guinea-pig mesotubarium using the Fura-2 technique. [Ca²⁺]_i and force were maximal at a relatively low (30 mM) concentration of extracellular K⁺ ([K⁺]_o), and declined at 90 and 140 mM K⁺. Plateau values of both [Ca²⁺]_i and force were higher in the presence of 5 · 10^–6 M ryanodine, indicating that the sarcoplasmic reticulum (SR) contributes to the decline with depolarization. Force and [Ca²⁺]_i at 90 mM K⁺ were both lower then the high-K⁺ solution was applied after a period in 30 mM K⁺ than after a period in normal solution (5.9 mM K⁺), consistent with inactivation of Ca²⁺ channels during prolonged depolarization. Addition of carbachol to the depolarized muscle caused a maintained increase in force without maintained increase in [Ca²⁺]_i. We conclude that the decrease in force at increased [K⁺]_o (the calcium-potassium paradox) is due to a membrane-potential-mediated decrease in [Ca²⁺]_i and, to a lesser extent, to desensitization of the contractile-regulatory apparatus to Ca²⁺.