Stimulus-dependent modulation of smooth muscle intracellular calcium and force by altered intracellular pH

Measurements of simultaneous force and intracellular Ca2+ concentration ([Ca2+](i)) in rat uterine smooth muscle have been made to elucidate the mechanisms involved when force produced spontaneously, by high-K+ depolarization or carbachol is altered by a change of intracellular pH (pH(i)). Rises in force and [Ca2+](i) were closely correlated for all forms of contraction, with the Ca2+ transient peaking before force. In spontaneously active preparations, alkalinization significantly increased, and acidification decreased, force and [Ca2+](i). Inhibition of the sarcoplasmic reticulum ATPase (cyclopiazonic acid) did not affect these changes, whereas removal of external Ca2+ abolished both responses, suggesting that the effect of pH(i) is on Ca2+ entry. Alkalinization caused a prolongation of the action potential complex, associated with a potentiation of contractile activity. Acidification produced hyperpolarization and abolition of action potentials and spontaneous activity, but did not prevent brief applications of carbachol or high-K+ from producing depolarization and increasing force, suggesting no impairment of the mechanism of generation of the action potential. For depolarized preparations, acidification increased tonic force and [Ca2+](i); the increase in the calcium signal persisted in zero-external calcium. In the presence of carbachol, acidification transiently increased force and [Ca2+](i), followed by a reduction in both. It is concluded that changes in pH(i) act at more than one step in excitation-contraction coupling and that changes in [Ca2+](i) can account for most of the changes in uterine force.