Dual actions of halothane on intracellular calcium stores of vascular smooth muscle

Background: Halothane has been reported to affect the integrity of intracellular Ca ²⁺ stores in a number of tissues including vascular smooth muscle. However, the actions of halothane on intracellular Ca ²⁺ stores are not yet fully understood. Methods: Employing the isometric tension recording method, the action of halothane in isolated endothelium-denuded rat mesenteric arteries under either intact or β-escin-membrane-permeabilized conditions was investigated. Results: Halothane (0.125-5%) produced concentration-dependent contractions in Ca ²⁺ free solution in both intact and membrane-permeabilized muscle strips. Ryanodine treatment or repetitive application of phenylephrine eliminated both caffeine- and halothane-induced contractions in the Ca ²⁺ free solution. When either halothane and caffeine, caffeine and halothane, phenylephrine and halothane, or inositol 1,4,5- triphosphate and halothane were applied consecutively in the Ca ²⁺ free solution in either intact or membrane-permeabilized muscle strips, the contraction induced by application of the second agent of the pair was inhibited compared to application of that agent alone. However, when procaine was applied before and during application of the first agent, the contraction induced by the first agent was inhibited and the contraction induced by the second agent was restored. Heparin inhibited the inositol 1,4,5-triphosphate- mediated contraction, but not contractions induced by halothane or caffeine. Halothane (0.125-5%), applied during Ca ²⁺ loading, produced concentration- dependent inhibition of the caffeine contraction (used to estimate the amount of Ca ²⁺ in the store) in both intact and membrane-permeabilized muscle strips. In contrast, halothane applied with procaine during Ca ²⁺ loading produced concentration-dependent enhancement of the caffeine contraction. This enhancement was observed only in the intact but not in the membrane- permeabilized condition. Conclusions: Halothane has two distinct actions on the intracellular Ca ²⁺ stores of vascular smooth muscle, a Ca ²⁺ releasing action and a stimulating action on Ca ²⁺ uptake. Halothane releases Ca ²⁺ from the stores that are sensitive to both caffeine/ryanodine and phenylephrine/inositol 1,4,5-triphosphate through a procaine-sensitive mechanism. The observed inhibitory effect on Ca ²⁺ uptake is probably caused by the Ca ²⁺ releasing action, whereas the stimulating action on Ca ²⁺ uptake after blockade of Ca ²⁺ release may be membrane-mediated.