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

Background: Halothane has been reported to affect the integrity of intracellular Ca2+ stores in a number of tissues including vascular smooth muscle. However, the actions of halothane on intracellular Ca2+ 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 beta-escin-membrane-permeabilized conditions was investigated. Results: Halothane (0.125-596) produced concentiation-dependent contractions in Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ loading, produced concentration-dependent inhibition of the caffeine contraction (used to estimate the amount of Ca2+ in the store) in both intact and membrane-permeabilized muscle strips. In contrast, halothane applied with procaine during Ca2+ lending 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 Ca2+ stores of vascular smooth muscle, a Ca2+ releasing action and a stimulating action on Ca2+ uptake. Halothane releases Ca2+ from the stores that are sensitive to both caffelne/ryanodine and phenylephrine/inositol 1,4,5-triphosphate through a precaine-sensitive mechanism. The observed inhibitory effect on Ca2+ uptake is probably caused by the Ca2+ releasing action, whereas the stimulating action on Ca2+ uptake after blockade of Ca2+ release may be membrane-mediated.