Figure 6-9 A, Proposed signaling pathways underlying volatile anesthetic (halothane and isoflurane)-induced contraction and relaxation in pulmonary artery smooth muscle. After Ca²⁺ release from intracellular stores, there are dose-dependent increases in force initially (associated with protein kinase C activation), which is followed by a decrease in force (associated with a Ca²⁺ -calmodulin-dependent protein kinase II activation). High concentrations of halothane may activate a protein kinase C-Ca²⁺ -calmodulin-dependent protein kinase II pathway. B, Example of biphasic (contraction-relaxation) effect of halothane on pulmonary arterial smooth muscle. Halothane dose-dependently enhanced Ca²⁺ -activated peak force as well as late relaxation. 0%, 1%, 2%, and 3%, halothane concentrations; ss, control force at steady state before halothane. (Adapted from Su JY, Vo AC: Ca²⁺ -calmodulin-dependent protein kinase II plays a major role in halothane-induced dose-dependent relaxation in the skinned pulmonary artery. Anesthesiology 97:207, 2002 and from Zhong L, Su JY: Isoflurane activates PKC and Ca²⁺ -calmodulin-dependent protein kinase II via MAP kinase signaling in cultured vascular smooth muscle cells. Anesthesiology 96:148, 2002.)