The differential effects of intravenous anesthetics on myofilament Ca2+ sensitivity in pulmonary venous smooth muscle.

BACKGROUND: Pulmonary venous contraction can increase pulmonary capillary pressure and pulmonary edema. In the present study, we investigated the direct effects of ketamine, etomidate, thiopental, and midazolam on pulmonary venous contraction and myofilament Ca 2+ sensitivity in permeabilized pulmonary venous smooth muscle (PVSM). METHODS: The effects of these IV anesthetics on acetylcholine contraction were assessed in isolated canine pulmonary vein rings. Tension and [Ca 2+ ] ι were measured simultaneously in fura-2 loaded endothelium-denuded PVSM strips after being permeabilized with α-toxin. The effects of the IV anesthetics on tension ([Ca 2+ ] ι remains constant) in the absence or the presence of muscarinic receptor activation (acetylcholine) were assessed. The immunofluorescence technique and confocal microscopy were used to localize the cellular distribution of protein kinase C (PKC) isoforms in PVSM cells before and after the addition of ketamine. RESULTS: Ketamine, etomidate, and midazolam each attenuated acetylcholine contraction dose-dependently, whereas thiopental had no effect. None of the IV anesthetics alone had an effect on tension in strips at constant [Ca 2+ ]; (i.e., they had no direct effect on myofilament Ca 2+ sensitivity). Acetylcholine increased tension by 56% ± 7% at constant [Ca 2+ ] ι . In acetylcholine-stimulated strips, etomidate, midazolam, and thiopental had no additional effect on tension at constant [Ca 2+ ] ι , whereas ketamine decreased tension by 33% ± 3%. Activation with acetylcholine induced translocation of PKCa from cytoplasm to membrane, and this effect was blocked by ketamine. CONCLUSIONS: Ketamine, etomidate, and midazolam each attenuated acetylcholine-induced pulmonary venous contraction. Ketamine attenuates acetylcholine contraction by inhibiting the acetylcholine-induced increase in myofilament Ca 2+ sensitivity and the acetylcholine-induced translocation of PKCa.