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Cellular Mechanism of Inhibitory Effect of Propofol on Uterine Smooth Muscle and its Clinical Implication
Abstract Number: BP-02
Abstract Type: Original Research
Propofol-induced smooth muscle relaxation has been extensively studied in arteries and tracheal smooth muscle. The effect of propofol on uterine smooth muscle is poorly understood.
METHODS: Term human uterine samples were collected during cesarean. Term pregnant rat uterine samples were collected for comparison. Isometric tension was measured to determine the effect of propofol on spontaneous (SMC) and oxytocin (1mU/ml) augmented muscle contraction (AMC) on strips of myometrium. Western immunoblotting was used to study cellular mechanisms.
RESULTS: The effect of propofol on SMC and AMC was assessed in rat uterine muscle and a non-cumulative dose-response curve to propofol (10-6 to 3.16x10-4 M) was built. The sensitivities of SMC and AMC to propofol were similar with IC50's around 100uM (10-4M) (SMC: mean±SE 93.7±10.47uM, n=7; AMC: 87.9±5.23uM n=7). Inhibition by propofol was rapidly and fully reversible (5.5±1 min to reach 50% and 22.7 ± 2.9min to reach 90% of maximal force). In human uterine muscle, 10-5M propofol inhibited oxytocin AMC (10-9M to 10-6M; p<0.05). To explore the cellular mechanism of propofol-induced relaxation, we compared the effect of propofol on the thin-filament and thick-filament regulation. Oxytocin increased the phosphorylation of ERK1/2 (extracellular signal-regulated kinase) (2.79±0.25 vs. 1.04±0.03 in control group, n=5), but failed to activate p-CAD (phospho-Caldesmon) - the end target of thin-filament regulation (1.04±0.04 vs. 1.06±0.02 in control group). Propofol inhibited neither p-ERK1/2 (2.39±0.36 vs. 2.79±0.25 in oxytocin group) nor p-CAD (1.07±0.05 vs. 1.04±0.04 oxytocin group), indicating that thin-filament regulation plays no role either in oxytocin AMC or propofol inhibitory effect. We examined the end target of thick-filament regulation (calcium dependent pathway): oxytocin increased myosin light chain phosphorylation (p-MLC) (1.64±0.62 vs. 1.04± 0.13 in control group). And Propofol inhibited oxytocin-activated p-MLC (1.03±0.2 vs. 1.64±0.62 in oxytocin group).
CONCLUSION: Oxytocin contraction is mediated via calcium-dependent pathway and activation of MLC. Propofol inhibits oxytocin AMC and attenuates oxytocin-induced MLC phosphorylation. The extremely high IC50 of propofol (120x higher than concentration of propofol induction dose) and complete recovery suggests that clinical propofol use doesn’t contribute to uterine atony, or increase the risk of postpartum hemorrhage.
Ref. Anaeth Intensive Care 1990;18:180-4.