Background

Surgical stress may cause immunosuppression especially in patients who have surgery for primary tumor removed. This study aimed to explore the effects of dexmedetomidine on immune and inflammatory response in patients undergoing radical gastrectomy.

Methods

After the institutional review board approval and written informed consent, forty patients undergoing radical gastrectomy were equally randomized to receive dexmedetomidine infusion (Dex group; 0.5 μg · kg(-1) initial dose followed by a maintenance dose of 0.4 μg · kg(-1) h(-1)) or normal saline infusion (NS group). Helper T lymphocytes (T helper 1 [Th1] and T helper 2 [Th2]), tumor necrosis factor-α, and interleukin-6 were measured during and after surgeries. Plasma catecholamine levels were also measured during surgery. Postoperative pain was measured by a visual analog scale.

Results

The percentage of Th1 increased significantly at the end of surgery, 24 h after surgery (P = 0.045 and 0.048, respectively), and Th2 decreased notably at the end of surgery in the Dex group (P = 0.030). Plasma levels of tumor necrosis factor-α (P = 0.045 and 0.036, respectively) and interleukin-6 (P = 0.049 and 0.042, respectively) differed significantly at the end of surgery and 24 h after surgery. Plasma epinephrine and norepinephrine levels decreased significantly at the beginning of surgery in the Dex group (P = 0.020 and 0.015, respectively). At the end of surgery, plasma dopamine levels decreased significantly in the Dex group (P = 0.048), but increased in the NS group. The visual analog scale pain score was lower in the Dex group than in the NS group 24 h after surgery (P = 0.046).

Conclusions

Dexmedetomidine has been shown to reduce surgical stresses and maintain Th1/Th2 balance. It has been shown to reduce inflammatory responses and exerts immunoprotective effect.

The calcium-activated KCa3.1 channel plays a crucial role in T-cell immune response. Genetic manipulation of T-cells to upregulate the expression of K+ channels has been shown to boost T-cell cytotoxicity in cancer. Here, we aimed to identify and characterize an activator that would augment KCa3.1 currents without affecting other channels. We synthesized five quinoline derivatives and used electrophysiology to screen them on KCa3.1 and a panel of 14 other ion channels. One quinoline derivative, SKA-346, activated KCa3.1 with an EC50 of 1.9 μM and showed selectivity against the other channels. In silico analysis using RosettaLigand and GLIDE demonstrated a well-converged pose of SKA-346 in a binding pocket at the interface between the calmodulin N-lobe and the S45A helix in the S4-S5 linker of the KCa3.1 channel. SKA-346 (30 mg kg-1), tolerated by mice after intra-peritoneal administration, exhibited a peak plasma concentration of 6.29 μg mL-1 (29.2 μM) at 15 min and a circulating half-life (t 1/2) of 2.8 h. SKA-346 could serve as a template for the development of more potent KCa3.1 activators to enhance T-cell cytotoxicity in cancer.