DangGuiSiNi Decoction and QiShenYiQi Pills Ameliorate Hyperpermeability and Edema Induced by Cold Exposure.

OBJECTIVE: Limb frostbite caused by cold exposure is a prevalent injury in winter. However, effective therapies remain limited, particularly for cold-induced edema. This study evaluated the therapeutic potential of DangGuiSiNi Decoction (DSD), QiShenYiQi Pills (QSYQ), and their combination in a rat model of cold-induced limb injury. METHODS: Male Sprague-Dawley rats (180-220 g) were subjected to hind limb frostbite through 5-min dry ice exposure. Animals were administered with DSD, QSYQ, or their combination via oral gavage either 2 h pre-exposure or 5 min post-exposure, followed by daily dosing for 7 days. Hennepin Score, hind limb blood flow, FITC-albumin extravasation, rhodamine 6G-labeled leukocyte adhesion, expression of tight/adhesion junction proteins and basement membrane components, transient receptor potential (TRP) channel proteins, ATP content, and norepinephrine levels at 2 h, 24 h, and 7 days post-exposure were assessed. RESULTS: The combination of DSD and QSYQ significantly alleviated frostbite-induced edema and gangrene. Compared with control group, cold exposure increased the expression of TRPA1, TRPM8, RhoA, ROCK, p-MLC, adrenergic receptor α2c and norepinephrine content, while decreased the expression of tight and adherent junction proteins claudin-5, ZO-1, JAM-1, basement membrane proteins laminin and collagen-IV, ATP content, and the activity of mitochondrial complex I, II, IV and V. DSD primarily counteracted the cold-sensing and vasoconstrictive pathways by reducing TRPA1/TRPM8 expression, norepinephrine levels, and RhoA/ROCK activation, thereby improving blood flow. In contrast, QSYQ enhanced vascular barrier integrity by upregulating junction and basement membrane proteins, and boosted energy supply by increasing ATP content and mitochondrial complex activities. The combination of DSD and QSYQ produced aggregated therapeutic effects. CONCLUSION: DSD attenuates frostbite by inhibiting temperature-sensing and vasoconstrictive pathways to ameliorate ischemia, whereas QSYQ protects vascular barrier function and mitigates edema by restoring energy metabolism. Their combination exhibits complementary and synergistic effects, supporting its use as a promising adjunctive therapy for cold-induced injury.