Unexpected wound effects of local arginine infusion: reduced granulation tissue formation and elevated homocysteine...

Background. Therapeutic use of supplemental arginine has been proposed as an efficacious method to produce nitric oxide (NO) from nitric oxide synthase (NOS) and proline and polyamines from arginase to improve wound healing. This study was designed to examine the effects of arginine on wound angiogenesis and granulation tissue formation.

A ventral hernia, surgically created in the abdominal wall of 12 swine, was repaired with silicone sheeting and skin closure. An osmotic infusion pump, inserted in a remote subcutaneous pocket, continuously delivered saline solution (n = 6) or L-arginine (n = 6) into the wound environment. Granulation tissue thickness was determined by ultrasonography. Fluid was aspirated serially from the developing wound compartment for measurement of nitrite/nitrate (NOx) and amino acid concentrations. On day 14, the animals were sacrificed, and the abdominal wall was harvested for histologic analysis.

In animals that received saline, a 4-fold increase in granulation tissue thickness was measured during the 14-day interval. In contrast, in L-arginine treated animals, the day 14 granulation tissue thickness was unchanged from day 4 values of saline treated animals (10.1 mm ± 1.1 mm versus 20.2 mm ± 1.7 mm at day 14; P < 0.05). Wound vessel count and vascular surface area estimates derived from image analysis of histologic sections were 2- to 3-fold lower in L-arginine animals compared to controls (P < 0.05). Progressive and sustained increases in wound fluid NOx and homocysteine levels were noted in L-arginine treated animals compared to controls (230 µm/L versus 75 µm/L at day 14 [P < 0.05]; peak 25.2 µm/L versus 17.3 µm/L at day 7 [P <0.05], respectively).

Supplemental arginine induces sustained NO production and creates a methylation demand, resulting in elevated homocysteine concentrations with consequent reductions in wound angiogenesis and granulation tissue formation. .