Major surgery diminishes systemic arginine availability and suppresses nitric oxide response to feeding in patients with early stage breast cancer

Abstract

Background & aims: Plasma arginine (ARG) levels are reduced in breast cancer, suggesting diminished systemic ARG availability. ARG and its product nitric oxide (NO) are important in early postoperative recovery due to its roles in immune function and wound healing. It remains unclear whether major surgery further diminishes systemic ARG availability due to enhanced ARG catabolism and/or insufficient endogenous ARG synthesis negatively affecting NO synthesis in patients with early stage breast cancer.

Methods: In 9 women with early stage breast malignancy and 9 healthy women with genetic predisposition to breast cancer, whole body ARG and citrulline (CIT) rates of appearances were measured to determine their production rates prior to and within 24 h after major breast surgery by stable isotope methodology in the postabsorptive and postprandial state. The conversions of CIT > ARG, ARG > CIT, and ARG > Urea (markers of de novo ARG and NO synthesis, arginase activity, respectively), and ARG clearance (reflecting ARG disposal capacity) were calculated.

Results: Prior to surgery, plasma ARG, CIT and glutamine concentrations were lower in cancer (P < 0.05) but no differences were found in the rate of appearances of ARG, CIT and their conversions. Surgery increased ARG clearance and reduced CIT rate of appearance, conversion of CIT > ARG (P < 0.001), and plasma ARG, CIT, ornithine concentrations (P < 0.001). Furthermore, postprandial increase in ARG > CIT conversion (P < 0.05), plasma ARG (P < 0.001) and CIT (P = 0.06) concentrations were lower after surgery. The cancer group had lower values for postprandial increase in ARG > CIT conversion, plasma CIT (P < 0.05) and glutamine concentrations (P = 0.08).

Conclusions: Major surgery in early stage breast cancer further reduces systemic ARG availability in the early phase of recovery due to a combined process of increased ARG catabolism and impaired endogenous ARG synthesis. The suppressed postprandial NO increase in early stage cancer suggests that specific nutritional approaches are advised to increase ARG availability after major surgery although the effects on postoperative recovery remain unclear. This trial was registered at clinicaltrials.gov as NCT00497380.

Keywords: Arginine kinetics; Breast surgery; Early stage breast cancer; Nitric oxide synthesis; Stable isotopes.

Figure 1

Kinetics of whole body arginine rate of appearance (Fig 1a), citrulline rate of appearance (Fig 1b), citrulline to arginine conversion (indirect marker of arginine de novo synthesis (Fig 1c), arginine clearance (1d) and arginine to citrulline conversion (indirect marker of nitric oxide synthesis (1e) in the breast cancer group (grey lines) and healthy control group (black lines), both pre-surgery (straight lines) and post-surgery (dotted lines), after intake of the conventional nutritional supplement at t=90 min. Values are mean (± S.E.M.). Two-factor repeated-measures ANOVA was used to test the Group (G) and Surgery (S) effect. There was a Surgery effect for whole body arginine and citrulline rate of appearance, citrulline to arginine conversion (P<0.01). There was no Group effect or Surgery X Group interaction.

Figure 2

Kinetics of plasma concentrations of arginine (Fig 2a), citrulline (Fig 2b), glutamine (Fig 2c), and ornithine (2d) in the breast cancer group (grey lines) and healthy control group (black lines), both pre-surgery (straight lines) and post-surgery (dotted lines), after intake of the conventional nutritional supplement at t=90 min. Values are mean (± S.E.M.). Two-factor repeated-measures ANOVA was used to test the Group (G) and Surgery (S) effect. There was a Surgery effect for plasma concentration of arginine, citrulline, glutamine, and ornithine (P<0.001). There was a Group effect for plasma concentration of arginine and glutamine (P<0.05). There was no Surgery X Group interaction.

Figure 3

Change (mean ±SEM values) in whole body arginine rate of appearance (Fig 3a), citrulline rate of appearance (fig 3b), citrulline to arginine conversion (indirect marker of arginine de novo synthesis (Fig 3c), arginine clearance (Fig 3d), and arginine to citrulline conversion (indirect marker of nitric oxide synthesis (Fig 3e) after meal intake (difference between postprandial and postabsorptive values), in the breast cancer group (black bar) and the healthy control group (open bar) before and within 24 hours after surgery. Two-factor repeated-measures ANOVA was used to test the Group (G) and Surgery (S) effect. There was a Surgery effect for arginine to citrulline conversion (P<0.05) and citrulline rate of appearance (P=0.06). There was a Group effect for arginine to citrulline conversion (P<0.05). There was no Surgery X Group interaction.

Figure 4

Change (mean ±SEM values) in plasma concentration of arginine (Fig 4a), citrulline (fig 4b), glutamine (Fig 4c), and ornithine (Fig 4d) after meal intake (difference between postprandial and postabsorptive values), in the breast cancer group (black bar) and the healthy control group (open bar) before and within 24 hours after surgery. Two-factor repeated-measures ANOVA was used to test the Group (G) and Surgery (S) effect. There was a Surgery effect for plasma concentration of arginine (P<0.001), citrulline (P=0.06) and ornithine (P<0.01). There was a Group effect for plasma concentration of citrulline (P<0.05) and glutamine (P=0.08). There was no Surgery X Group interaction.