Exogenous nitric oxide modulates the systemic inflammatory response and improves kidney function after risk-situation abdominal aortic surgery.
OBJECTIVE
Renal impairment is a very frequent complication of aortic surgery requiring prolonged suprarenal clamping, especially if it is associated with previous hemorrhage. The aim of this study was to assess the beneficial effect of the administration of a nitric oxide (NO) donor on renal function through a modulation of the systemic inflammatory response in a model of abdominal aortic surgery.


METHODS
Twenty-five minipigs were divided into five groups. Under anesthesia, the animals were subjected to suprarenal aortic-iliac clamping (for 30 minutes) and bypass with a Dacron-collagen prosthetic graft impregnated in rifampicin, with or without associated hemorrhage (40% of total blood volume). Prophylaxis with cefazolin was implemented. The five groups were (1) the sham group (only aortic dissection), (2) the clamping and bypass (C) group, (3) hemorrhage preclamping and bypass (H+C) group, (4) the same as group C but with the administration of the NO donor molsidomine (4 mg/kg intravenously) (C+NO group), (5) the same as the H+C group but with the administration of the NO donor molsidomine (4 mg/kg intravenously) (H+C+NO group). The following were determined: (1) kidney function (serum creatinine), (2) serum cytokines (tumor necrosis factor alpha [TNF-alpha] and interleukin-10 [IL-10]); (3) neutrophil infiltration (myeloperoxidase [MPO]) in the kidney, (4) oxygen free radicals (superoxide anion [SOA] and superoxide dismutase [SOD]) in the kidney, (5) serum nitrites, (6) soluble and kidney tissue cell adhesion molecule (soluble intercellular adhesion molecule-1 [sICAM-1], soluble vascular cell adhesion molecule-1 [sVCAM-1], intercellular adhesion molecule-1 [ICAM-1], and vascular cell adhesion molecule-1 [VCAM-1]), (7) inducible nitric oxide synthase (iNOS) in the kidney, and (8) nuclear factor-kappaB (NF-kappaB) in the kidney. Determinations were made during ischemia at 15 minutes post-reperfusion; at 24, 48, and 72 hours; and on day 7.


RESULTS
The different insults used in the experimental model led to deterioration in kidney function and an increase in the systemic (and renal) inflammatory response at all levels investigated. Treatment with an NO donor, both with and without associated hemorrhage, reduced the inflammatory response at the systemic (TNF-alpha and IL-10) and kidney (MPO, SOA, and SOD) levels, normalizing kidney function. Likewise, exogenous administration of NO improved the excessive production of NO (nitrites) via iNOS. This was also reflected in a reduction in CAMs and of NF-kappaB expression. The hypotension induced by molsidomine was transitory and did not elicit hemodynamic repercussions.


CONCLUSIONS
In our experimental model, prophylactic treatment with the NO donor molsidomine regulates the systemic inflammatory response and minimizes damage at the kidney level. Clinical Relevance The importance of this article resides in the fact that an experimental study that clarifies the effect of the donors of NO under circumstances as similar as possible to those of the human clinic, such as aortic surgery under hypovolemic shock (ruptured aortic aneurysm) have been little studied, most of these studies being performed in rodents without bypass. Using a model with one or two simultaneous insults (aortic clamping with/without previous hemorrhage) that is very similar to the human clinical situation (abdominal aortic rupture), we confirm the findings of previous work related to the beneficial effects of NO donors.
Lozano
Francisco S
FS
Angiology and Vascular Surgery Service, University Hospital of Salamanca, Spain. marcellobb@bol.com.br
López-Novoa
José M
JM
Rodriguez
José M
JM
Barros
Marcello B
MB
García-Criado
Francisco J
FJ
Nicolás
Juan L
JL
Parreño
Alvaro
A
Revilla
José
J
Gómez-Alonso
Alberto
A
D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000503:physiopathology / Q000601:surgery*; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D007668:Kidney / Q000187:drug effects*; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology; D008297:Male; D008981:Molsidomine / Q000494:pharmacology* / Q000627:therapeutic use; D016328:NF-kappa B / Q000097:blood; D020030:Nitric Oxide Donors / Q000494:pharmacology* / Q000627:therapeutic use; D009195:Peroxidase / Q000097:blood; D015427:Reperfusion Injury / Q000517:prevention & control; D013552:Swine; D013556:Swine, Miniature; D018746:Systemic Inflammatory Response Syndrome / Q000517:prevention & control; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood
D016328:NF-kappa B; D020030:Nitric Oxide Donors; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D016753:Interleukin-10; D003404:Creatinine; D008981:Molsidomine; D009195:Peroxidase