Increased matrix metalloproteinase activity after canine cardiopulmonary bypass is suppressed by a nitric oxide scavenger.
OBJECTIVE
We tested whether nitric oxide scavenging with a ruthenium-based compound (AMD6221) would improve hemodynamics and alter nitric oxide synthase and matrix metalloproteinase activities in a canine model of cardiopulmonary bypass.


METHODS
Dogs were randomized to either cardiopulmonary bypass (n = 12) or control (n = 12) groups. They were further randomized to receive a continuous infusion of AMD6221 or placebo. Cardiopulmonary bypass was maintained for 90 minutes, and then, 4 hours later, dogs were killed. Cardiac, lung, and brain sections were snap frozen in liquid nitrogen for determination of nitric oxide synthase, matrix metalloproteinase 2, and matrix metalloproteinase 9 activities.


RESULTS
After cardiopulmonary bypass, 3 of 6 placebo-treated (cardiopulmonary bypass-placebo) and 0 of 6 AMD6221-treated (cardiopulmonary bypass-6221) animals required phenylephrine infusion to maintain a predetermined blood pressure (P <.05). Total fluid administration was lower in the cardiopulmonary bypass-6221 group compared with that in the cardiopulmonary bypass-placebo group (983 +/- 134 vs 1617 +/- 254 mL, respectively; P <.005). After cardiopulmonary bypass, matrix metalloproteinase 2 and matrix metalloproteinase 9 activities in the lung, left ventricle, and left atrium were decreased in the cardiopulmonary bypass-6221 group compared with that in the cardiopulmonary bypass-placebo group (P <.05). Ca(2+)-independent nitric oxide synthase activity and matrix metalloproteinase 2 activity in the brain were also lower (P <.05) in the cardiopulmonary bypass-SCV group. Finally, neutrophil expression of CD18, an adhesion complex, was lower at 4 hours after cardiopulmonary bypass in the cardiopulmonary bypass-6221 group compared with that in the cardiopulmonary bypass-placebo group (38 +/- 27 vs 81 +/- 11; P <.05).


CONCLUSIONS
We found that (1) infusion of an nitric oxide scavenger, AMD6221, was associated with improved predefined hemodynamics; (2) cardiopulmonary bypass increased activities of Ca(2+)-independent nitric oxide synthase and matrix metalloproteinases in multiple organs; and (3) AMD6221 could ameliorate the increased generation of nitric oxide and increased matrix metalloproteinase activities.
Mayers
Irvin
I
Department of Medicine, University of Alberta, Edmonton, Canada. imayers@ualberta.ca
Hurst
Thomas
T
Radomski
Anna
A
Johnson
David
D
Fricker
Simon
S
Bridger
Gary
G
Cameron
Beth
B
Darkes
Marilyn
M
Radomski
Marek W
MW
D000818:Animals; D001923:Brain Chemistry; D018821:CD18 Antigens / Q000276:immunology; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D004195:Disease Models, Animal; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use*; D006331:Heart Diseases / Q000209:etiology* / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D006439:Hemodynamics / Q000187:drug effects; D007249:Inflammation; D007262:Infusions, Intravenous; D008168:Lung / Q000737:chemistry; D020778:Matrix Metalloproteinase 2 / Q000032:analysis / Q000187:drug effects* / Q000276:immunology*; D020780:Matrix Metalloproteinase 9 / Q000032:analysis / Q000187:drug effects* / Q000276:immunology*; D009206:Myocardium / Q000737:chemistry; D009504:Neutrophils / Q000276:immunology; D009569:Nitric Oxide / Q000276:immunology*; D019001:Nitric Oxide Synthase / Q000187:drug effects* / Q000276:immunology*; D052248:Nitric Oxide Synthase Type I; D009942:Organometallic Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D004369:Pentetic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
C453459:AMD 6221; D018821:CD18 Antigens; D016166:Free Radical Scavengers; D009942:Organometallic Compounds; D009569:Nitric Oxide; D004369:Pentetic Acid; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9