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J Thorac Cardiovasc Surg 2003;125:661-668
© 2003 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Increased matrix metalloproteinase activity after canine cardiopulmonary bypass is suppressed by a nitric oxide scavenger

From Departments of Medicine^a and Pharmacology,^c University of Alberta, Edmonton, Alberta, Canada, AnorMED,^e Langley, British Columbia, and the Departments of Medicine^b and Anaesthesia,^d University of Saskatchewan, Saskatoon, Saskatchewan, Canada.

Supported by an unrestricted grant from AnorMED and by a grant from the Saskatchewan Heart and Stroke Foundation. MWR is a Canadian Institutes of Health Research Scientist.

Received for publication Feb 15, 2002. Revisions requested April 30, 2002; revisions received June 23, 2002. Accepted for publication Aug 22, 2002. Address for reprints: Irvin Mayers, MD, Department of Medicine, Room 2E4.38, Walter C Mackenzie Health Sciences Centre, Edmonton, Alberta, Canada T6G 2B7 (E-mail: imayers{at}ualberta.ca).

Objectives: 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). Ca²⁺-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 Ca²⁺-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.

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