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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

Irvin Mayers, MDa, Thomas Hurst, MVSb, Anna Radomski, MDc, David Johnson, MD, MPHd, Simon Fricker, PhDe, Gary Bridger, PhDe, Beth Cameron, PhDe, Marilyn Darkes, BSce, Marek W. Radomski, MD, PhDc

From Departments of Medicinea and Pharmacology,c University of Alberta, Edmonton, Alberta, Canada, AnorMED,e Langley, British Columbia, and the Departments of Medicineb 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).


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
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.


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Cardiopulmonary bypass (CPB) initiates an inflammatory injuryGo 1 associated with increased proinflammatory cytokines.Go 2 Proinflammatory cytokines can activate downstream signaling, leading to generation and release of other inflammatory mediators. We showed that activities of 2 enzyme families, nitric oxide synthase (NOS) and gelatinases (matrix metalloproteinase [MMP] 2 and MMP-9) are increased in human myocardial tissue after CPB.Go 3 Increased MMP activities and increased NOS products are independently associated with cardiac dysfunction.Go Go 4,5 A new class of drugs that binds plasma nitric oxide (NO) to the metal ruthenium have been recently developed.Go 6 In the current study we showed that treatment with AMD6221, an NO scavenger, can ameliorate some of the CPB-induced increases in MMPs and improve postoperative hemodynamics.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Animal preparation
These studies were approved by the University of Saskatchewan Animal Care Committee and complied with published National Institutes of Health guidelines. Mongrel dogs (weight 20-25 kg) were anesthetized with pentobarbital (15 mg/kg), intubated, and mechanically ventilated (Harvard Model 607). Anesthesia was maintained by means of continuous infusion of pentobarbital (1.0 mg x kg-1 x h-1), morphine (0.1 mg x kg-1 x h-1), and vecuronium bromide (0.1 mg x kg-1 x h-1). A pulmonary artery catheter was used to measure mean pulmonary artery pressure, pulmonary capillary wedge pressure, mean right atrial pressure (PRA), and cardiac output (CO). Mean systemic artery pressure (PSA) and arterial blood gas sampling were obtained through a femoral artery catheter.

We have previously described our CPB model.Go 7 Briefly, the heart was exposed through a midline sternotomy. After heparinization (5000 U administered intravenously followed by 1000 U/h administered intravenously), catheters were placed in the left and right atria to complete the bypass circuit. A balloon angioplasty catheter (6F) positioned proximal to the aortic valve through the right internal carotid artery acted to internally crossclamp the aorta when inflated. CPB was initiated by using a membrane oxygenator (Capiox Hollow Fiber Oxygenator) and a blood pump (Sarns Model 5000 Console) at 100 mL/kg flow. Cold (7°C-8°C) antegrade cardioplegia solution was delivered, and then the aorta was occluded by means of inflation of the angioplasty balloon. Blood cardioplegia (BCD4 Sharely), initially with 30 mEq of KCl and subsequently decreasing the concentration to 10 mEq of KCl, was continuously administered to eliminate electrical activity. The animals were cooled (24°C), and the aortic occlusion was maintained for a further 50 minutes. Before deflating the aortic balloon, 150 mL of warm cardioplegic solution without KCl supplementation was administered. Then the angioplasty balloon was deflated, mechanical ventilation was resumed, and the animals were warmed over 30 minutes. Therefore CPB lasted a total of 90 minutes. We prospectively chose to maintain PSA at greater than 60 mm Hg by first increasing PRA to 15 mm Hg by means of fluid administration and then infusing phenylephrine. The animals were maintained for 4 hours after CPB.

Experimental groups
Dogs were randomized to CPB (n = 12) or control (n = 12) groups. Dogs receiving CPB were further randomized to receive a continuous infusion of AMD6221, an NO scavenger (CPB-6221 group, n = 6), or to receive a placebo (CPB-placebo group, n = 6). AMD6221 was continuously infused (128 mg x kg-1 x h-1), starting before the sternotomy and ending 30 minutes after termination of CPB (Figure 1). We selected this dose on the basis of pilot data that examined the efficacy of AMD6221 as an NO scavenger (data not shown).



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  		Fig. 1. Mean ± SD values of Ca2+-dependent and Ca2+-independent NOS activity. Values are shown for the left atrium and left ventricle. *Significant difference (P < .05) between CPB (filled bars) and control (open bars) groups. #Significant difference between control and AMD6221-treated groups (P < .05).

 
The biochemical and physiologic effects of AMD6221 in normal dogs have previously not been characterized. Therefore we treated the control dogs to a similar protocol but did not perform a sternotomy or placement of CPB-related catheters. The drug infusions (AMD6221 or placebo) were administered over times similar to those of the CPB-treated animals. At the conclusion of the studies, all animals were killed by means of barbiturate overdose. Biopsy specimens (0.5 cm2) from the left ventricle, left atrium, lung (right lower lobe), and brain (cerebral cortex) were obtained, frozen in liquid nitrogen, and stored at -70°C until assayed (see below).

Measurements and calculations
After catheter insertions, baseline blood samples were obtained for routine hematology, biochemistry, and blood gas measurement (Table 1). Hemodynamic measurements, including CO, PSA, pulmonary artery pressure, pulmonary capillary wedge pressure, mean left atrial pressure, and PRA, were repeated at 1 and 4 hours after bypass and as needed to maintain our predetermined hemodynamic goals. Neutrophil expression of CD18 was measured with flow cytometry (FACScan), as previously described.Go 8 Briefly, after cells were prepared, they were incubated with an irrelevant, isotype-matched, FITC-conjugated rat monoclonal antibody (MCA1125F, Serotech Ltd) or FITC-conjugated rat anti-human CD18 antibody (MCA503F, Serotech) that cross-reacted with canine. Flow cytometric analysis was restricted to neutrophils on the basis of forward-angle and right-angle light scatter. Neutrophil CD18 expression was determined as the percentage of cells with a fluorescence exceeding that of cells reacted with the irrelevant isotype-matched control.


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  		Table 1. Selected hemodynamic values
 
NOS activity was measured in homogenized tissue samples, as previously described.Go 9 Briefly, tissue aliquots were incubated with L[U-14C]-arginine (Amersham) for 20 minutes in the appropriate buffer. NOS-dependent L-citrulline formation expressed as picomoles per minute per milligram of protein was used as an index of enzyme activity. A Ca2+-chelating agent (ethyleneglycol-bis-[ß-aminoethylether]-N,N,N,N-tetraacetic acid, 1 mmol/L) was used to differentiate between Ca2+-dependent and Ca2+-independent NOS activities of enzymes. Tissue MMP activity was measured by means of zymography, as previously described,Go 10 by using 7% SDS-PAGE with copolymerized gelatin as a substrate. Enzyme activity was expressed as arbitrary units per milligram of protein. Tissue NOS and MMP activities were obtained at only one time point, and that was after the animals were killed.

Statistics
Data (means ± SD) were compared between periods and groups with a 1-way or 2-way analysis of variance, as appropriate, and when the F statistic showed a significant difference, a Student-Newman-Keuls multiple comparison test was used to determine specific group and period differences. We prospectively limited the possible number of comparisons to limit required correction factor. Spearman correlation was used to assess the interaction between CD18 expression and NOS or MMP activity.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Hemodynamics and gas exchange
PSA and CO decreased, whereas systemic vascular resistance increased over time in the CPB groups (Table 1Go). To achieve our predefined hemodynamic end points (PSA >=60 mm Hg and PRA <=15 mm Hg), 3 of 6 CPB-placebo animals required a phenylephrine infusion compared with 0 of 6 the CPB-6221 animals (P < .05). Total fluid administration was reduced in the NO scavenger groups compared with that in the placebo groups.

Comparing baseline values to 4 hours after CPB (Table 2), PO2 decreased in the CPB-6221 group and the CPB-placebo group (P < .05), and intrapulmonary shunting increased (19% ± 10% vs 18% ± 14%, respectively; P > .05). Neutrophils, as a percentage of white blood cell counts, increased from baseline to 4 hours after CPB in the CPB-placebo group (66% ± 7% to 83% ± 5%, P = .03). CD18 expression at 4 hours after CPB was lower in the CPB-6221 group compared with that in the CPB-placebo group (P < .05).


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  		Table 2. Selected biochemical and hematologic values in all 4 groups
 
NOS and MMP activities
CPB did not significantly influence Ca2+-dependent NOS activities in heart, brain, and lung tissues (Figures 1Go and 2). However, CPB significantly increased Ca2+-independent NOS activities (P < .05) compared with control groups in the heart, brain, and lung. Administration of AMD6221 did not significantly influence NOS activities in the lung, ventricular, or atrial samples (Figure 2Go), but brain Ca2+-independent NOS activity was significantly reduced (P < .05) in the CBP-6221 group compared with in the CPB-placebo group. MMP-2 and MMP-9 activities were significantly (P < .05) increased in the CPB-placebo group compared with in the control-placebo group in the heart and lung (Figure 3). Only MMP-2 was significantly (P < .05) increased in the brain in the CPB-placebo group compared with in the control-placebo group (Figure 4). MMP activity was significantly reduced in the CPB-6221 group compared with that in the CPB-placebo group (P < .05). MMP activity, except brain MMP-9, was positively correlated to CD18 peak expression ({rho} = 0.46-0.73, P < .005). NOS activity was not correlated to CD18 peak expression (P > .05).



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  		Fig. 2. Mean ± SD values of Ca2+-dependent and Ca2+-independent NOS activity. Values are shown for the lung and brain. Note that in the brain Ca2+-dependent NOS includes neuronal-type NOS. *Significant difference (P < .05) between CPB (filled bars) and control (open bars) groups. #Significant difference between control and AMD6221-treated groups (P < .05).

 


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  		Fig. 3. Mean ± SD values of MMP activity. Values are shown for the left atrium and left ventricle. *Significant difference (P < .05) between CPB (filled bars) and control (open bars) groups.

 


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  		Fig. 4. Mean ± SD values of MMP activity. Values are shown for the lung and brain. *Significant difference (P < .05) between CPB (filled bars) and control (open bars) groups.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
Experimental model
Our model of CPB differs in some aspects from the human setting. The dogs, unlike human subjects, did not have known preexisting heart disease. Intraoperative bypass grafting was not performed, and aortic flow was occluded with an internal rather than external crossclamp. We previously showed that sham bypass can independently activate inflammatory pathways,Go 8 and therefore our control animals were not subjected to sham CPB. Within these limitations, our findings are representative of the human CPB procedure. Of note, the myocardial changes of NOS and MMP activities in these canine studies mimic those found after human CPB.Go 3 This allows the extrapolation of these broader animal findings to the human setting.

AMD6221 represents a new class of drugs on the basis of the ability of a ruthenium(III) polyaminocarboxylate complex to react rapidly with NO to form a stable and inert ruthenium(II) nitrosyl complex. The effects of AMD6221 on NO have been studied by using a murine macrophage cell line.Go 11 AMD6221 was shown to rapidly and irreversibly bind NO without influencing inducible NOS (iNOS) activity or iNOS expression. These compounds might have other unforeseen actions, but it is clear that they can selectively bind NO and thereby reduce plasma NO concentrations.

NOS and CPB
The NOS family of enzymes includes calcium-dependent (neuronal-type NOS and endothelial-type NOS) and calcium-independent (iNOS) isoenzymes.Go 12 We hypothesized that increased proinflammatory cytokinesGo 2 can activate downstream inflammatory enzymes (eg, iNOS, MMP-2, and MMP-9) and contribute to the myocardial dysfunction that commonly follows CPB.Go 13 We have previously shown that increased NO delivery can reduce expression of neutrophil adhesion complex CD18.Go 7 In contrast, our current findings that an NO scavenger also decreases CD18 expression are novel and suggest that the source of NO is important in the modulation of CD18 expression. Excessive NO generation by iNOS is also associated with formation of peroxynitrite, a potent oxidant. Peroxynitrite exerts a dual effect on blood-cell adhesion because low concentrations of peroxynitrite decrease and high concentrations increase leukocyte and platelet activation.Go 14 Thus adhesion-inhibitor effects of pharmacologic NO could result from its antioxidant properties,Go 15 whereas scavenging of inducible NO by AMD6221 could decrease excessive peroxynitrite generation and leukocyte activation.

Proinflammatory cytokines are increased after CPBGo 2 and can induce cardiac iNOS,Go 16 which in turn impairs cardiac function.Go 17 Excessive cardiac NO decreases cardiac contractilityGo 18 through activation of cyclic guanosine monophosphate-dependent protein kinases or through increased peroxynitrite formation.Go 5 There is a balance between excessive and insufficient NO needed to achieve optimum cardiac function.Go Go 19,20 We therefore hypothesized that an NO scavenger restricted to the intravascular space could prevent injurious excessive NO but still allow regional vasoregulation. In addition, scavenging by AMD6221 is favored in high concentrations of NO because the reaction between the scavenger and NO is second order,Go 22 thereby reducing excessive NO with less effect on basal NO concentrations. Our findings of improved hemodynamics in the AMD6221-treated CPB group are consistent with this hypothesis. That AMD6221 does not affect iNOS activity in the heart and lung is also in keeping with previous cell-culture findings.Go 10 We cannot explain the decrease in brain iNOS activity but speculate that it might be as a result of altered feedback control of brain iNOS.

MMPs and heart function
In the current study we have shown that MMP-2 and MMP-9 activity in the heart is increased after CPB. Increased MMP activity, in turn, is associated with decrements in cardiac function that might, in part, be due to degradation of sarcomeres with resultant disorganization of the contractile apparatus.Go 23 There is extensive literature documenting that altering the balance between MMPs and tissue inhibitor of metalloproteinases toward increased MMP activity plays a pathophysiologic role in the progression of cardiac dysfunction in congestive heart failure.Go 4 We have previously shown that increased NOS, MMP-2, and MMP-9 activities are found within myocytes after CPB.Go 3 In the same study we also found that tissue inhibitor of metalloproteinases 4 expression is decreased, thus concluding that CPB results in relatively unopposed increases in myocardial MMP activities. We therefore now speculate that increased iNOS activity increases plasma NO, which in turn upregulates cardiac MMP activity. We further speculate that administration of the NO scavenger AMD6221 by reducing plasma NO prevents this cardiac upregulation of MMP activities and thereby reduces postoperative cardiac dysfunction.

Noncardiac organ injury
Our findings of increased cardiac iNOS activity support prior observations of CPB-associated increases of NO generation,Go 25 and we have now extended these observations to other organs, including brain and lungs. We have now shown that CPB is associated with increased iNOS activity in brain tissue. Although we do not have direct evidence that iNOS in this setting causes brain injury, there is evidence in another model that increased NO production worsens cerebral function.Go 26 We have found that AMD6221 ameliorates the increased brain iNOS activity, suggesting that this might serve as a therapeutic target to improve neural function after CPB.

Carney and colleaguesGo 27 previously found that pharmacologic inhibition of MMPs ameliorated a porcine lung injury after CPB. Our findings of increased MMP-2 and MMP-9 activity after CPB confirm the biologic basis for the relevance of their findings. We have extended these observations to also show that MMP-2 activity is increased in brain samples after CPB. These observations link human brain injury (eg, cerebral edemaGo 28 and neuronal dysfunctionGo 29) after CPB with the cellular changes (increased NOS and MMP-2 activities) capable of causing these gross changes.

NOS and MMP as therapeutic targets
The pharmacologic inhibition of these inflammatory enzymes could be clinically beneficial in preventing organ dysfunction after CPB. We have previously shown that infusion of GSNO, an NO donor, could ameliorate some of the adverse sequellae of CPB.Go 7 We now show that scavenging circulating NO can also improve hemodynamics and decrease selected inflammatory enzymes activities. The hemodynamic parameters we chose (mean blood pressure of >60 mm Hg with a PRA of at least 15 mm Hg) are similar to the clinical parameters routinely followed after human coronary artery bypass grafting surgery. The AMD6221-treated animals were able to reach these end points with decreased requirements for intravenous fluids, despite decreased requirements for phenylephrine compared with those in the placebo-treated animals. This suggests that the NO scavenging improved vascular tone, reduced intravascular fluid transudation, or both. In addition, neutrophil CD18 surface expression was decreased in the NO scavenger-treated animals. Decreased neutrophil adhesion can also reduce CPB-associated organ dysfunction.Go 8

We have also shown that systemic infusion of that NO scavenger can decrease MMP-2 activity in the brain after CPB. This might be mediated through decreased peroxynitrite production because peroxynitrite is known to induce MMP activity.Go 21

In summary, there is a complex relationship among these inflammatory mediators. The treatment with AMD6221 was able to influence several aspects of the systemic inflammatory response after CPB. These potentially beneficial events occurred without adversely affecting systemic vascular resistance or CO. Therefore NO scavengers might represent a new class of compounds to reduce the adverse effects of CPB.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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