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Ann Thorac Surg 2004;77:2130-2137
© 2004 The Society of Thoracic Surgeons

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Original article: cardiovascular

Changes in mesenteric vascular reactivity and inflammatory response after cardiopulmonary bypass in a rat model

^a Department of Thoracic and Cardiovascular Surgery, Rouen University Hospital, Rouen, France
^b Inserm 9920, Rouen University Medical School, Rouen, France
^c Department of Biostatistics, Rouen University Hospital, Rouen, France

Accepted for publication October 8, 2003.

^* Address reprint requests to Dr Doguet, Department of Thoracic and Cardiovascular Surgery, Charles Nicolle Hospital, 1 rue de Germont, 76031 Rouen Cedex, France
e-mail: chirurgie.thoracique.cardio-vasculaire{at}chu-rouen.fr

	Abstract

Top Abstract Introduction Material and methods Results Comment Conclusion Acknowledgments References

 
BACKGROUND: Mesenteric ischemia and acidosis leading to intestinal ischemia has been observed during cardiopulmonary bypass (CPB) despite normal flow in the mesenteric vessels. The aim of this study was to assess mesenteric endothelium-dependent reactivity and vasoconstrictor responses of small mesenteric arteries in a rat model of CPB without aortic cross-clamping.

METHODS: After femoral cannulation a partial 90 minutes CPB was performed with hemodynamics and blood gas parameters monitoring. Blood samples and segments of small mesenteric arteries were obtained in rats sacrificed 2.5 hours (CPBH2.5) or 6 hours (CPBH6) after femoral cannulation. Sham surgery (sham H2.5, sham H6) was performed with femoral cannulation only. Segments of small mesenteric arteries were placed in a myograph in order to assess the contractile response to phenylephrine (with or without NO synthase inhibitor) or the endothelium-dependent relaxation to acetylcholine. Systemic inflammation was evaluated by measuring plasma concentrations of TNF. Pulmonary and intestinal infiltration of activated leukocytes was assessed by immunohistochemistry.

RESULTS: CPB induced increased contractile response to phenylephrine which persisted after blockade of NO synthesis as well as transient impairment of endothelium-dependent relaxations. CPB also led to early and marked release of TNF.

CONCLUSIONS: CPB was responsible for mesenteric endothelial dysfunction and direct increase in the contractile response to 1-adrenergic agonist with increased systemic inflammatory response. This phenomenon might contribute to an increase in the risk of mesenteric ischemic events during cardiac surgery especially when vasopressor agents are used.

	Introduction

Top Abstract Introduction Material and methods Results Comment Conclusion Acknowledgments References

 
Cardiopulmonary bypass (CPB) has been shown to be associated with systemic inflammatory response leading to postoperative organ dysfunction [1, 2]. Blood interaction with extracorporeal circuit artificial surfaces activates humoral and cellular inflammatory cascades and may contribute to this dysfunction [3–5].

CPB causes complement activation with release of C3a and C5a fractions which may increase vascular permeability, vasoconstriction, neutrophil activation, and induce cytokine expression (tumor necrosis factor [TNF], interleukin [IL]-1 to 6–8). TNF and IL-1 induce vasodilatation and expression of specific adhesion molecules such as E-selectin and intercellular adhesion molecule-1 (ICAM-1) promoting adhesion of leukocytes to endothelial cells [6–8].

Mesenteric ischemia and acidosis leading to bowel ischemia have been observed during CPB despite normal flow in the mesenteric vessels [9]. Mesenteric ischemia represents 5%–27% of abdominal complications occurring after CPB with a mortality of 30%–93% [10]. Approximately 25% of these ischemic complications result from splanchnic hypoperfusion and vasospasm [10, 11].

Bowel ischemic injury has been attributed to regional hypoperfusion secondary to hypotension during CPB [12]. Vasopressor agents may increase intestinal ischemia despite improvement of perfusion pressure [13]. The possible contribution of endothelial dysfunction and/or changes in vascular reactivity in these complications are relatively unknown.

Vascular endothelium is the interface between blood and the vascular wall and plays a major role in the regulation of inflammatory response and smooth muscle cells tone. Vasomotor tone results from the interaction of circulating substances, components of vascular wall, and surrounding tissue. Production of vasomotor substances modulate the balance between vasoconstriction and vasodilatation. As NO inhibits endothelial neutrophil adhesion and reduces expression of adhesion molecules (ICAM-1, vascular cell adhesion molecule-1 [VCAM-1]), a decrease in its production could trigger an inflammatory response. This is particularly true in a context of mesenteric ischemia which causes microvascular mesenteric endothelial dysfunction and activates inflammation [14–17].

Only a few studies [18] have been focused on evaluating the effects of contact between blood and circuit in the absence of ischemia and its consequences on mesenteric vascular function. The aim of our study was to assess the changes in mesenteric vascular reactivity and inflammatory response induced by blood and circuit contact in a rat model of partial CPB.

	Material and methods

Top Abstract Introduction Material and methods Results Comment Conclusion Acknowledgments References

 
All circuits were sterilized and used only once. A polyvinyl chloride (PVC) miniature extracorporeal circuit was made (internal diameter: 2.5 mm and length: 60 cm [group Cair LGL, Civrieux d'Azergues, France]) and connected to a Gambro roller pump (Fresenius, France) equipped with silicon tube (internal diameter: 5 mm, length: 20 cm [Raumedic, Rehau, Germany]). A 20 ml syringe was used as cardiotomy reservoir. A pediatric oxygenator membrane, Capiox 308 (Terumo Corporation, Osaka, Japan), was modified with two silicon caps [19]. The priming volume was reduced to 45 ml comprising 20 ml of fresh arterial blood drawn from rats used as donors and 25 ml of gelatin solution, Gelofusine 4% (B-Braun Medical Ltd., Boulogne, France). A blood flow of 100 ml · kg^–1 · min^–1 was achieved in the circuit. Pure oxygen was delivered to the membrane oxygenator at a flow of 75 ml/min adjusted to blood gases.

Surgical procedure
Male Wistar rats (Charles River, Saint Aubin Les Elbeuf, France) weighing 470 ± 10 g were anesthetized with intramuscular ketamine (80 mg/kg) and chlorpromazine chlorhydrate (2 mg/kg). Reinjections were performed every hour through the right jugular vein. The rats were paralyzed with pancuronium bromide (1 mg/kg) and were continuously ventilated orally (Ugo Basile, Biological Research Apparatus, Comerio, Varese, Italy) with an 18 G tracheal tube. Heart rate (HR) and mean arterial pressure (MAP) were monitored continuously on a Gould ES2000 recorder (Gould, Ballainvilliers, France). Blood temperature and rat body temperature were maintained with heating lights and controlled by esophageal temperature monitoring. Arterial blood gases, taken from the right carotid artery, were determined at 0, 30, 60, 90, and 180 minutes.

CPB procedure
Partial CPB was instituted by femoral vessels cannulation. Femoral vein and femoral artery were exposed and respectively cannulated with 16G and 22G heparinized catheters (Terumo Corporation, Osaka, Japan). Heparin was administered: 250 IU/kg for the study rat and the same dose in the priming. All animals received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" (National Institute of Health Publication No. 85 to 23, revised 1985).

Experimental procedure
Four groups of 6 rats were constituted: two groups underwent 90 minutes CPB and two groups of sham surgery with only femoral cannulation (Fig 1). CPB H2.5: sacrifice was done 1 hour after cessation of CPB, ie, 2.5 hours after cannulation. CPB H6: sacrifice was done 4.5 hours after cessation of CPB, ie, 6 hours after cannulation. Sham H2.5: sacrifice was done 2.5 hours after cannulation. Sham H6: sacrifice was done 6 hours after cannulation.

View larger version (13K): [in this window] [in a new window]   Fig 1. Experimental procedure. (CPB = cardiopulmonary bypass.)

In order to eliminate any possible effect in TNF due to transfusion, we assessed the TNF level 2.5 hours after blood transfusion in a separate control group. Measurements were performed for 4 rats.

Just before sacrifice a laparotomy was performed and a section of mesenteric loop was removed and immediately immersed into cold oxygenated physiologic crystalloid control solution composed of the following (mM/L): NaCl 118.3, KCl 4.7, CaCl₂ 2.5, NaHCO₃ 25, MgSO₄ 1.2, KH₂PO₄ 1.2, ethyl diamine tetetric acid (EDTA) 0.02, and glucose 11.1. A third-order division segment of the mesenteric artery was dissected under microscope. Arterial segments 1.5–2 mm long were obtained distal to the occlusion site and mounted on a myograph for isometric tension recording (JP Trading, Aarhus, Denmark). One section was connected to a tension transducer and the other was mounted on a displacement device operated with a micromanometer. During the mounting process the myograph chamber was filled with cold oxygenated (95%O₂–5%CO₂, pH 7.4, 4°C) solution. After balance adjustment the vessels were progressively stretched by 1 mN increments using the micromanometer. The corresponding measured force was read and wall tension calculated by dividing this force by vessel length. Internal circumference (IC) of the arterial segment was calculated for each level of stretch using the micromanometer. The Laplace law was used to calculate the effective pressure. The stepwise distention was stopped when the effective pressure was above 100 mm Hg. The relation between effective pressure and IC was fitted to an exponential curve using computer software and the circumference of the vessel corresponding to a transmural pressure of 100 mm Hg was calculated. The vessels were then set to a normalized IC equal to 0.9 x IC₁₀₀ which corresponded to the IC for which the active contraction is maximal. Internal diameters (ID) of the arteries were then calculated as ID₁₀₀=IC₁₀₀/. After normalization the vessels were allowed to settle for 30 minutes during which the chamber temperature was progressively increased to 37°C.

After another 60 minute adjustment period during which the vessels were washed segments were exposed to increasing concentrations of phenylephrine (10^–8–10^–5 mol/L) with or without NO synthase inhibitor N^G-nitro L-arginine (L-NA; 10^–5 mol/L). Relaxations to acetylcholine (10^–8–3.10^–5 mol/L) or the NO donor sodium nitroprusside (SNP; 10^–8–3.10^–5 mol/L) were assessed in arteries precontracted by phenylephrine. Vascular samples were washed twice and allowed to settle for 30 minutes between each measurement. Concentration response curves are expressed as final molar concentration in the chamber. All drugs were obtained from Sigma (la Verpillère, France).

Evaluation of inflammatory response
At cannulation (TNF₀) and at sacrifice (TNF₁), blood samples were obtained through the venous cannula and were immediately centrifuged at 10.000 G for 20 minutes. Plasma aliquots were stored at –80°C (liquid nitrogen) for TNF concentration measurement. After filtration through a 0.22 mm filter, TNF concentration was measured with an immunoassay kit (rat TNF Ultrasensitive Elisa) (Biosource International Cytoscreen, Camarillo, CA). The minimal detectable dose of TNF was less than 0.7 pg · ml^–1.

At time of sacrifice, left lung and intestine samples were collected and stored at –80°C (liquid nitrogen) for immunohistochemistry with anti-CD45 antibody (Cliniscience, Ambion, France) and histology (hemotoxyline-eosine staining).

Data analysis
All results are expressed as mean ± standard error of the mean (SEM). In all in vitro experiments, n refers to the number of animals from which arteries were taken. In vitro microvessels reactivity data and hemodynamic data were analyzed for group differences respectively at each concentration of drug and at each time of the study using a Student t test. A p value less than 0.05 was considered statistically significant. Statview version 5.0 (SAS Institute Inc., Cary, NC) was used for data analysis.

	Results

Top Abstract Introduction Material and methods Results Comment Conclusion Acknowledgments References

 
Values of arterial oxygen (PaO₂), carbon dioxide (PaCO₂) pressures and pH are shown in Table 1. There were no significant differences between CPB and sham groups. Values of hemoglobin were significantly lower in the CPB groups compared with the sham groups due to hemodilution induced by the priming volume of CPB circuit (p < 0.0001).

View larger version (16K): [in this window] [in a new window]   Fig 2. Mean values ± standard error of the mean of heart rate according to the time. *p < 0.05 cardiopulmonary bypass (CPB) versus sham at T90, T105, T150; +p = 0.001 CPB versus sham at T120.

Compared with sham rats contractile responses to phenylephrine were significantly increased in the two CPB groups for 3.10^–6 M concentration (p = 0.007 CPB H2.5 vs. sham H2.5 and p = 0.025 CPB H6 vs. sham H6). There were no differences in the maximal contractile responses obtained at the 10^–5 M concentration (Fig 3). Contractile responses to phenylephrine increased in all groups in presence of the NO synthase inhibitor L-NA (Fig 4).

View larger version (11K): [in this window] [in a new window]   Fig 3. In vitro contraction responses of noncontracted ileal microvessels to phenylephrine. Contractions are expressed in gram (mN/mm) *p = 0.007 cardiopulmonary bypass (CPB) H2.5 versus sham H2.5 at 3.10–6 M; +p = 0.025 CPB H6 versus sham H6 at 3.10–6 M.

View larger version (12K): [in this window] [in a new window]   Fig 4. In vitro contraction responses of noncontracted ileal microvessels to phenylephrine after infusion with NG-nitro L-arginine (L-NA) in the organ bath. Contractions are expressed in gram (mN/mm). *p = 0.008 cardiopulmonary bypass (CPB) H2.5 versus sham H2.5 at 3.10–6 M; +p = 0.009 CPB H6 versus sham H6 at 3.10–6 M.

Compared with sham rats the responses to acetylcholine were significantly lower in the CPB H2.5 group for concentrations ranging from 3.10^–8 M–3.10^–5 M.(Fig 5) In contrast, the relaxations to acetylcholine did not significantly differ between the CPB H6 and sham H6 groups. The relaxing responses to SNP were similar in all groups (Fig 6).

View larger version (13K): [in this window] [in a new window]   Fig 5. In vitro contraction responses of precontracted ileal microvessels to acetylcholine. Responses are expressed as % relaxation of phenylephrine-induced precontraction. *p < 0.05 cardiopulmonary bypass (CPB) H2.5 versus sham H2.5.

View larger version (14K): [in this window] [in a new window]   Fig 6. In vitro contraction responses of precontracted ileal microvessels to sodium nitroprusside. Responses are expressed as % relaxation of phenylephrine-induced precontraction.

View larger version (11K): [in this window] [in a new window]   Fig 7. Two mean values ± standard error of mean of tumor necrosis factor (TNF)- measurements. TNF0 was the blood sample obtained at the time of cannulation TNF1 at the end of experiment. *p < 0.0001 TNF0 versus TNF1 in all groups; +p < 0.0001 cardiopulmonary bypass (CPB) H2.5 versus sham H2.5 for TNF1.

View larger version (121K): [in this window] [in a new window]   Fig 8. Immunohistochemical analysis of pulmonary and intestinal inflammation after sham surgery or cardiopulmonary bypass (CPB). Sections were stained using a fluorescent anti-CD45 antibody. Sections from sham rats display little accumulation of polymorphonuclear neutrophil (PMN) leukocytes. In contrast, CPB was accompanied by a significant accumulation of PMN (arrows) both in the intestine and in the lung. (A) sham 2.5, lung; (B) CPB H2.5, lung; (C) sham 2.5, intestine; (D) CPB H2.5, intestine.

	Comment

Top Abstract Introduction Material and methods Results Comment Conclusion Acknowledgments References

Minimal surgical aggression by femoro–femoral cannulation without sternotomy was achieved to minimize inflammatory response due to surgical trauma. Then inflammatory response observed can be considered as mainly due to blood contact with artificial surfaces. Gu and associates [20] reported that surgical access (sternotomy), despite the absence of CPB, induced complement activation in patients who underwent off-pump coronary artery bypass grafting.

In our partial CPB model, without aortic clamping, systolo–diastolic blood flow was preserved avoiding ischemia/reperfusion injury in the mesenteric territory. Ischemia/reperfusion increased oxidative stress and oxygen free radical generation which contributes to increase endothelial dysfunction and inflammatory response.

Hemodynamic results showed that MAP was lower at the time of cannulation. In CPB groups the time required to prepare the extracorporeal circuit led to a different level of anesthesia which could explain these results despite a similar anesthesia procedure. Heart rate increased in the CPB groups at the end of CPB and remained higher during 1 hour (Fig 2). This phenomenon could not be explained by hemodilution. In fact HR increased at the end of CPB whereas hemodilution was already present at the start of CPB. Moreover the HR increase was directly correlated with the TNF peaks. Heart rate increase could be due to TNF release.

Impairment of mesenteric endothelium-dependent relaxation caused specifically by CPB was observed shortly after CPB and was transient (Fig 5). Tofukudji and associates [18] reported the role of C5a on mesenteric dysfunction after CPB. They observed an impairment of the mesenteric artery relaxation in pigs in response to ADP and substance p when comparing the sham group (sternotomy and laparotomy) and the CPB sham group (CPB without C5a antibody) suggesting a relationship between the effects of C5a and the mechanisms of endothelial dysfunction. However endothelium-independent relaxation to SNP was not altered [18]. In our study relaxing response to SNP were similar in all groups indicating no alteration in the ability of the vascular smooth muscle to relax in response to exogenous NO.

The effect of CPB on endothelial cells appears variable and may depend on the vascular territories studied. Kirshborn and associates [21] reported the effects of CPB on endothelium-dependent vasodilatation in the lung and demonstrated that CPB did not alter the responses to acetylcholine. Cooper and associates [22] obtained similar results with pulmonary veins and renal arteries. This suggests that splanchnic endothelium might be more sensitive to CPB than that in other territories.

The impairments that we observed were rather moderate and could be explained by the fact that our CPB model did not involve aortic cross-clamping and thus no ischemia/reperfusion phenomenon. Furthermore arterial pressure was maintained at normal levels and this could partly explain the moderate mesenteric endothelial injury observed.

In the present study mesenteric arteries isolated 6 hours after cannulation (CPB H6 group) showed an increased contractile response to an 1-adrenergic agonist. This increased contractile response could be secondary to a decreased production of endothelium-derived relaxing factors (NO). NO basal release continuously prevented smooth muscle cell contraction which may be explained by the increased contractile response observed in the presence of a NO synthase inhibitor.

The increased contractile response after CPB observed in our study persisted after in vitro NO synthase inhibition. This suggests that this increase is not dependent only on a decrease in NO basal release and therefore is independent of the endothelial dysfunction.

Our results are in agreement with O'Dwyer and associates [23] who reported that during CPB, phenylephrine had minimal effects on femoral vascular resistance but greater effects on the splanchnic circulation. Phenylephrine increased systemic vascular resistances although the vasoconstrictive effect was predominantly observed in visceral organs and renal cortex rather than in the femoral muscular territory [23]. These findings suggest that a marked regional perfusion disparity may exist when perfusion pressure is pharmacologically restored.

TNF measurements were performed in order to evaluate the inflammatory response induced by CPB. In our study TNF levels rapidly increased after the onset of CPB. Jansen and associates [7] demonstrated a peak of TNF values 2.5 hours after the onset of CPB. Menasché and associates [6] found an increase of C3a during CPB and a peak of TNF 2 hours after the end of CPB. No significant difference was observed before and during the 2.5 hours after transfusion.

These results suggest that TNF might be one of the triggers of the cascade production of inflammatory mediators. Cytokines are active on vascular reactivity and induction of adhesion molecules. For example, E-selectin, which is absent from inactivated endothelium, is expressed by inflammation and may be induced by TNF and IL-1. Activation of such adhesion molecules results in endothelial adhesion of polymorphonuclear neutrophiles [3, 4, 8] which have been previously implicated as major triggers of endothelial dysfunction.

We observed that the time-course of endothelial dysfunction was parallel to TNF production. TNF levels were maximal 1 hour after the end of CPB and decreased afterwards. In parallel the endothelium-dependent relaxation impairment was maximal 1 hour after the end of CPB. These results suggest that the mesenteric endothelial damage induced by CPB was related to the inflammatory response. However, during the present study, we were unable to establish which phenomenon occurred first.

In contrast we found that the time course of the increase in contractile response to phenylephrine was neither related to change in TNF levels nor endothelial dysfunction. The dissociation between endothelial dysfunction and increased contractile response is also supported by the observed effects of NO-synthase inhibitors. This suggests that the increased response to phenylephrine is not due to an altered release of NO but probably to a direct effect on smooth muscle cell contractility. Tofukudji and associates [18] studied the role of a monoclonal antibody against C5a on the contractile responses to phenylephrine. They found that C5a may have direct vasoconstrictive effects on blood vessels. Complement activation could be at the origin of mesenteric arteries hypercontractility [18].

The increase in contractile response and decrease in endothelium-dependent vasodilatation observed may have important consequences. They may contribute to increase the risk of postoperative vascular spasm or microvascular contraction in patients after cardiac surgery and may contribute to inadequate mesenteric perfusion. These local changes may also lead to the development of acidosis and transmural mesenteric ischemia. In addition endothelial dysfunction may itself be a trigger of an increased inflammatory response ultimately leading to organ dysfunction.

	Conclusion

Top Abstract Introduction Material and methods Results Comment Conclusion Acknowledgments References

 
CPB induces transient and moderate endothelial dysfunction associated with increased mesenteric artery vasoconstriction. Several risk factors and cardiovascular diseases are responsible for endothelium-dependent re-laxation impairment. Simultaneous effects of pathologic conditions and CPB on the vasculature may induce digestive complications after cardiovascular surgery which could be aggravated by vasopressor agents.

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Conclusion Acknowledgments References

 
The authors thank Richard Medeiros (Rouen University Hospital Medical Editor) for his valuable help in editing the manuscript, Jean Michel Adde for his expert technical assistance, and Terumo Laboratory for their material assistance.

	References

Top Abstract Introduction Material and methods Results Comment Conclusion Acknowledgments References

 

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