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Eur J Cardiothorac Surg 1999;15:346-352
© 1999 Elsevier Science NL

Acute pulmonary hypertension after cardiopulmonary bypass in pig: the role of endogenous endothelin

^a Laboratoire de Chirurgie Experimentale, Faculte de Medecine de Nancy, Nancy, France
^b Pharma Division, Preclinical Research, F. Hoffmann-la Roche Ltd, CH-4002 Basel, Switzerland

Received 8 June 1998; received in revised form 21 December 1998; accepted 8 January 1999.

Corresponding author. Service de Chirurgie Cardiaque et de Transplantation Cardiothoracique, C.H.U. de Brabois, Rue du Morvan, 54511 Vandoeuvre les Nancy, France. Tel.: +33-383-153-034; fax: +33-383-440-844; e-mail: jp.carteaux@chu-nancy.fr

	Abstract

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Background: Acute pulmonary hypertension occurring after cardiopulmonary bypass can be a cause of post-operative morbidity and mortality. The purpose of this study was to investigate whether bosentan, a non-peptidic mixed endothelin antagonist affected the pulmonary hypertension induced by experimental cardiopulmonary bypass. Methods: Pigs were anesthetized and instrumented to determine hemodynamic measurements. Pigs were randomized to receive either 3 mg/kg bolus+7 mg/kg per h bosentan(n=8) or saline (n=7). All pigs underwent 90 min of cardiopulmonary bypass and were further observed for a 120-min period. Results: In the control group, cardiopulmonary bypass induced a dramatic pulmonary hypertension (+78±13%, P<0.005) and accompanied an increase of pulmonary vascular resistance (+228±50%, P<0.005), whereas, in the treated group, bosentan completely prevented these deleterious effects of cardiopulmonary bypass with only a moderate decrease of systemic vascular resistance (-19±14.6%, P<0.05). Conclusions: The present findings support the hypothesis that endogenous endothelin is a mediator of acute pulmonary hypertension occurring after cardiopulmonary bypass. Bosentan, a mixed endothelin antagonist completely prevented pulmonary hypertension after cardiopulmonary bypass and may, therefore, have therapeutic applications in the management of patients following cardiac surgery.

Key Words: Acute pulmonary arterial hypertension • Cardiopulmonary bypass • Endothelin • Bosentan • Pig

	Introduction

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Acute pulmonary hypertension and elevated pulmonary vascular resistance, associated with cardiac surgery involving cardiopulmonary bypass (CPB), can be a cause of morbidity and mortality during the post-operative period [1].

Extensive contact between blood and artificial surfaces during CPB is known to activate a host of mediators, including the complement cascade, thrombin, oxygen free radicals and vasoactive mediators. This results in the activation of platelets and neutrophils. Furthermore, the diversion of pulmonary blood flow during CPB causes potential ischemia reperfusion injury of the lung.

In addition to these excessive stimuli, CPB is associated with functional alteration of the endothelial cells which may play a major role in the development of post-CPB PH [2]. Endothelial cells produce vasodilators such as nitric oxide (NO), prostacyclin (PGI₂), platelet activating factor (PAF), and vasoconstrictors such as thromboxane A₂ and endothelin 1.

Endothelin-1 (ET-1), a 21-amino acid peptide which has been identified from cultured porcine aortic endothelial cells, is the most widely distributed isoform and seems to play a major role in certain pathological situations [3]. Vasoactive effects of this peptide are mediated by at least two receptor subtypes, namely ET_A and ET_B.

Exogenous administration of ET-1 has been shown to be very effective on the pulmonary vascular bed, where it induces smooth vascular muscle cell contraction and proliferation [4].

Endogenous ET-1 production is stimulated by shear changes, hypoxia and by several agonists including epinephrine, angiotensin II, thrombin, interleukins and endotoxin [3].

Elevated plasma levels of ET-1 have been found in various pathological situations such as arteriosclerosis, systemic hypertension, chronic pulmonary hypertension, cardiogenic shock and early phase of myocardial infarction. More recently, increased plasma levels of ET-1 were observed in patients with pulmonary hypertension and congenital heart disease, or in elderly patients, during and after CPB [5].

Experimentally, ET receptor antagonists have been shown to protect against various physiopathological conditions where vasospasm namely, ischemic renal vasoconstriction, cerebral vasospasm after subarachnoid hemorrhage and hypoxic pulmonary hypertension seemed involved.

Recently, potent non-peptidic ET receptor antagonists have been synthesized [6], we tested the hypothesis that the administration of bosentan, a non-peptidic mixed antagonist (ET_A and ET_B), could be beneficial in a model of pulmonary hypertension after CPB.

	Methods

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All animals in this study received human care in compliance with the European Convention on animal care. This study was approved by our institutional ethics committee.

Generals
Domestic 3–5-month-old pigs weighing 25–35 kg were fasted overnight and premedicated with ketamine 10 mg/kg and diazepam 0.2 mg/kg, i.m. Anesthesia was induced and maintained with thiopentone sodium (initial dose of 5 mg/kg followed by a continuous infusion at a mean dose of 50–100 mg/kg per h) until the end of the experiment. The animals were intubated with a cuffed endotracheal tube and the lungs were ventilated at a minute volume of 150 ml/kg with room air and oxygen. Arterial blood gases, pH and hemoglobin determination were performed on an ABL II automated blood gas analyzer throughout the procedure (Radiometer A/S, Copenhagen, Denmark). Adjustments were made to maintain the Pa CO₂ in the range of 35 to 45 mmHg. The animals were placed in supine position. The left external jugular vein was cannulated with a flow-directed catheter placed into the right atrium to provide a suitable site for thermodilution and central venous pressure (CVP) measurements. The right external jugular vein was exposed and a Swan–Ganz catheter was passed into the pulmonary arterial to measure mean pulmonary artery pressure (MPAP), capillary wedge pressure (PCWP), and cardiac output (CO) by thermodilution (Oximetric 3 system, Abbott, France). Following mid-sternal thoracotomy, a 5.Fr high-fidelity micronanometer (Miller Instruments, Houston, Tx) was inserted into the left ventricle via a stab wound made through the apex to measure left ventricular pressure (LVP). LV first derivative of pressure (dp/dt) was calculated from the LV pressure signal, and LV(dp/dt)max was defined as the positive maximum of LV(dp/dt). An aortic catheter was inserted into the aortic arch to measure mean arterial pressure (MAP). Heart rate was calculated by a cardiotachometer triggered by arterial pressure. A circumferencial electromagnetic flow probe (2 mm, Hellige, Freiburg, Germany) was placed around an exposed portion of the proximal left anterior descending artery and was connected to a flow meter (Servmed, Hellige) for measurement of the coronary blood flow. A circumferential electromagnetic flow probe (3.5 mm, Hellige) was also placed around the left carotid for measurement of the carotid blood flow. The signals representing the hemodynamic variables described above, were recorded on a physiologic multichannel recorder (model 3800, Gould, Cleveland, OH). Systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR) were calculated using standard formulae.

Cardiopulmonary bypass
The animals were heparinized (300 IU/kg) and CPB was established with cannulation through the right atrial appendage and ascending aorta for 90 min. The CPB was achieved by using a pump (Sarns, Ann Armor, MI), a sterile bubble lung–blood oxygenator and sterile polyvinyl chloride tubing. In order to minimize the hemodilution due to the priming of the system, all tubing was adapted to make the circuit as short as possible. The priming volume of the circuit was 800 ml of saline solution. The perfusion rate was stabilized around 100–150 ml/kg. The ventilation was stopped. The pigs were cooled during 60 min to a rectal temperature of 28°C and rewarmed over 30 min to 37°C. Occasionally the heart fibrillated during CPB requiring cardioversion with 5 J. After 90 min, the ventilation was resumed, the pigs were weaned from CPB and were observed for a further 120 min period. The hemoglobin value showed an decrease during the CPB of no more than 35% as a result of hemodilution, with no further decrease during the experiment. During the post-operative CPB period, the pump reservoir blood was transfused into the pig through the arterial cannula in order to keep central venous pressure in the range of 5 to 15 mmHg. Heparin was not neutralized by protamine administration. At the end of the experiment, the animals were killed by an overdose of pentobarbital.

Radio immunoassays
Blood samples were collected throughout the study for the determination of the plasma concentration of ET-1 by radio immunoassay as described earlier [7]. Briefly, plasma (400 ml, triplicates) was extracted on Sep Pak Vac cartridges (Waters, Milford, MA). The cartridges were eluted with 2.0 ml of methanol–water (90:10, v/v). The elutes were dried in a Vortex-Evaporator (Haake Buchler, Fairfield, NY) and reconstituted in assay buffer. The extraction recovery as measured in plasma was 2 95%.

Experimental design
After completion of the surgical preparation the pigs were allowed to stabilize for 15 min without intervention. The pigs were randomized into two groups: one group receiving saline (control, n=7) and one group receiving the endothelin receptor antagonist (bosentan, n=8). Thirty minutes before the institution of CPB, the bosentan group received a sodium salt of bosentan as an intravenous bolus (3 mg/kg) followed by an infusion (7 mg/kg per h). The control group received an equal volume of saline solution.

Compounds
Heparin (Heparine Choay, Sanofi Winthrop, Gentilly, France); bosentan (Ro 47-0203) a non-peptide mixed antagonist of the ET receptors, was kindly provided by Dr. J.P. Clozel (F. Hoffmann-la Roche, Basel, Switzerland).

Statistical analysis
Analysis was blind to the investigator. Results are expressed as the mean±SEM. After the completion of the surgical preparation and a stabilization period, the initial hemodynamic variables (baseline) were compared with an unpaired two tail t-test with a Bonferroni–Holmes correction for multiple comparison (Staiview, Version 4.01; Abacus Concepts, Berkeley, LA). The response curve of the hemodynamic variables to the experiment, with and without bosentan, was compared by a two-way analysis of variance with repeated measures (Super ANOVA, Version 1.11; Abacus Concepts). P<0.05 was considered significant.

	Results

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Initial hemodynamics (Table 1)
After completion of the surgical preparation and a 15 min stabilization period, there were no differences in initial hemodynamic variables (baseline) between the pigs assigned to saline treatment and those receiving bosentan, the ET receptor antagonist.

View larger version (52K): [in this window] [in a new window]   Fig. 1. The effects of bosentan (n=8) on hemodynamic variables in anesthetized pigs compared with saline injections (control, n=7).The time point of measurement was 10 min after bosentan administration. Values are the mean±SEM, expressed as a percentage of baseline hemodynamic values. HR, heart rate; MAP, mean arterial pressure; MPAP, mean pulmonary artery pressure; CVP, central venous pressure; LV(dp/dt)max, positive maximum of LV(dp/dt); CO, cardiac output; CBF, coronary blood flow; CaroBF, carotid blood flow; SVR, systemic vascular resistance; PVR, pulmonary vascular resistance. *P<0.05, **P<0.005, versus control.

View larger version (32K): [in this window] [in a new window]   Fig. 2. Hemodynamics characteristics during the post-CPB period. Bosentan, n=8; control, n=7. Values are the mean±SEM, expressed as a percentage changes of baseline hemodynamic values (B) before cardiopulmonary bypass and bosentan administration. MAP, mean arterial pressure; MPAP, mean pulmonary artery pressure; SVR, systemic vascular resistance; PVR, pulmonary vascular resistance; CO, cardiac output; LV(dp/dt)max, positive maximum of LV(dp/dt); CVP, central venous pressure. Repeated measures ANOVA P-value for treatment effect are presented when P<0.05.

View larger version (24K): [in this window] [in a new window]   Fig. 3. Systemic (SVR) and pulmonary vascular resistance (PVR) 120 min after CPB. Values are the mean±SEM, expressed as a percentage change of baseline values before cardiopulmonary bypass and bosentan administration.

After CPB, no difference in cardiac output, SVR, LV(dp/dt)max, CVP, carotid blood flow and coronary blood flow were demonstrable between the two groups. LV(dp/dt)max tended to decrease in bosentan treated pigs. This was not significant. However, the positive ionotopic effect of ET-1 is well known and blockade by bosentan may result in the withdrawal of this effect.

Plasma ET-1 concentrations (Table 3)
In the control group, plasma ET-1 concentration was stable around 35 pg/ml during CPB and rose to 53.5±11 pg/ml 120 min after CPB. Bosentan induced a dramatic increase of plasma ET-1 levels that was not influenced by CPB.

	Discussion

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The present study points out that a non-peptidic endothelin receptor antagonist can prevent acute pulmonary arterial hypertension after experimental CPB in the pig. The dramatic effect of bosentan on the PVR was accompanied by a modest decrease of SVR emphasizing the selectivity of endothelin blockade for the pulmonary bed.

Paroxysmal pulmonary hypertension compromises the post-operative outcome of many children with congenital heart disease or of patients having mitral valve surgery and can dominate the early morbidity and mortality. The main aim of this study is to look at one way of preventing post-CPB pulmonary hypertension. Several observations suggest, that the increase in pulmonary resistance occurring after CPB is linked to a profound alteration of the pulmonary endothelial function [2]. CPB stimulates the production of a host of vasoactive substances, subsequently initiating a pseudo-inflammatory response. Potential etiological factors include activation of the complement, thrombine generation, oxygen free radicals and vasoactive mediator liberation and subsequent neutrophil and platelet activation. In addition, the diminution and re-establishment of pulmonary artery blood flow occurring during CPB could induce an ischemia-reperfusion injury characterized by alveolar epithelial cells and capillary endothelial cells injury. These findings lead to a variety of dysfunctions, such as an increased vascular permeability, an impaired production of endothelium-derived relaxing factors (EDRF), an increase in respiratory resistance and more importantly, pulmonary hypertension [2]. These findings imply an important role in pulmonary endothelial damage and a subsequent imbalance between endothelium-derived vasoconstrictors and vasodilators in the pathogenesis of this particularly acute pulmonary hypertension.

Pulmonary endothelium produces both vasodilators (NO, PGI₂) and vasoconstrictors (thromboxane, endothelin-1) which determine the pulmonary vasomotor tone. Previous studies have highlighted the pulmonary endothelial dysfunction after CPB manifested as impaired endothelium dependent vasodilatation in response to acetylcholine [2]. Whereas, endothelium-independant vasodilators such as inhaled NO, sodium nitroprusside or prostacyclin, acting directly on the vascular smooth muscle are effective on post-operative pulmonary hypertension, showing the absence of smooth muscle dysfunction. Inhaled NO has the advantage of a more effective and selective pulmonary effect than other intravenous vasodilators, the use of which is frequently limited by their systemic hypotensive effects [8]. Several hypotheses have been suggested to explain endothelium dysfunctioning after CPB: failures of NO production, NO synthase substrate limitation, failure of the receptor mediated endothelium-dependent vasodilatation (G protein or phospholipase second messenger system). Beside impaired endothelium-dependent vasodilatation, CPB equally induced an increased production of endothelium-derived vasoconstrictors, thromboxane A2 and endothelin, altering the balance between vasoconstriction and vasodilatation and ultimately resulting in pulmonary hypertension. Among the various mediators incriminated in paroxysmal pulmonary hypertension, ET-1 has recently retained a special interest. Moreover, the role of ET-1 has been suspected in a variety of diseases with abnormal vasotone, such as cerebral vasospasm after subarachnoid hemorrhage, cardiac ischemia after heart surgery, acute renal failure and pulmonary hypertension [3]. Increased levels of plasma ET-1 were found in pulmonary hypertension associated with congenital diseases, mitral stenosis and in Eisenmenger syndrome [9]. After surgical repair of congenital heart disease, the decrease of pulmonary hypertension paralleled those of ET-1 plasma levels [5]. Several theories have been put forward to account for the association between post-surgical pulmonary hypertension and raised plasma ET-1. An increase of local shear stress, hypoxia, activated neutrophils and PAF are present after heart surgery and are also known as important modulators of the ET-1 release [3]. The use of heparin-coated system enables the attenuation of both activated neutrophils and increase in ET-1 plasma levels [10]. On the other hand, hypothermia induced by CPB increases ET-1 plasma levels [11].

The role of ET-1 in models of pulmonary hypertension has been inferred based upon various experimental findings. Bosentan, as with other ET antagonists, reduced hypoxia-induced or monocrotaline-induced pulmonary hypertension in rats [12] [13]. It was recently shown that bosentan dramatically decreased acute pulmonary hypertension in a model of septic shock in pigs [14]. More interestingly, in normal piglets, inhibition of endothelin-converting enzyme 1 attenuates post-CPB pulmonary hypertension [15]. In addition, in lambs with preexisting increased pulmonary blood flow and endothelial dysfunction, bosentan eliminated the increase in pulmonary vascular resistance induced by hypothermic CPB [16].

The current study has several advantages and limitations. The use of a piglet model of CPB mimics the clinical situation more closely than isolated vessel preparations. In addition, the duration and the temperature of CPB are clinically relevant for standard cardiac surgery. As heparin–protamin complex can induce dramatic pulmonary vasoconstriction, we elected to eliminate it from our protocol. Thus, in our study, CPB PH was independent of the heparin–protamin reaction. In the control group, mean pulmonary arterial pressure and pulmonary vascular resistance were significantly augmented after CPB. The exact mechanisms for these responses to CPB remain unclear, but potential explanations include an increased pulmonary vascular reactivity in piglet and the role of endothelin in the maintenance of the porcine pulmonary and systemic vascular tone [17]. In the control group, plasma ET-1 concentration rose moderately 120 min after CPB. Since endogenous ET-1 acts on the pulmonary vascular tone in a paracrine manner, rather than as a circulating substance, the plasma concentration of ET-1 did not correlate with the degree of post-CPB pulmonary hypertension. The blockade of the receptors with bosentan induced a reactive increase of the ET-1 plasma levels. The most likely explanations include, the displacement of ET-1 from its receptors, decreased clearance of ET-1, and a dysfunction of a feedback mechanism secondary to ET-1 blockade. One another potential limitation of the present study is that we do not know, to what extent human response to ET antagonists is similar to pigs. Indeed pigs show a high sensitivity to ET antagonists with a substantial decrease in systemic blood pressure that might not be observed to the same degree in humans [18] However, a recent study showed that in patients with congestive heart failure, bosentan had a proportionally higher effect on the pulmonary bed than on the systemic vascular bed [19] This suggests that it is potentially possible to prevent acute pulmonary hypertension using an endothelin antagonist with a relatively good selectivity for the pulmonary bed.

This study shows that in our model, ET-1 is a significant contributor to the pathophysiology of post-CPB pulmonary hypertension. Therefore, the use of endothelin antagonist during CPB offers exciting new therapeutic avenues in the treatment of life-threatening acute pulmonary hypertension and warrants further study.

	Acknowledgments

 
The authors acknowledge the financial support from grant UPRES EA 971068. We thank Dr. B.M. Loffler for the determination of plasma levels of ET-1.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Bruno Schjöth Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Carteaux, J.-P. Articles by Villemot, J.-P. Search for Related Content PubMed PubMed Citation Articles by Carteaux, J.-P. Articles by Villemot, J.-P.