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J Thorac Cardiovasc Surg 2001;122:365-370
© 2001 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology (CPS)

Endothelin receptor subtype A blockade selectively reduces pulmonary pressure after cardiopulmonary bypass

From the Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, SC.

This work is supported by National Institutes of Health grants R01HL56603 and R01HL57952 and by an unrestricted grant from the Texas Biotechnology Corporation (San Diego, Calif).

Received for publication June 6, 2000. Revisions requested Sept 8, 2000; revisions received Feb 2, 2001. Accepted for publication Feb 5, 2001. Address for reprints: Francis G. Spinale, MD, PhD, Division of Cardiothoracic Surgery, 114 Doughty St, Suite 625, Charleston, SC 29425.

Abstract

Background: The bioactive peptide endothelin-1 is elevated during and after cardiopulmonary bypass and exerts cardiovascular effects through its 2 receptor subtypes, endothelin-1A and endothelin-1B. Increased endothelin-1A receptor stimulation after cardiopulmonary bypass can cause increased pulmonary vascular resistance and modulate myocardial contractility. However, whether and to what degree selective endothelin-1A blockade influences these parameters in the postbypass setting is not completely understood.
Objectives: Our objective was to measure left ventricular function and hemodynamics in a porcine model of cardiopulmonary bypass after selective blockade of endothelin-1A.
Methods: Adult pigs (n = 23) underwent 90 minutes of cardiopulmonary bypass and were randomized 30 minutes after bypass to receive a selective endothelin-1A antagonist (TBC 11251, 10 mg/kg; n = 13) or saline vehicle (n = 10).
Results: After bypass and before randomization, pulmonary vascular resistance rose nearly 4-fold, and left ventricular preload recruitable stroke work fell to one third of baseline values (both P < .05). In the vehicle group pulmonary vascular resistance continued to rise, and preload recruitable stroke work remained reduced. However, after endothelin-1A blockade, the rise in pulmonary vascular resistance was significantly blunted compared with that in the vehicle group. Moreover, the reduction in pulmonary vascular resistance with endothelin-1A blockade was achieved without a significant change in systemic perfusion pressures.
Conclusions: The present study demonstrated that increased activity of the endothelin-1A receptor likely contributes to alterations in pulmonary vascular resistance in the postbypass setting. Selective endothelin-1A blockade may provide a means to selectively decrease pulmonary vascular resistance without significant effects on systemic hemodynamics.

Neurohormonal system activation is common after cardiopulmonary bypass (CPB). ¹ For example, systemic levels of the potent bioactive peptide endothelin-1 (ET-1) increase 2-fold to 3-fold during and after CPB. ^2,3 The effects of ET-1 are mediated through 2 main receptor subtypes, endothelin-1A (ET_A) and endothelin-1B (ET_B). ⁴ In vascular beds stimulation of ET_A receptors results in contraction. In contrast, stimulation of endothelial ET_B receptors causes vasorelaxation by release of the vasodilators nitric oxide, epoprostenol (prostacyclin), or both. ⁵ ET-1 has also been shown to affect myocardial contractility. ^1,6,7 ET-1 is normally present in the plasma at very low concentrations, ⁸ but increased systemic levels of ET-1 occur in a number of disease states. ^8-12 The increased ET-1 level in the post-CPB setting is associated with increased pulmonary arterial pressure and vascular resistance. ^13-15 The nonselective ET-1 receptor antagonist, bosentan, has been deployed in several cardiovascular disease states. ^16,17 For example, in both clinical and experimental models of pulmonary hypertension, nonselective ET-1 blockade with bosentan decreased systemic and pulmonary vascular resistance (PVR). ¹⁷ The pulmonary vascular endothelium has a significant role in local regulation and maintenance of normal pulmonary vasomotor tone and in mediating the hypertensive response to CPB. ^3,18,19 Endothelial ET_B receptor stimulation induces vasorelaxation, particularly in the pulmonary bed. ²⁰ Furthermore, the ET_B receptor is an important clearance mechanism for circulating ETs. ²¹ Thus blockade of the ET_B receptor in the post-CPB setting may not be desirable, and selective ET_A receptor inhibition may be of greater utility. Accordingly, the goal of this study is to evaluate the effects of selective ET_A receptor antagonism after CPB on pulmonary and systemic hemodynamics.

Methods

Overview

For these studies, an intact porcine model of CPB with cardioplegic arrest was used. ²² After baseline measurements under normothermic conditions, CPB with myocardial arrest using conventional hypothermic crystalloid cardioplegic solution was instituted. After reperfusion and separation from CPB, hemodynamics were assessed, and the pigs were randomized to either ET_A receptor inhibition or vehicle. Measurements were then performed for 90 minutes after separation from CPB. All animals were treated and cared for in accordance with the National Institutes of Health "Guide for the Care and Use of Laboratory Animals" (National Research Council, Washington, 1996).

Drug and dose selection

For these studies, the selective ET_A receptor antagonist TBC 11251 (Texas Biotechnology Corporation, Houston, Tex) was used. This compound has demonstrated high specificity for the ET_A receptor and is one of the most selective ET_A antagonists reported. ²³ In an initial series of studies, chronically instrumented pigs were used to perform arterial pressure response studies, as described in previous studies. ²⁴ In brief, 5 pigs (20 kg, Hambone Farms) chronically instrumented with an aortic access catheter received an intravenous injection of ET-1 (0.4 µg/kg, Sigma Chemical Co, St Louis, Mo). Blood pressure was recorded at baseline and continuously for 20 minutes after ET-1 administration. After hemodynamics had returned to baseline values, TBC 11251 at 10 mg/kg was reconstituted to a standard volume of 5 mL by means of sterile saline solution and infused intravenously over a 10-minute period. Hemodynamic measurements were repeated at 1 to 20 minutes after injection. This dose of the ET_A antagonist did not significantly reduce resting arterial pressure. A second ET-1 challenge was administered, and blood pressure and heart rate were recorded continuously for at least 30 minutes after the challenge. Satisfactory ET_A receptor blockade was defined as an approximately 75% reduction in the ET-1–mediated increase in arterial pressure. The dose used in these studies resulted in significant inhibition of this ET-1–mediated blood pressure response, as shown inFigure 1. Thus an intravenous dose of 10 mg/kg was used in the CPB studies. This initial study used an exogenous delivery of purified ET-1 to define a dosing paradigm for the CPB study and does not necessarily reflect the actions or plasma levels of this peptide in vivo.

View larger version (16K): [in this window] [in a new window]   Fig. 1. The percentage change in mean arterial pressure after infusion of 10 µg of ET-1 in conscious pigs (n = 5). Infusion of the selective ETAantagonist (10 mg/kg TBC 11251) caused a significant reduction in the ET pressor response. *P< .05 versus control values.

For the CPB studies, 23 pigs (45 kg) were instrumented to measure hemodynamics and left ventricular (LV) function. ²² On the day of the study, the pigs were fully anesthetized, and arterial pressure monitoring was instituted. A multiluminal thermodilution catheter (7.5F, Baxter Healthcare Corp, Santa Ana, Calif) was then positioned in the pulmonary artery. The arterial line and pulmonary artery catheter were connected to externally calibrated transducers (Statham P23ID, Carolina Medical Inc, King, NC). A median sternotomy was performed, and the great vessels were isolated. A precalibrated microtipped transducer (7.5F; Millar Instruments Inc, Houston, Tex) was placed in the LV apex through a small stab wound and secured with a purse-string suture. A flow probe was placed over the anterior portion of the ascending aorta and connected to a digital flowmeter (HT107; Transonic Systems, Inc, Ithaca, NY) for continuous measurement of LV stroke volume and cardiac output. The electrocardiographs, pressure waveforms, and flow-probe signals were recorded with a multichannel recorder (Hewlett-Packard, Palo Alto, Calif), as well as being digitized on a computer for subsequent analysis at a sampling frequency of 250 Hz (80386 processor; Zenith Data Systems, St Joseph, Mo). After collection of baseline hemodynamics and LV function, the pigs were anticoagulated with sodium heparin (300 U/kg) to achieve an extended activated clotting time of longer than 400 seconds (ACTII; Medtronic HemoTec, Inc, Englewood, Colo). Arterial cannulation was obtained, and then a 12-gauge catheter (DLP Inc, Grand Rapids, Mich) was placed at the root of the aorta for intermittent infusion of cardioplegic solution and use as an LV vent. Venous cannulation (34F; CR Bard Inc, Santa Ana, Calif) was then performed, and CPB was initiated. The CPB circuit contained a membrane oxygenator (Bentley Univox Spiral Gold, Bentley Laboratories, Irvine, Calif) and was driven by a modular roller pump system (Sarns 5000, 3M Healthcare, Ann Arbor, Mich). The aorta was crossclamped, and an oxygenated, hypothermic crystalloid cardioplegic solution (500 mL of Na⁺, 130 mmol/L Cl^–, 109 mmol/L K⁺, 24 mmol/L Ca²⁺, 1.8 mmol/L, and 30 mEq/L HCO₃^– at 4°C) was delivered through the aortic root catheter. CPB was continued for 90 minutes with 500 mL of cardioplegic solution administered at 30-minute intervals after the initial cardioplegic dose. During CPB, neither systemic hypothermia nor topical cooling were used, and total flow was maintained within 2.5 to 3.0 L/min to maintain the mean systemic arterial pressure at a goal of 75 mm Hg. At completion of the cardioplegic arrest period, the crossclamp was removed, and the myocardium was reperfused. If ventricular fibrillation occurred during the initial reperfusion period, defibrillation was performed at 20 J with internal paddles. No inotropic or vasoactive agents were used at any time during the protocol, and protamine was not administered. At 30 minutes after crossclamp removal, LV function and systemic hemodynamics were recorded. After these measurements, the randomization scheme and experimental protocol were initiated.

Randomization

At the 30-minute postbypass period, the 23 pigs were randomly assigned to receive either vehicle alone or the ET_A receptor antagonist, as shown inFigure 2. The randomization scheme was based on ear tag numbers, and the treatment assignment remained blinded to the investigators throughout the study. The cardiothoracic surgery veterinarian maintained the code list, prepared the compounds, and performed the infusion. The randomization codes were not broken until the completion of the study protocol. LV function and systemic hemodynamics were then measured at 60 and 90 minutes after separation from CPB.

View larger version (16K): [in this window] [in a new window]   Fig. 2. Schematic of the experimental design. After baseline measurement of LV function and hemodynamics, CPB with complete myocardioal arrest was performed for 90 minutes. Measurements of LV function and hemodynamics were performed at 30 minutes after release of the aortic crossclamp and separation from CPB. At this time, randomization was performed in a blined fashion in which pigs reveived the ETA antagonist or vehicle. Measurements were then repeated for 60 and 90 minutes after CPB.

Plasma samples were obtained during the study for measurement of plasma ET-1 levels in the presence and absence of ET_A blockade. Baseline collection occurred immediately after placement of the arterial monitoring line. Blood samples were collected during CPB at 30, 60-, and 90-minute time points. The next sample collection occurred after aortic crossclamp release and a 30-minute stabilization period, just before randomization. Final samples were collected after randomization at 30 and 60 minutes after ET_A blockade or saline infusion. All blood samples were collected from arterial catheters placed after induction of anesthesia. Samples were collected in heparinized tubes and immediately centrifuged. Plasma was decanted and stored at –70°C until the time of assay. ET-1 levels were measured with a commercially available high-sensitivity radioimmunoassay kit (RIK-6901; Penninsula Laboratories, Inc, San Carlos, Calif) by using a previously described method. ²⁵

Data analysis

Changes in LV function and hemodynamics after CPB with cardioplegic arrest were initially compared with baseline values by means of analysis of variance (ANOVA). Likewise, changes in plasma ET-1 concentrations before, during, and after CPB were compared with baseline values by using ANOVA. Specific comparisons between pre- and post-CPB values were performed with a Bonferroni adjusted t test. Comparisons between untreated and treated groups at the time points after CPB were examined with an ANOVA for repeated measures. All statistical analyses were performed with statistical software programs (BMDP Statistical Software Inc, Los Angeles, Calif). Results are presented as means ± SEM.

Results

All of the pigs entered into the protocol were successfully weaned from CPB and randomized at 30 minutes after bypass. Summary LV function and hemodynamic values are presented inTable 1. LV function and mean arterial pressure were reduced after cardioplegic arrest and CPB. Heart rate and pulmonary artery pressure were increased at 30 minutes after separation from CPB. In both the vehicle (n = 10) and ET_A blockade groups (n = 13), arterial pressure remained reduced throughout the study period. Mean pulmonary artery pressure was significantly lower in the ET_A receptor blockade group at 60 and 90 minutes after CPB. Systemic vascular resistance was reduced in the ET_A receptor blockade group when compared with that of the vehicle group but did not reach statistical significance (P = .25).

View larger version (16K): [in this window] [in a new window]   Fig. 3. PVR significantly increased after crossclamp removal and separation from CPB. In the vehicle group PVR increased in a time-dependent manner, with longer periods after separation from CPB. In marked contrast, PVR fell from 30-minute post-CPB values after infusion of the ETAreceptor antagonist. Sample sizes for each time point are shown inTable 1. *P< .05 versus baseline values; +P< .05 versus 30 minutes after CPB; #P< .05 versus vehicle.

View larger version (15K): [in this window] [in a new window]   Fig. 4. Plasma ET-1 levels, expressed as percentage change from baseline, increased significantly after CPB. ET-1 levels continued to rise after infusion of the ETA receptor antagonist, with significant difference from vehicle by 90 minutes after CPB. *P < .05 versus baseline values; +P < .05 versus 30 minute after CPB; #P < .05 versus vehicle.

Neurohormonal system activation is a common sequelae of CPB. ¹ Elevated circulating levels of the bioactive peptide ET-1 have been identified after CPB and persist into the early postoperative period. ^2,3 ET-1 has been shown to exert potent vasoconstrictive effects on the pulmonary vascular bed and to modulate myocardial contractility. ^6,7,10,20 The major findings of this study were 2-fold. First, circulating levels of ET-1 are elevated after competitive ET_A receptor blockade administered after CPB. Second, the introduction of selective ET_A receptor blockade significantly blunted the rise in PVR after CPB without significantly affecting systemic perfusion pressures.

The effects of ET-1 are mediated through 2 predominant receptor subtypes, ET_A and ET_B. ^4,10 The ET_A receptor is expressed mainly on vascular smooth muscle cells, where it activates a second messenger system, resulting in increased intracellular Ca²⁺ concentrations and contraction. ²⁶ The ET_A receptor also appears to modulate the inotropic effect of ET-1. ^26,27 The ET_B receptor is found mainly on endothelial cells, where activated second messenger systems induce the release of nitric oxide and epoprostenol, with resultant vascular relaxation. ^4,5 The ET_B receptor is also a vital clearing mechanism for ET-1. ²¹ Given the elevated levels of ET-1 after CPB, blockade of the potentially beneficial effects of the ET_B receptor may not be desirable. Consistent with past reports, this study demonstrated elevated circulating levels of ET-1 after CPB. ^2,3 This study also demonstrated significantly higher plasma ET-1 concentrations in the group receiving ET_A blockade. This is not unexpected because the drug used in the study is a competitive inhibitor, and elevated levels likely reflect displacement of ET-1 from ET_A receptors. This provides further evidence that the dose of ET_A antagonist used in the present study provides a pharmacologic effect at the level of the ET receptor system.

The underlying mechanisms for increased vasoconstriction within the pulmonary circuit in the early post-CPB setting are likely multifactorial. Acute ET_A receptor inhibition significantly blunted the rise in PVR after CPB without significantly affecting systemic perfusion pressures, thus providing direct evidence that ET_A receptor activation within the pulmonary circuit is a contributing factor. Right ventricular dysfunction is not uncommon after CPB, ^28,29 and increased PVR can exacerbate this condition. Inhaled nitric oxide has been demonstrated to reduce PVR in patients after cardiac operations. ^30,31 ET_B receptor stimulation provides an intrinsic pathway of nitric oxide and epoprostenol production, contributing to physiologic vasodilation in the pulmonary circuit. In the present study the infusion of a selective, competitive ET_A antagonist resulted in increased circulating levels of ET-1. Increased plasma ET-1 in this setting could lead to enhanced ET_B receptor activation, with subsequent pulmonary vasodilation. Thus, the reduction seen in PVR with selective ET_A receptor blockade may occur through 2 complementary mechanisms: through the direct antagonism of ET_A receptor–mediated vasoconstriction and through the potentiation of ET_B receptor–mediated vasorelaxation.

In addition to effects in the pulmonary vascular bed, ET-1 has been shown to influence contractile function in the myocardium both in intact animal preparations and in isolated myocyte systems. ^6,7,9 Exposure of normal myocardial preparations to increasing concentrations of ET-1 has been shown to induce a mild positive inotropic effect. ¹⁴ However, with underlying myocardial contractile dysfunction, increased ET-1 levels exert a negative inotropic effect. ⁶ The effects of ET_A receptor blockade on indices of global LV ejection performance observed in the present study need to be considered in the context of the experimental design used versus the clinical CPB setting. Inotropic stimulation with calcium, ß-adrenergic receptor antagonists, or both is commonly performed in the early post-CPB setting; however, in the present study no vasoactive or inotropic interventions were used because these would have confounding influences on the experimental design. Thus, whether and to what degree ET_A receptor blockade would influence myocardial contractile performance remains to be established.

Although a number of studies have documented increased ET-1 levels after CPB, ^2,3 the investigations with ET-1 blockade are limited, with the majority using nonselective ET-1 blockade or a converting enzyme inhibitor. ^32-34 Of the studies with selective ET_A antagonism, the primary focus has been animal models of congenital heart disease. ^35,36 For example, a recent study evaluated the effect of selective ET_A antagonism in a lamb model of experimentally induced high flow pulmonary hypertension. ³⁵ The investigators were able to show that PVR was significantly lower after CPB in lambs pretreated with the selective antagonist. The present study builds on these reports by using a conventional model of CPB and specifically evaluating systemic perfusion indices and myocardial performance in addition to pulmonary hemodynamics.

Many cardiac operations require CPB, with the potential for some degree of postoperative hemodynamic instability. Although off-pump coronary revascularization is an option for selected patients, CPB is still necessary for a significant number of patients undergoing coronary bypass. ^37,38 In effect, the most compromised coronary patients are frequently selected out to undergo operation with CPB, and CPB is still necessary for most valve and extensive aortic procedures. Thus, improved strategies for preventing and treating the hemodynamic sequelae of CPB are a significant clinical goal. The present study demonstrated that selective ET_A antagonism blunted the inevitable rise in PVR in a porcine model of CPB without affecting systemic hemodynamic stability. These results suggest that selective ET_A blockade may prove a useful new therapeutic modality in the limited armamentarium for treatment of pulmonary hypertension after CPB.

Acknowledgments

We thank Simona C. Baicu, Jeffrey A. Sample, Nancy Harper, Mary C. King, Karla Zeigler, Joseph Sistino, and Dr Tom Brock for their time and expertise.

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				S. Verma, A. Maitland, R. D. Weisel, S.-H. Li, P. W. M. Fedak, N. C. Pomroy, D. A. G. Mickle, R.-K. Li, L. Ko, and V. Rao Hyperglycemia exaggerates ischemia-reperfusion-induced cardiomyocyte injury: Reversal with endothelin antagonism J. Thorac. Cardiovasc. Surg., June 1, 2002; 123(6): 1120 - 1124. [Abstract] [Full Text] [PDF]

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