Ann Thorac Surg 2002;74:727-732
© 2002 The Society of Thoracic Surgeons
Original article: cardiovascular
Is there a role for endothelin-blockade early after coronary artery bypass grafting?
Ulf Lockowandt, MDa*,
Anders Franco-Cereceda, MD, PhDa
a Department of Thoracic Surgery, Karolinska Hospital, Stockholm, Sweden
Accepted for publication April 21, 2002.
* Address reprint requests to Dr Lockowandt, Department of Thoracic Surgery, Karolinska Hospital, 171 76 Stockholm, Sweden
e-mail: ulf.lockowandt{at}ks.se
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Abstract
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Background. Diverse results exist regarding myocardial release of endothelin after coronary artery bypass grafting. Because endothelin may be involved in regulation of coronary blood flow, postoperative endothelin-blockade could influence the surgical outcome. In this study, we have evaluated the cardiac outflow of endothelin and effects on coronary flow by endothelin-blockade immediately after completion of the coronary bypass grafting.
Methods. Thirty patients were subjected to infusions of endothelinA blocker (BQ-123, 260 nmoL/min for up to 30 minutes) or endothelinA blocker and endothelinB blocker (BQ-123 and BQ-788, 260 and 250 nmol/min, respectively, for up to 30 minutes) into a veingraft anastomosed to a coronary vessel, and the coronary blood flow was measured. Plasma levels of endothelin from the coronary sinus and the periphery were determined.
Results. There were no significant changes in flow caused by endothelinA blockade alone or in combination with endothelinB blockade. There were no immediately increased levels of endothelin after surgery or after infusions of the endothelin blockers.
Conclusions. Endothelin blockade does not influence the immediate perioperative myocardial blood flow after coronary bypass grafting. There is no significantly increased myocardial outflow of endothelin, and endothelin does not have any influence on the basal tone of the coronary vessels in the early phase after coronary bypass grafting.
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Introduction
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It is well known that the endothelium is involved in the regulation of local vascular tone through release of both vasodilator and vasoconstrictor substances [1]. More than a decade ago, the endothelium was shown to synthesize the vasoactive peptide endothelin (ET) through enzymatic cleavage of the propeptide Big ET, and further studies have revealed a group of ET isopeptides named ET-1, ET-2, and ET-3 [2]. ET has been shown to evoke a variety of effects in the cardiovascular system, including vasoconstriction, vasodilatation [3], and positive inotropic and chronotropic actions [4]. The vascular effects of ET are mediated through interaction with ETA and ETB receptors. The ETA receptor is selective for ET-1 and causes vasoconstriction, whereas the ETB receptor is nonselective for the ET isopeptides and mediates vasodilatation [5]. In addition, reports suggest the existence of ETB receptor subtypes: an ETB1 receptor on the endothelium-mediating endothelium-dependent vasodilatation, and the ETB2 receptor on smooth muscle cells causing vasoconstriction [6].
Results regarding increased levels of ET-1 in the venous outflow from the heart during coronary artery bypass grafting (CABG) has been conflicting. Several authors report a lack of increase of ET-1 [7, 8], or a selective increase in diabetic patients only [9, 10], whereas other authors demonstrate an increase of ET-1 in the coronary sinus after CABG [11–13]. It is well known that ET-1 is a potent constrictor of human coronary arteries and of vessels used as grafts in CABG [14].
Based on in vitro experiments evaluating the effects of ET-1 in human coronary arteries as well as in graft material commonly used in coronary bypass surgery, it has been suggested that blockade of ETA receptors may prove beneficial in preventing spasm in coronary arteries and grafts, and thus, in preventing postoperative myocardial ischemia after CABG [15].
In this study, we have determined the cardiac outflow of vasoactive substances derived from the endothelium, that is, ET-1, nitric oxide (NO), and prostacyclin (by determination of the stable metabolite 6-keto-PGF1
), immediately after coronary bypass operations and after intracoronary infusion of selective ETA and ETB blockers. To further assess a possible role for ET in CABG, we also evaluated the effects of ET receptor blockade on the graft flow (ie, indirectly the coronary blood flow).
The extent of vascular dysfunction in the patients randomized in this study was assessed by evaluating endothelium-dependent (acetylcholine; ACh) and endothelium-independent (adenosine; ADO) vasodilatation.
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Material and methods
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This study was approved by the Ethics Committee of the Karolinska Hospital. A total of 30 patients with angina pectoris undergoing CABG gave their informed consent to the investigation.
Functional experiments
The patients were randomized into five groups of 6 patients each. In these five groups, either vehicle only or endothelinA blocker or endothelinA blocker in combination with endothelinB blocker was infused, 10 or 30 minutes, indirectly into a coronary vessel (for details, see Table 1).
For patient demographics, see Table 2.
The patients were operated on as routine cases with the use of cardiopulmonary bypass (CPB), aortic cross-clamp, and ante- and retrograde blood cardioplegia. CPB was initiated using a centrifugal pump (BP 80; Biomedicus Biomed, Houston, TX) and a membrane oxygenator (Affinity; Medtronic Inc., Minneapolis MN) primed with Ringer’s acetate solution. During CPB, the temperature was allowed to drift to 34°C. Flow was kept around 4.7 L/min and mean arterial pressure (MAP) at about 75 mm Hg. The cardioplegic solution was mixed 1:4 with blood and delivered at a temperature of 6°C. The cardioplegic solution consisted of KCL (100 mmol), MgSO4 (8 mmol), glucose (28 mmol), and THAM (Tris hydroxymethyl-aminomethane) (20 mmol) dissolved in a saline (0.9%) solution to a volume of 1,000 mL.
ET blockers were administered dissolved in 0.9% NaCl using an IVAC TIVA syringe pump (Alaris Medical Systems, Basingstoke, Hampshire, UK) and a fine needle (0.4 mm) into a vein graft anastomosed to either a diagonal branch of the left anterior descending artery or a marginal branch of the circumflex artery. The infusions were given after completion of grafting with the patients off-pump but still cannulated and connected to the heart-lung machine, as required by the Ethics Committee. The flow in the targeted coronary vessel and hemodynamics were continuously measured and registered before infusion, and at 10, 20, 30, and 40 minutes after beginning of infusion (Fig 1a
and Fig 1b). All infusions were followed by a bolus injection of ACh (10 µg dissolved in 1 mL of 0.9% NaCl), and the flow and hemodynamics were registered (Fig 1a and Fig 1b). Subsequent to the injections of ACh, a bolus dose of ADO was given (18 µg dissolved in 1 mL of 0.9% NaCl), (Fig 1a and Fig 1b).
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Fig 1. (a) Schematic illustration of the experimental protocol in group I (vehicle only for 10 minutes), group II (BQ-123, 260 nmol/min for 10 minutes), and group IV (BQ-123 and BQ-788, 260 and 250 nmol/min, respectively, for 10 minutes). Solid arrow = flow and hemodynamic registration; dashed arrow = blood samples. (b) Schematic illustration of the experimental protocol in group III (BQ-123, 260 nmol/min for 30 minutes) and group V (BQ-123 and BQ-788, 260 and 250 nmol/min, respectively, for 30 minutes). (ACh = acetylcholine; ADO = adenosine.)
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The maximum doses given of BQ-123 (7.8 µmol) and BQ-788 (7.5 µmol) were chosen based on preliminary experiments in which 20 nmol to 10 µmol was administered and hemodynamic responses were recorded. Thus, the doses given were found to be devoid of any influence on mean systemic blood pressure (MAP), and similar doses have previously been shown to influence human local endogenous ET-vasoactive tone in vivo [16].
Blood flow in the targeted coronary artery was monitored using an ultrasonic flow probe model 2SB (Transonic Systems Inc., New York, NY) placed around the vein graft just proximal to the site of administration of substances. Hemodynamic parameters, including MAP, mean coronary sinus pressure (MCSP), mean pulmonary artery pressure (MPAP), and ST segment deviation, were continuously recorded with a Tram 600 SL module, connected to a Tramscope 12C (Marquette Electronics Inc., Milwaukee, WI). All patients were monitored with transesophageal echocardiogram throughout the operation.
Plasma for analysis of ET-1, NO, and 6-keto-PGF1 was obtained from the radial artery and coronary sinus simultaneously before bypass, 5 minutes after starting bypass, 1 minute after removing the cross-clamp, and after weaning off bypass. Plasma was also obtained from the radial artery and coronary sinus, immediately before infusion of ET blocker or vehicle only, at 10 minutes (not in groups III or V) and at 30 minutes after the infusions and at 1 minute after injections of ACh and ADO, respectively (Fig 1a and Fig 1b). The samples were collected in vacuum tubes, kept on ice slush, and centrifuged (10 minutes, 4°C) at 4,000 rpm within 30 minutes of collection of the last sample. The plasma was then frozen at -70°C and stored until analyzed.
Plasma determination of 6-keto-PGF1
Plasma samples were analyzed for the content of 6-keto-PGF1, the stable breakdown product of prostacyclin, using a commercially available enzyme immunoassay (Biotrak RPN 221; Amersham, Buckinghamshire, UK). This assay combines the use of peroxidase-labeled 6-keto-PGF1 conjugate, a specific antiserum that can be immobilized onto precoated microtiter plates and one pot stabilized substrate solution. This provides a rapid and sensitive nonisotopic method for determination of 6-keto-PGF1. The detection limit for the kit was 3.0 fg/L.
Plasma determination of ET-1
For extraction of ET-1-like immunoreactivity, the samples were heated at 95°C in water for 10 minutes, homogenized, and centrifuged. The content of ET-1-like immunoreactivity was then determined by radioimmunoassay using an antiserum raised against ET-1 in rabbits (RAS 6911; Peninsula, Belmont, CA). Human ET-1 labeled with iodine-125 (125I) was used as tracer and synthetic ET-1 as standard. The assay samples were incubated at 4°C in 0.1 mol/L phosphate buffer, pH 7.4, containing 0.1% bovine serum albumin and 0.1% Triton-X. The detection limit of the assays was 1.0 pmol/L.
Plasma determination of NO
Total NO was analyzed by a commercially available assay kit (DE 1600; R&D, Minneapolis, MN). Briefly, this assay involves the enzymatic conversion of all nitrate to nitrite by nitrate reductase. The detection of total nitrite is then determined as color azo dye product of the Griess reaction, which absorbs visible light at 540 nm. The sensitivity of the NO assay was 1.35 µmol/L.
Drugs
BQ-123 [Cyclo (D-Asp-Pro-D-Val-Leu-D-Trp) · Na, C31H41N6O7 · Na;] is a synthetic and highly selective ETA receptor antagonist. BQ-788 (N-cis-2.6-Dimethylpiperidinocarbonyl-
-MeLeu-D-Trp(MeOCO)-D-Nle-OH · Na, C34H50N5O7 · Na;) is a synthetic and selective ETB receptor antagonist with a selectivity ratio of 200 relative to the ETA receptor. BQ-123 and BQ-788 were obtained from Clinalfa AG (Laufelfingen, Switzerland). Adenosin was from Item Development AB (Stockholm, Sweden), and acetylcholin was from OMJ Pharmaceuticals Inc. (San Germán, Puerto Rico).
Statistical evaluation
Hemodynamics were statistically analyzed by Student’s t test. ET-1, NO, and 6-keto-PGF1 were analyzed with either Wilcoxon signed rank test or Friedman repeated measurement with Dunn’s multiple comparison. (INSTAT software, version 2.01; GraphPad, San Diego, CA): A p value less than 0.05 was considered significant. Values are given as means ± SD.
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Results
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Clinical outcome
No adverse effects by the infusions were noted in any of the patients with regards to electrocardiogram (ECG) changes or influence on cardiac function as evaluated by perioperative transeosophageal echocardiography. No patient had to be reinstalled on CPB, and there were no hospital deaths among the patients.
ET blockers and hemodynamics
The baseline hemodynamics did not differ significantly between the groups. There was no significant influence on MAP, MCSP, or MPAP at 10, 20, 30, and 40 minutes after the beginning of BQ-123 alone or in combination with BQ-788 (data not shown).
ET blockers and blood flow
Coroary blood flow was not influenced by infusion of vehicle alone (group I) (basal flow of 42.2 ± 14.3 mL/min) (Fig 2a). Ten minutes of ETA blockade, BQ-123 (group II), did not influence the flow in the targeted coronary vessel (basal flow of 46.6 ± 13.0 mL/min) (Fig 2a). Combined ETA and ETB blockade, BQ-788, for 10 minutes did not influence the coronary blood flow (basal flow of 42.8 ± 21.1 mL/min) (Fig 2a). Thirty minutes of ETA blockade alone (group IV) did not influence the flow (basal flow of 29.7 ± 13.9 mL/min) (Fig 2b). ETA blockade in combination with ETB blockade for 30 minutes did not influence the flow (basal flow of 30.8 ± 14.0 mL/min) (Fig 2b).
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Fig 2. (A) Coronary blood flow indirectly measured as vein graft flow after infusions in group I (vehicle only for 10 minutes), group II (BQ-123, 260 nmol/min for 10 minutes), and group IV (BQ-123 and BQ-788, 260 and 250 nmol/min, respectively, for 10 minutes). Values are given as means ± SD. (B) Coronary blood flow indirectly measured as vein graft flow after infusions in group III (BQ-123, 260 nmol/min for 30 minutes) and group V (BQ-123 and BQ-788, 260 and 250 nmol/min, respectively, for 30 minutes). Values are given as means ± SD.
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Acetylcholine, adenosine, and hemodynamics
Neither ACh nor ADO exerted any significant influence on MAP, MCSP, or MPAP (data not shown).
Acetylcholine, adenosine, and blood flow
ACh caused a rapid and significant decrease in the targeted coronary blood flow in all patients (p < 0.05 in all groups compared with baseline, without any statistical significance between the groups). Adenosine evoked a significant increase of the blood flow in all patients (p < 0.05 in all groups compared with baseline, without any statistical significance between the groups) (Fig 3).
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Fig 3. Coronary blood flow indirectly measured as vein graft flow after infusion of acetylcholine (ACh) and adenosine (ADO). Group I (0.9% NaCl only; 1 mL/min for 10 minutes), group II (endothelinA blocker BQ-123; 260 nmol/min for 10 minutes), group III (endothelinA blocker BQ-123 in combination with endothelinB blocker BQ-788; 260 and 250 nmol/min, respectively, for 10 minutes), group IV (BQ-123; 260 nmol/min for 30 minutes), and group V (BQ-123 in combination with BQ-788; 260 and 250 nmol/min, respectively, for 30 minutes). For significance, see text. Values are given as means ± SD.
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Endothelin, NO and PGI2
Basal plasma levels of 6-keto-PGF1 were significantly higher in the coronary sinus compared with the arterial levels (Table 3). After institution of CPB, there was a further increase in the coronary sinus 6-keto-PGF1 levels paralleled by a smaller, but significant increase in arterial 6-keto-PGF1-levels (Table 3). After aortic cross-clamp removal, arterial and coronary sinus levels of 6-keto-PGF1 decreased to remain at similar levels throughout the rest of the experiment.
Arterial and coronary sinus levels of ET-1 and NO remained unchanged throughout the experiment and were not influenced by CPB or any infusion of substances (Table 3).
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Comment
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The aim of the present study was to determine possible cardiac release of ET-1 during and immediately after CABG. We also evaluated the effect of ETA receptor blockade alone or combined with ETB receptor blockade in vivo to assess possible influence on myocardial blood flow. Finally, to further assess the function and integrity of the vascular endothelium after CABG, endothelium-dependent (ACh) and endothelium-independent (ADO) coronary vasodilatation was studied, and NO and PGI2 outflow from the heart was also evaluated.
Optimal blood flow in grafts and coronary vessels after coronary bypass surgery is of outmost significance. Increased cardiac outflow of the potent vasoconstrictor peptide ET-1 has been detected after myocardial ischemia [17]. However, cardiac outflow of ET-1 peri- and post-CABG is controversial [7, 8, 11–13] and of clinical importance. ET-1 constricts coronary vessels and vessels used as grafts in CABG [14]. It has therefore been suggested that ET blockade may prove beneficial in enhancing graft flow after coronary bypass surgery [15].
It was not possible to detect increased levels of ET-1 in the coronary effluent (coronary sinus) after reperfusion of the ischemic heart in our study, and ETB receptor blockade did not alter the coronary sinus levels of ET-1, in spite of the known ability of ETB receptor blockade to displace the ET binding and increase plasma levels of ET-1 [18].
The used dose of BQ-123 was based on preliminary experiments of our own, where the dose was shown to be devoid of any hemodynamic effects per se. The observation time was 40 minutes after the beginning of the infusions (10 or 30 minutes), which should be sufficient to detect any possible changes. A third of the presently used dose has been shown to alter peripheral arterial tone, well within the time span used in our experiment, when infused in humans in vivo [16]. Interestingly, it was recently demonstrated that local intracoronary administration of ET blockade significantly dilated coronary vessels in patients with coronary artery disease [19]. Based on the present study, however, there seems to be no major immediate cardiac release of ET-1- or ET-mediated coronary vasoconstriction during CABG, which is also indicated by the lack of influence of ET blockade on the coronary circulation immediately after CABG.
We detected a significant increase in the coronary sinus effluent of PGI2 after institution of CPB and cross-clamp removal. Myocardial release of prostacyclin during ischemia is derived from mainly endothelial cells and has potent vasodilator and platelet aggregation inhibiting actions with myocardial and endothelial protective effects [20, 21]. Because myocardial outflow of PGI2 from the heart during ischemia is pH dependent and attenuated by cyclo-oxygenase inhibitors [22], the observed outflow of PGI2 in our study suggest active release and not merely spill-over from disrupted endothelial cells. Due to the methodological setup used, it was not possible to measure coronary sinus blood flow in the patients, and subsequently, no correlation between NO, ET-1, 6-keto-PGF1 outflow, and myocardial blood flow could be established. Therefore, the lack of increased myocardial outflow of ET-1 or NO could reflect difficulties in detection of released substances in relation to increased postischemic flow. Moreover, the sampling periods may be too short, too few, or not properly timed. In the ischemic rabbit heart, reperfusion causes an immediate outflow of PGI2, whereas the outflow of NO is markedly delayed [20]. Because ET-1 release and demand is regulated by de novo synthsis, the present findings do not exclude the possibility for later increase in plasma of ET-1. Furthermore, more than 90% of ET is released abluminally, that is, towards the smooth muscle cells, and plasma levels may thus represent only a fraction of the released peptide.
NO is released from endothelial cells by a number of stimuli, including shear stress, ischemia, autocoids, and hormones, as well as platelet-derived substances [23]. In the coronary circulation, flow-dependent vasodilatation is endothelium dependent and mediated by NO, and thus local responses from the endothelium are important in regulation of adequate coronary blood flow. The lack of changes in cardiac NO outflow in our study indicates the presence of coronary artery disease in which NO mechanisms are impaired [24]. Indeed, endothelium-dependent vasodilatation (ACh) was absent in our patients.
Coronary artery disease is well known to be associated with endothelial vasodilator dysfunction. Interestingly, also brief coronary ischemia attenuates endothelial vasodilatation [25] but seems to have less influence on endothelium-independent vasodilatation [26]. In accord, ADO caused vasodilatation and ACh caused vasoconstriction in our study. To what extent the underlying disease or the ischemic insult is responsible for this attenuation of vasodilator activity remains to be established. The cause of impaired endothelium-dependent vasodilatation in patients undergoing coronary bypass surgery may be related to the underlying atherosclerotic disease, perioperative myocardial ischemi,a or the use of ECC, but remains to be further investigated.
In conclusion, patients with coronary artery disease subjected to conventional bypass surgery using ECC exhibit postischemic cardiac release of PGI2 but not NO or ET-1. ET receptor blockade does not improve immediate myocardial blood flow in these patients. Therefore, a role of ET in regulation of immediate coronary blood flow after CABG seems unlikely.
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Acknowledgments
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This work was supported by grants from the Swedish Heart and Lung Foundation and the Wallenberg Foundation and by funds from the Karolinska Institute.
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References
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Abstract
Introduction
