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Ann Thorac Surg 1996;61:1775-1780
© 1996 The Society of Thoracic Surgeons

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Original Article: Cardiovascular

Pulmonary Vasoconstriction Due to Impaired Nitric Oxide Production After Cardiopulmonary Bypass

Division of Cardiothoracic Surgery and bDepartments of Pediatrics and cPharmacology, UCLA School of Medicine, Los Angeles, California

Accepted for publication February 9, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. Pulmonary hypertension is a serious complication after cardiopulmonary bypass (CPB). This study tests the hypothesis that CPB provokes oxidant-mediated pulmonary endothelial dysfunction, leading to reduced nitric oxide (NO) production and pulmonary vasoconstriction.

Methods. Twelve piglets underwent 2 hours of CPB. In 6 of them, CPB prime was supplemented with N-mercaptopropionylglycine and catalase, whereas the others were not treated. Left and right ventricular function were evaluated from end-systolic elastance and Starling analysis. Pulmonary vascular resistance and transpulmonary NO production (measuring NO₂^-, NO₃^-) were determined to assess pulmonary endothelial function.

Results. Cardiopulmonary bypass caused a significant increase in pulmonary vascular resistance (83 ± 12 to 212 ± 30 dynes • cm^-5 • s kg^-1Au: set correctly?, p < 0.05), associated with a reduction of NO production (8.8 ± 1.4 to 2.5 ± 0.5 µmol/min, p < 0.05) and depressed right ventricular function (56 ± 12% of control), whereas N-mercaptopropionylglycine and catalase added to the CPB allowed a substantial improvement of these deleterious effects of CPB.

Conclusions. Cardiopulmonary bypass impairs pulmonary NO production, resulting in pulmonary vasoconstriction and right ventricular dysfunction, which can be reduced by antioxidants. These findings imply the validity of NO inhalation therapy for postoperative pulmonary hypertension as a supplementation of endogenous endothelium-derived relaxing factor.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Recently cardiopulmonary bypass (CPB) has been used with increasing frequency in the early infancy or newborn period to repair congenital heart defects. Postoperative pulmonary hypertension, however, is an important complication after intracardiac repair, contributing to operative mortality. Cardiopulmonary bypass per se is known to alter many factors simultaneously [1–5], including complement/neutrophil activation [5], oxygen free radicals [2, 3], and vasoactive-mediator generation [4], contributing to postbypass heart and lung complications [1, 4]. Recent studies have shown that endothelium (in coronary [6], pulmonary [7], and other vascular endothelium [8, 9]) is the principle target lesion of oxygen free radicals from extracellular sources (ie, activated leukocytes), leading to endothelial dysfunction and endothelium-dependent vasoconstriction.

We speculate that CPB provokes an oxidant-mediated pulmonary endothelial dysfunction, leading to pulmonary vasoconstriction. This experimental study tests the hypotheses that CPB in immature piglets may reduce nitric oxide (NO) production, increase pulmonary vascular resistance, and depress right ventricular performance, and that these deleterious effects of CPB can be limited by antioxidants.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Eighteen 2- to 3-week-old Yorkshire Duroc piglets (4 to 6 kg) were premedicated intramuscularly with 0.5 mg/kg of diazepam, anesthetized with 30 mg/kg of pentobarbital, followed by 5 mg/kg intravenously per hour, and ventilated by a volume-limited respirator (Servo 900D; Siemens, Elema, Sweden) through a tracheostomy (fractional concentration of oxygen (FiO₂), 1.0; tidal volume, 15 mL/kg; mean airway pressure, 20 to 24 cm H₂O; positive end-expiratory pressure, 0 cm H₂O). All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH publication 85-23, revised 1985). The ductus arteriosus was ligated routinely with a surgical clip through a left fourth intercostal thoracotomy. The heart was exposed by median sternotomy, and transducer-tipped catheters (Millar) were placed in the left ventricle, thoracic aorta, left atrium, and right atrium. A fluid-filled catheter connected to an external transducer was placed into the pulmonary artery. These signals were routed to a recorder (MT 9000; Astro-Med Inc, West Warwick, RI) by signal conditioners (model 13-4615; Gould Inc, Eastlake, OH). A thermodilution probe (No. 4) was directed into the main pulmonary artery and connected to a cardiac output computer (model 9520A; American Edwards Laboratory, Santa Ana, CA).

Arterial blood gases, electrolyte, and hemoglobin measurements (Blood Gas System 288; CIBA-Corning, Medfield, MA) were measured to ensure the optimal extracorporeal circulation. A heating pad maintained the monitored rectal temperature at 38°C.

An eight-electrode-equipped conductance catheter (with a distance between each electrode of 0.4 cm; Webster Laboratories, Baldwin Park, CA) was inserted through the left ventricular apex, connected to a Sigma-5-DF signal conditioner-processor (Leycom, Oegstgeest, Netherlands). After systemic heparinization (3 mg/kg intravenously) a single-stage venous cannula (20F) and an aortic cannula (8F) were inserted into the right atrial appendage and the left subclavian artery. The extracorporeal circuit was primed with packed red blood cells from donor pigs, with calcium added to counteract the citrate, hetastarch (Hespan; DuPont, Wilmington, DE) and Plasma-Lyte electrolyte solution (Baxter Healthcare, Deerfield, IL). During extracorporeal circulation, arterial oxygen tension (PaO₂) was maintained at 400 to 500 mm Hg, and perfusion flow at 100 mL • min^-1 • kg^-1. Hematocrit was kept approximately 30% throughout the experiment.

Experimental Groups
CONTROL GROUP.
Six piglets were anesthetized, instrumented, and observed over a period of 5 hours. Functional and biochemical data were measured at the end of the experiment.

CARDIOPULMONARY BYPASS GROUP.
Twelve piglets underwent 120 minutes of CPB using Sarns membrane oxygenators, followed by 60 minutes of observation after CPB. In 6 piglets, the bypass prime was supplemented with N-mercaptopropionylglycine (MPG, 80 mg/kg) plus catalase (50,000 U/kg) [MPG+CAT], whereas the other 6 piglets were not treated [CPB].

Evaluations
CARDIAC PERFORMANCE.
Left ventricular pressure and conductance catheter signals were amplified and digitalized to record left ventricular pressure-volume loops. A series of pressure-volume loops under variable loading conditions was generated by rapid transient occlusion of the inferior vena cava during a 7-second period of apnea, at a control condition and 60 minutes after discontinuing CPB [10]. Parallel conductance was corrected by the hypertonic saline method as described previously [11]. The end-systolic pressure-volume relationship was analyzed by a user interactive videographics program "Spectrum" on a 383/33 MHz IBM PC. Left ventricular performance was described as the slope of linear regression (end-systolic elastance), as described previously [11].

Right ventricular performance before and after CPB was evaluated by infusing blood from the CPB circuit at 5 mL • kg^-1 • min^-1 over 3 minutes to record right ventricular function curve (stroke work index versus central venous pressure). Postoperative functional recovery was expressed as percent of control right ventricular stroke work index at a central venous pressure of 8 mm Hg.

PULMONARY CIRCULATION.
Pulmonary Vascular Resistance. Cardiac output was determined by duplicate injections of 1 mL of 4°C cold saline into a central venous catheter during the control state and 30 and 60 minutes after discontinuing CPB. Pulmonary vascular resistance index (PVRI) was calculated using following equation:

PVRI=(PAP-LAP)/CO [mm Hg • L^-1 • min^-1]

xBody weight [kg],

where PAP is mean pulmonary artery pressure, LAP is left atrial pressure, and CO is cardiac output in liters per minute.

Pulmonary Nitrate/Nitrite Production.
Nitric oxide concentration was determined in pulmonary artery and vein plasma as its spontaneous oxidation products nitrite (NO₂^-) and nitrate (NO₃^-), which were reconverted to • NO and quantitated with a sensitive chemiluminescence assay using a nitrogen oxides analyzer (model 2108, NO_x analyzer; DASIBI Environmental Corp, Glendale, CA). The method was modified to increase the sensitivity of the detector to 0.8 ppb of NO (1 pmol/0.1 mL of test sample) [12]. Plasma samples were obtained during the control condition, 30 minutes and 60 minutes after discontinuing CPB. Pulmonary NO production was calculated using the following equation:

NO production (µmol • min^-1 • kg^-1)=(NO_LA-NO_PA)

xCO [mL/min]/Body weight [kg],

where NO_LA = NO concentration in left atrial (LA) plasma, NO_PA = NO concentration in pulmonary artery (PA) plasma.

LUNG.
The ratio between arterial and alveolar oxygen partial pressure (a/A PO₂ ratio) was calculated with the following formula:

a/A ratio=PaO₂/PAO₂, where PAO₂

=(P_atm-PH₂O) FiO₂-PACO₂.

This ratio is relatively stable with a varying FiO₂, unlike the classic alveolar-arterial gradient. The normal a/A ratio is 0.75.

Static lung compliance was determined from duplicate expirations using a Siemens 900D ventilator. Expiratory plateau pressure was recorded from two breaths each at four different tidal volumes (15, 30, 45, and 60 mL). Lung compliance was expressed as mL/cm H₂O and assessed by percent recovery after CPB.

After the functional assessment, lung biopsy specimens were immediately frozen and stored in liquid nitrogen and tissue levels of hydroxyconjugated dienes were determined as described previously [13]. The content of conjugated dienes was expressed as absorbance at 233 nm (A₂₃₃ nm/mg lipid). Another lung specimen was taken to measure lung water content and expressed as percent of wet weight.

Statistical Analysis
Data were analyzed with StatView V2.0 on an Apple Macintosh IICi. Analysis of variance was used for comparisons between groups. Differences were considered significant at a probability level of less than 0.05. Group data are expressed as mean ± standard error of the mean.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
There was no difference in a/A ratio, systemic venous oxygen tension, and ventilatory settings between groups. Lung compliance was decreased and parenchymal conjugated dienes content was slightly increased in the CPB group, however, without reaching statistical significance because of a marked dispersion of the results (Table 1). Pulmonary vascular resistance index increased markedly from 83 ± 12 to 212 ± 32 (p < 0.05) after CPB without treatment [CPB]. Conversely, adding antioxidants to pump prime [MPG + CAT] substantially avoided pulmonary vasoconstriction after bypass and retained almost normal pulmonary vascular resistance after discontinuing bypass (Fig 1). Hemodynamic changes before and after CPB were summarized in Table 2.

View larger version (15K): [in this window] [in a new window]   Fig 1. . Alterations in pulmonary vascular resistance index (PVRI). Horizontal bar indicates the values in control piglets without bypass (mean ± standard error). Note that pulmonary vascular resistance index was markedly increased after cardiopulmonary bypass (CPB) without treatment (CPB), whereas adding antioxidants, N-mercaptopropionylglycine (MPG, 80 mg/kg) and catalase 50,000 U/kg to pump prime (MPG/CAT) substantially avoided pulmonary vasoconstriction after bypass and retained almost normal pulmonary vascular resistance after discontinuing bypass.

View larger version (23K): [in this window] [in a new window]   Fig 2. . Nitrite (NO2-) and nitrate (NO3-) plasma concentrations in the pulmonary artery (PA) and the left atrial blood (LA). Samples were taken during a control period (pre) and 30 minutes and 60 minutes after discontinuing cardiopulmonary bypass (CPB) (post 30min, post 60min). (CPB = piglets underwent 120 minutes of cardiopulmonary bypass without additives; MPG/CAT = piglets underwent 120 minutes of cardiopulmonary bypass with N-mercaptopropionylglycine (MPG, 80 mg/kg) and catalase (50,000 U/kg) added to the prime.)

View larger version (16K): [in this window] [in a new window]   Fig 3. . Pulmonary nitrite (NO2-)/nitrate (NO3-) production. Horizontal bar indicates the values in control piglets without bypass (mean ± standard error). Cardiopulmonary bypass without treatment (CPB) reduced nitric oxide (NO) (NO2- + NO3-) production assessed by 70% after discontinuing bypass, whereas adding antioxidants to pump prime (MPG/CAT) markedly limited a reduction in NO (NO2-/NO3-) production after cardiopulmonary bypass.

View larger version (19K): [in this window] [in a new window]   Fig 4. . Right ventricular performance. Right ventricular performance was evaluated preoperatively (pre) and postoperatively (post) by recording right ventricular function curves, right ventricular stroke work index (RVSWI) versus central venous pressure (CVP). (CPB = piglets underwent 120 minutes of cardiopulmonary bypass without additives; MPG/CAT = piglets underwent 120 minutes of cardiopulmonary bypass with MPG and catalase added to the prime.)

View larger version (30K): [in this window] [in a new window]   Fig 5. . Right ventricular functional recovery. Postoperative right ventricular functional recovery was expressed as percent of control right ventricular stroke work index at a central venous pressure of 8 mm Hg. (Control = piglets without cardiopulmonary bypass; CPB = piglets underwent 120 minutes of cardiopulmonary bypass without additives; MPG/CAT = piglets underwent 120 minutes of cardiopulmonary bypass with MPG and catalase added to the prime; *p < 0.05 versus control; p < 0.05 versus cardiopulmonary bypass.)

View larger version (30K): [in this window] [in a new window]   Fig 6. . Postoperative left ventricular performance. (Control = piglets without cardiopulmonary bypass; CPB = piglets underwent 120 minutes of cardiopulmonary bypass without additives; Ees = end-systolic elastance; MPG/CAT = piglets underwent 120 minutes of cardiopulmonary bypass with MPG and catalase added to the prime.)

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

Vascular endothelium is known to regulate a vascular tone by releasing vasoactive mediators, including endothelium-derived relaxing factor (EDRF) and prostacyclin. It is well established that endothelium (in coronary [6], pulmonary [7], and other vascular endothelium [8, 9]) is the initial target lesion of free radical attack from extracellular sources (ie, activated leukocytes), resulting in endothelium-dependent vasoconstriction. Ohlstein and Nichols [9] have shown in an in vitro study that activated neutrophils, which are casually involved in CPB, caused endothelium-dependent vasoconstriction in the normal rabbit aortic segments. In the present study, EDRF or nitric oxide was determined in plasma as its oxidation product, nitrite (NO₂^-) and nitrate (NO₃^-) because of its short half-life [19]. Because the biological reaction of NO can be accounted for by spontaneous oxidation of NO to NO₂^- and NO₃^-, their measurement allows for determination of the respective NO concentration. We confirmed in vivo that CPB per se produces pulmonary vasoconstriction in parallel to reduced pulmonary NO₂^-/NO₃^- production. Nevertheless, we cannot provide direct evidence for endothelial dysfunction in the present study where an impaired response to endothelium-dependent vasodilator was not tested, and a direct link between pulmonary vasoconstriction and reduced production of NO cannot be established conclusively. Furthermore other vasoactive mediators, such as endothelin, prostaglandins, and bradykinin, may be involved in the pathogenesis of the observed pulmonary vasoconstriction.

Oxidants are known to induce vasoconstriction or endothelial dysfunction, and it is well documented that O₂^- is responsible for inactivating EDRF, resulting in vasoconstriction [6, 20]. On the other hand, hydrogen peroxide and subsequent production of hydroxyl radical seem to be the principal effectors of a more profound type of endothelium damage and subsequent morphologic disruption [21]. A recent study suggests that O₂^- may interact with EDRF (NO) to generate peroxynitrite (OONO^-) that decomposes to highly reactive hydroxyl radical [22]. Marczin and colleagues [7] have shown that brief exposure to H₂O₂ causes a dose-dependent impairment of pulmonary endothelial function (EDRF release). They used cocultures of calf pulmonary artery endothelial cells and rabbit pulmonary artery smooth muscle cells; they postulated that EDRF synthesis, assessed by cyclic guanosine monophosphate formation in smooth muscles, was inhibited by hydrogen peroxide and iron-catalyzed hydroxyl radical formation that attacked cellular thiols. To assess the importance of a reduced NO production by endothelial damage rather than the inactivation of an otherwise normally produced NO, we tested the effects of MPG (hydroxyl radical scavenger) and catalase (scavenger for hydrogen peroxide), none of which is targeted at scavenging O₂^- (the primary responsible for NO inactivation). Our observations showing the protective effects of MPG and catalase are quite in accordance with the findings by Marczin and co-workers [7] and strongly suggest that these oxidant species, rather than the inactivation of EDRF by O₂^-, are responsible for the pathogenesis of pulmonary vasoconstriction after bypass.

From the present study, we concluded that CPB impairs pulmonary NO₂^-/NO₃^- production, resulting in vasoconstriction and a subsequent decrease in right ventricular performance, and that these deleterious effects of CPB in immature piglets can be avoided by adding antioxidants. These findings infer indirectly that the oxidant-mediated pathway is involved in the pathogenesis of nitric oxide-related pulmonary vasoconstriction after bypass, and validate the use of inhaled NO for treatment of postoperative pulmonary hypertension in neonates [23], to supplement endogenous EDRF production.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
We thank Garland Hodges, Russell Byrns, and Nanci Stellino for technical assistance, and Judith Becker for word processing assistance.

This research was supported by National Heart, Lung, and Blood Institute grants HL-40675 and HL-40922 and by the University of California Tobacco-Related Disease Research program.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr Morita, 3-19-18 Nishi-shimbashi, Minato-ku 105, Tokyo, Japan.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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This Article Abstract 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): Kai Ihnken Gerald D. Buckberg Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Morita, K. Articles by Ignarro, L. J. Search for Related Content PubMed PubMed Citation Articles by Morita, K. Articles by Ignarro, L. J.