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Ann Thorac Surg 1999;67:522-527
© 1999 The Society of Thoracic Surgeons

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Original Articles

Effects of chronic pulmonary overcirculation on pulmonary vasomotor tone

^b Division of Cardiothoracic Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
^a Department of General Surgery, Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
^c Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
^d Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
^e Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA

Accepted for publication July 11, 1998.

Address reprint requests to Dr Bousamra, Division of Cardiothoracic Surgery, Medical College of Wisconsin, 9200 W Wisconsin Ave, Milwaukee, WI 53226

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. A model of shunt-induced pulmonary hypertension was used to study the effects of pulmonary overcirculation on endothelial nitric oxide synthase (eNOS) and cytochrome P450-4A (cP450-4A) vasodilatory mechanisms and related hemodynamic responses.

Methods. An aortopulmonary shunt was constructed in 6-week-old piglets (n = 7, sham-operated controls n = 8). Hemodynamic measurements were made 4 weeks later under serial experimental conditions: baseline (fractional concentration of oxygen, 0.4); inhaled nitric oxide, 25 ppm (INO); hypoxia (fractional concentration of oxygen, 0.14); hypoxia + INO; N-nitro-L-arginine methylester (L-NAME 30 mg/kg intravenously, competitive NOS inhibitor); and L-NAME + INO. Lung protein levels of eNOS and cP450-4A and NOS activity were compared between groups.

Results. Shunted animals had a higher baseline pulmonary artery pressure (p < 0.05). L-NAME resulted in a greater increase in pulmonary vascular resistance in shunted animals (150% ± 26% shunt versus 69% ± 14% control; p = 0.01). The INO administered during baseline conditions decreased pulmonary vascular resistance only in control animals (p < 0.05). Protein levels of eNOS and NOS activity were similar in both groups; however, cP450-4A protein levels were decreased in the shunted group (p = 0.02).

Conclusions. The NO production was preserved in shunted animals but they demonstrated greater vasodilatory dependence on NO, evidenced by an exaggerated increase in pulmonary vascular resistance after NOS inhibition. Loss of the cP450-4A vasodilatory system may be the driving force for NO dependency in the shunted pulmonary circulation.

	Introduction

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Effective therapy for congenital heart disease associated with systemic-to-pulmonary shunting can be compromised by the development of pulmonary hypertension [1]. Although end-stage pulmonary hypertension (Eisenmenger’s complex) has become an uncommon entity with early detection of congenital heart defects, even modest degrees of pulmonary hypertension can have profound clinical ramifications. For example, infants with large ventricular septal defects, truncus arteriosus, and atrioventricular canal defects are prone to perioperative pulmonary hypertensive crises. Alternatively, children with single ventricle physiology must maintain low pulmonary vascular resistance (PVR) during infancy, in spite of surgically created systemic-to-pulmonary artery shunts, to be candidates for subsequent Fontan palliation.

Nitric oxide (NO) has been shown to be an important endogenous pulmonary vasodilator that may have a role in the pathogenesis of pulmonary hypertension [2, 3]. In an isolated perfused ferret lung preparation, Chammas and colleagues [4] demonstrated flow-induced pulmonary vasodilation that was reversed by nitric oxide synthase (NOS) inhibition. Similarly, in an adult canine model of pulmonary overcirculation, Zangwill and associates [5] found that opening a subclavian artery-to-pulmonary artery shunt produced an increase in pulmonary artery pressure and pulmonary vascular resistance only after competitive blockade of NOS. Together these studies suggest that flow-induced pulmonary vasodilation is mediated through NO. Celermajer and colleagues [6] studied children with increased pulmonary blood flow with fixed pulmonary vascular disease and demonstrated no vasodilatory response to acetylcholine, an endothelium-dependent vasodilator, or the NO donor, nitroprusside. Giaid and Saleh [7] demonstrated that adult patients with pulmonary hypertension resulting from congenital heart defects were found to have decreased immunohistochemical staining for endothelial NOS (eNOS) in lung biopsy specimens compared to controls. Taken together these clinical investigations imply that patients with end-stage pulmonary vascular disease have dysfunction of NO-dependent vasodilatory mechanisms.

Nitric oxide is only one of several endogenous agents affecting pulmonary vasomotor tone. The pulmonary vascular effects of prostaglandins and other arachidonic acid metabolites have been examined by several investigators [8–10]. Recently, Birks and colleagues [11] demonstrated that 20-hydroxyeicosatetraenoic acid, derived from arachidonic acid by the microsomal enzyme cytochrome P450-4A (cP450-4A) is produced in human lung tissue, and causes significant vasodilation in isolated human pulmonary arteries. Whether and how this endogenous compound is involved in the development of pulmonary hypertension is yet to be determined.

We hypothesized that chronic pulmonary overcirculation results in pulmonary vasomotor changes that are NO dependent. To examine this hypothesis in a model of pulmonary overcirculation, we studied the hemodynamic effects of acute hypoxia, inhaled nitric oxide, and NOS inhibition in infant swine 4 weeks after constructing an aortopulmonary shunt. In addition to the intact animal studies, we measured protein levels of eNOS and cP450-4A, as well as NOS activity, in lungs from these animals.

	Material and methods

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Pulmonary shunt procedure
Twenty weanling infant pigs were entered into the following surgical protocol, which was in compliance with the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (NIH publication 85-23, revised 1985) and approved by the Animal Studies Committees of the Zablocki Veterans Administration Hospital and the Medical College of Wisconsin. Preoperatively, the animals were sedated with an intramuscular injection of acepromazine (1.5 mg/kg) and ketamine (30 mg/kg). Normal saline was infused at 5- to 10-mL · kg^-1 · h^-1 through an ear vein. Endotracheal intubation was performed and general anesthesia was induced with halothane gas in oxygen. The animals were mechanically ventilated (tidal volume of 10 to 15 mL/kg and a respiratory rate of 15 to 20 breaths/min) and heart rate and rhythm were monitored continuously. Cefazolin (25 mg/kg) was administered intravenously for antibiotic prophylaxis.

The left hemithorax was entered through the third intercostal space. Eleven animals underwent a shunt procedure. The descending thoracic aorta was partially occluded and a 6-mm polytetrafluoroethylene graft was sewn end-to-side to the aorta 1 cm distal to the left subclavian artery. The distal end of the graft was sewn end-to-side to the partially occluded main pulmonary artery. After deairing, the graft was unclamped and demonstrated to be patent by evidence of a pulse and thrill. After hemostasis and lung expansion, the chest was drained and closed. Halothane inhalation was stopped and mechanical ventilation was maintained until respiratory function was recovered. Postoperatively, intramuscular cefazolin (25 to 30 mg/kg twice a day) and the analgesic buterphenone intramuscularly at 0.01 mg/kg every 8 hours were continued for 3 days. Intramuscular furosemide (1 mg/kg) was given every 2 to 3 days to prevent frank congestive heart failure.

Nine sham-operated animals served as controls. These animals underwent a similar thoracotomy with identical fluid, anesthetic, and ventilatory management. The aorta and main pulmonary artery were partially clamped for a similar duration without placement of an interposition graft. These animals received identical postoperative antibiotic and analgesic treatments and were allowed to recover for 4 weeks before study.

Three shunted animals died during the postoperative period due to congestive heart failure determined by clinical and postmortem examination. One died during hypoxic ventilation during experimental study. All control animals reached experimental study, although one animal was excluded from analysis because of persistent acidosis and air embolism from an unrecognized rupture of the pulmonary artery catheter balloon. Thus, eight animals in the control group and seven in the shunted group completed the surgical procedure and the subsequent experimental protocol.

Intact animal experiment
After 4 weeks the animals were studied as previously described by Nelin and colleagues [12]. Briefly, the pigs were sedated with a mixture of aceprozamine (1.5 mg/kg) and ketamine (30 mg/kg) given intramuscularly and placed supine on a servo-controlled heating blanket. Body temperature was maintained at 37° to 38°C. Each pig was anesthetized with intravenous sodium pentobarbital (10 mg/kg) and dosing was repeated hourly (5 mg/kg). Pancuronium bromide (0.1 mg/kg) was administered intravenously every 15 to 30 minutes to maintain paralysis. Shunt patency was confirmed by auscultation. Tracheostomy was performed, and the animal was ventilated with a tidal volume of 10 to 12 mL/kg and a rate of 12 to 18 breaths/min. End-expiratory pressure was set at 1 to 2 mm Hg. A polyethylene cannula was advanced through the carotid artery into the aorta for blood pressure monitoring and a second cannula placed in the left internal jugular vein for cardiac output injections. The right external jugular vein was cannulated with a 7F thermistor-tipped pulmonary artery catheter and positioned to permit measurement of balloon occlusive pulmonary artery wedge pressure (PAW). The pulmonary arterial pressure (PAP), and aortic blood pressure were measured continuously. The PAW was measured at end-expiration during each experimental condition. Oxygen saturation was measured from blood samples obtained from the right ventricle (mixed venous), pulmonary artery, and aorta in three shunted animals. Machine failure prevented further determinations. The hematocrit was measured at the start of each study, then periodically throughout the experiment. Arterial blood partial pressure of oxygen, carbon dioxide, and pH were determined after stabilization during each condition studied. Tidal volume and rate were adjusted to maintain the partial pressure of carbon dioxide between 35 and 40 mm Hg. Intravenous administration of sodium bicarbonate was used to maintain the pH at 7.35 to 7.45.

Pulmonary blood flow (PBF) was measured by thermodilution using a cardiac output computer (model 9520; American Edwards, Santa Ana, CA) with a bolus injection of 5 mL of room temperature saline into the left internal jugular catheter. The reported values for PBF are the average of three injections under each condition. The PVR was calculated as

The following sequence of ventilatory conditions were studied: baseline (fractional concentration of oxygen, 0.4); baseline + 25 ppm inhaled NO (INO); baseline; hypoxia (fractional concentration of oxygen, 0.14); and hypoxia + 25 ppm NO (H + INO). After returning to baseline conditions and repeating the hemodynamic measurements, the NOS inhibitor N-nitro-L-arginine methylester (L-NAME 30 mg/kg intravenously) was given and measurements were repeated during L-NAME (fractional concentration of oxygen, 0.4) and L-NAME + INO. The control and hypoxic gas mixtures were made with calibrated flow meters. NO in N₂ was bled into the inhaled line and NO and NO₂ concentrations were measured by using an electrochemical detector [13].

At the conclusion of each experiment, the animal was euthanized by exsanguination, and a postmortem examination was performed. The heart was harvested for right ventricular free wall and left ventricular wet and dry weights and shunt patency was confirmed. Wedge lung biopsies of the right lower lobe were obtained and immediately frozen in liquid nitrogen and stored at -80°C for subsequent Western blot analyses and NOS activity assays. Western blot analyses were prepared according to the methods previously reported by Birks and colleagues [11]. 135-Kd and 55-Kd bands were selected for eNOS and cP450-4A analyses, respectively.

Nitric oxide synthase activity
Using the same microsomal preparations from the lung tissue homogenates of sham and shunt pigs, we determined nitric oxide synthase activity by measuring the conversion of radiolabeled arginine to citrulline. Samples containing 100 µg of protein were incubated with ³H-L-arginine (0.2 µCi, 20 µmol/L) in 100 µL of assay buffer (20 mmol/L 5N-[2-hydroxyethyl] piperazine-N-N’-[2-ethanesulfonic acid], 2 mmol/L CaCl₂, 1 mmol/L NADPH, 1.25 µg/mL calmodulin, 2.5 µmol/L flavin adenine dinucleotide, 1 µmol/L flavin mononucleotide, 20 µmol/L tetrahydrobiopterin) for 5 minutes at 37°C. The reactions were stopped by adding 50 µL of 20 mmol/L ethyleneglycol-bis-N,N,N’,N’,-tetraacetic acid. An aliquot (35 µL) of the radioactive sample was derivatized with 70 µL of o-phtaldialdehyde reagent (#P-0532; Sigma, St. Louis, MO). Products were then separated on a C-18 reverse phase high-performance liquid chromatography column, using an isocratic flow consisting of 11.5% methanol, 11.5% acetonitrile, 1% tetrahydrofuran, and 0.1 mol/L KH₂PO₄. Radioactive products were monitored using an on-line radioactive flow detector (model 171; Beckman, San Ramon, CA).

Statistical analysis
Hemodynamic values between the sham and shunted animals were compared using analysis of variance with a Neuman-Keuls post-hoc test. The differences between conditions in the same animal group were compared using a paired t test. Analysis of variance was also used for comparison of band density in Western blots. The NOS activity results were compared with an unpaired t test. A p value less than 0.05 was considered statistically significant.

	Results

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
General similarities between control and shunted animals with respect to size, weight gain, arterial blood gases, and hematocrit are reflected in Table 1. The presence of a hemodynamically significant systemic-to-pulmonary shunt was demonstrated by biventricular enlargement (Table 1), an increased systemic pulse pressure, and a mean Qp/Qs = 1.5 (Table 2 ) in shunted animals. Baseline hemodynamic data are compared between groups in Table 2. Shunted animals demonstrated an elevated mean PAP and an increased wedge pressure. Baseline pulmonary vascular resistance was unchanged by the shunt procedure.

View larger version (106K): [in this window] [in a new window]   Fig 1. (A) Cross section of a small pulmonary artery from a shunted animal demonstrating medial hypertrophy. (B) Pulmonary arteriole of a shunted animal demonstrating medial thickening and intimal hyperplasia.

View larger version (18K): [in this window] [in a new window]   Fig 2. Bar graph depicting pulmonary vascular resistance (PVR), expressed as percent change from baseline during each experimental condition. (INO = inhaled nitric oxide [25 ppm] given during baseline conditions; H = hypoxia [fractional concentration of oxygen, 0.14]; H+INO = inhaled nitric oxide administered during hypoxic ventilation; NAME = nitric oxide synthase inhibitor administered intravenously as 30 mg/kg; NAME+INO = inhaled nitric oxide added to the ventilation gas [fractional concentration of oxygen, 0.4] after the infusion of nitric oxide synthase inhibitor.) *Different from sham, p < 0.05.

Western blot analyses demonstrated similar levels of the constitutive enzyme eNOS in both groups but decreased cP450-4A levels in the shunted group (p < 0.05) (Fig 3 ). NOS activity assays also revealed a similar degree of enzyme activity in both groups (mean, 1.53 ± 0.07 nmol of citrulline/mg protein per minute sham versus 1.48 ± 0.12 nmol of citrulline/mg protein per minute shunt).

View larger version (16K): [in this window] [in a new window]   Fig 3. Summary of Western blot analyses. Densitometry of immunospecific protein bands were determined on a scanning laser densitometer with uniform background correction. (cP450-4A = cytochrome P450-4A; eNOS = endothelial nitric oxide synthase.) Values are stated as mean ± standard error of the mean, *p < 0.05 sham versus shunt.

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

Pulmonary blood flow was measured using the thermodilution technique with a Swan-Ganz catheter placed in a lobar artery. Although there may be some inherent problems with this method used in the shunted animal, the measurements obtained were highly reproducible within a given animal with values consistently within 10% of each other. Alternative methods of pulmonary blood flow measurement also have draw backs in this setting. Use of the Fick principle involves measurement of mixed venous saturation within the pulmonary artery, but inhomogenous mixing of blood distal to the shunt may yield inconsistent mixed venous saturation values. Measurements obtained by ultrasonic flow probes may be inaccurate due to the turbulence associated with the shunt. In addition, their placement requires reoperative thoracotomy. In this experiment the use of the thermodilution technique avoided a repeat thoracotomy necessary for direct methods of measuring pulmonary blood flow. Thus, extensive mediastinal dissection with its inherent tissue trauma, blood loss, and associated systemic responses did not complicate our results.

Several inferences can be made from the series of hemodynamic studies. In the sham-operated group, treatment with inhaled NO caused a small but significant decrease in basal pulmonary vascular resistance. This suggests that in the sham-treated animals there was some basal pulmonary vascular tone. This finding is consistent with previous studies in intact pigs wherein inhaled NO caused a small but significant decrease in pulmonary vascular tone [12]. In contrast, the shunted animals had no response under basal conditions to inhaled NO. One possible explanation for this is that the shunted animals had no basal pulmonary vascular tone, that is, the pulmonary vasculature was maximally dilated. The difference between the sham and shunted animals would suggest a role for flow-induced pulmonary vasodilation in the shunted animals. It has previously been found that flow-induced pulmonary vasodilation does occur in the lung [4].

The most notable physiologic contrast between the two groups was the pulmonary hemodynamic response to the infusion of L-NAME. The PVR increase in the shunted animals was twice that of the sham animals. This suggests that the flow-induced vasodilation seen in the shunted animals was NO dependent. This is consistent with the findings of Zangwill and colleagues [5] who found that opening a subclavian artery-to-pulmonary shunt only produced a change in PVR in dogs after inhibition of NOS. Similarly, x-ray angiographic studies in isolated lungs found that flow-induced pulmonary arterial dilation was completely inhibited by L-NAME [4]^.Therefore, it seems likely that the shunted animals demonstrated NO-dependent flow-induced pulmonary vasodilation to maintain a low pulmonary vascular resistance. A second possibility is that the shunt procedure resulted in down-regulation of other vasodilatory pathways, such that the pulmonary circulation become dependent on endogenous NO production to maintain a low PVR. Support for this conclusion comes from the cP450A data, where we found that the shunt procedure decreased protein levels of cP450A. This would suggest that levels of 20-hydroxyeicosatetraenoic acid, a potent vasodilator, were decreased in the shunted lungs. Therefore, it may be that the interaction between the various vasodilator pathways is altered by the shunt procedure.

It has been shown repeatedly in cell cultures that pulmonary arterial endothelial cells subjected to flow have increased NO production and increased eNOS protein compared to cells subjected to no flow [14, 15]. Consistent with this finding in pulmonary arterial endothelial cells one might expect that the shunted animals would have an increase in eNOS protein compared to the sham animals. However, we found that the levels of eNOS and the NOS activity were not different between the two groups. Thus, it may be that the change in flow caused by the shunt was not enough to result in increased eNOS protein and activity.

Our experiments demonstrated no significant difference between the two groups in their PVR response to hypoxia or hypoxia+INO. In contrast, De Canniere and colleagues [16] observed that compared to sham operated pigs, pigs with an aortopulmonary shunt of 2 months’ duration had blunted pulmonary vascular reactivity in response to acute hypoxia. This difference in results may be attributable to the duration of exposure to pulmonary overcirculation. In the experiments of De Canniere and associates [16], the shunted pigs were subjected to pulmonary overcirculation for a minimum of 8 weeks, whereas our shunted pigs were studied after 4 weeks of pulmonary overcirculation.

The two groups also differed significantly in their response to inhaled NO after infusion of L-NAME. The PVR in the sham group returned essentially to basal levels, whereas the PVR in the shunted group remained significantly elevated. This difference may be due to arterial remodeling seen in the shunted animals. After treatment with L-NAME these arteries might be expected to vasoconstrict more than normal arteries owing to medial hypertrophy, thus manifesting a higher PVR response. If the arteries, which were significantly constricted by L-NAME in the shunted animals, were anatomically distant from the alveolus, then one might expect that these arteries would not dilate to inhaled NO. This concept is consistent with recent x-ray angiographic findings suggesting that arteries >900 µm do not respond to inhaled NO [17]. This finding may have implications as to why some children with pulmonary overcirculation due to congenital heart disease do not respond well to inhaled NO.

We conclude that NO production is preserved in the early stages of shunt-induced pulmonary hypertension and that it becomes the dominant vasodilatory pathway maintaining a low PVR, such that its abolishment leads to marked pulmonary hypertension. The compromise of an alternative endogenous vasodilatory mechanism, such as the cytochrome P450-4A pathway, could be the driving force behind the greater NO dependence seen in the shunted animals. Furthermore, these results may have implications in timing of operative repair of congenital heart lesions associated with pulmonary overcirculation. We speculate that some children with congenital heart disease may be refractory to INO therapy because of hypertrophy of vessels upstream of the alveolar gas.

	Acknowledgments

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We thank Dr Candice Fike, Mark Kaplowitz, and Carol Thomas for their assistance.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments 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): Michael Bousamra, II Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Parviz, M. Articles by Nelin, L. D. Search for Related Content PubMed PubMed Citation Articles by Parviz, M. Articles by Nelin, L. D.