Original Article
Impairment of Endothelium-Dependent Pulmonary-Artery Relaxation in Chronic Obstructive Lung Disease
N Engl J Med 1991; 324:1539-1547May 30, 1991
- Abstract
- Abstract
Background.
Endothelial cells release endothelium-derived relaxing factor (EDRF) in a variety of vascular beds, including the pulmonary circulation. However, the role of EDRF-mediated pulmonary-artery relaxation in chronic hypoxic lung disease is unknown.
Methods.
We studied endothelium-dependent relaxation mediated by EDRF in vitro in pulmonary arteries that had been obtained from 22 patients undergoing heartlung transplantation for end-stage chronic obstructive lung disease. Control pulmonary arteries were obtained from 15 patients undergoing lobectomy for lung carcinoma who did not have evidence of other chronic lung disease. The responses of all vascular rings (external diameter, 1.2 to 3.4 mm) to the endothelium-dependent vasodilators acetylcholine and adenosine diphosphate were studied immediately after lung excision.
Results.
Pulmonary arterial rings from the patients with chronic lung disease developed a greater tension (2.19±0.16 g) in response to phenylephrine (10–6 M) than the rings from control patients (1.28±0.18 g, P<0.05). Inhibition of EDRF synthesis by treatment with NG-monomethyl-L-arginine (10–4 M) eliminated this difference, increasing the tension in the rings from the controls (P<0.01) but not in those from the patients with chronic lung disease. Rings from control patients relaxed in response to cumulative doses (10–10 to 10–5 M) of acetylcholine (maximal relaxation, 81.3±3.9 percent) and adenosine diphosphate (maximal relaxation, 85.3±2.6 percent). By contrast, rings from patients with chronic obstructive lung disease achieved only 41.3±4.8 percent of maximal relaxation in response to acetylcholine (n = 32) and 49.4±5.5 percent in response to adenosine diphosphate (n = 24) (P<0.001, as compared with control rings). Rings from both the controls and the patients with chronic lung disease relaxed similarly in response to the endothelium-independent vasodilator sodium nitroprusside (10–4 M). There was an inverse correlation between the degree of intimal thickening and the level of maximal relaxation of the rings from the patients with chronic lung disease (r = -0.60, P<0.001). Maximal relaxation was also related directly to the partial pressure of arterial oxygen before transplantation (r = 0.68, P<0.01) and inversely to the partial pressure of arterial carbon dioxide before transplantation (r = -0.55, P<0.01), but not to the forced expiratory volume in one second (r = 0.19, P not significant).
Conclusions.
Endothelium-dependent pulmonary-artery relaxation in vitro is impaired in arteries from patients with end-stage chronic obstructive lung disease. Such impairment may contribute to the development of pulmonary hypertension in chronic hypoxic lung disease. (N Engl J Med 1991; 324:1539–47.)
Article Activity
- Article
CHRONIC obstructive lung disease causing hypoxemia leads to the development of pulmonary hypertension and cor pulmonale.1 The prognosis of cor pulmonale is determined by the severity of the pulmonary hypertension.2 However, the manner in which prolonged alveolar hypoxia causes chronic pulmonary hypertension remains unknown.3
In rats, the induction of chronic hypoxia causes ultrastructural changes of the endothelial cells of pulmonary vessels.4 In patients, pulmonary hypertension secondary to chronic obstructive lung disease is associated with thickening of the intima of the pulmonary arteries.5 Furthermore, the degree of intimal thickening is related to the severity of lung disease.5 , 6
Endothelial cells release potent and locally active vasodilators — namely, prostacyclin and endothelium-derived relaxing factor (EDRF).7 EDRF is one of the most powerful endogenous vasodilators8 and is now identified with nitric oxide.9 The synthesis of nitric oxide requires a substrate, L-arginine,10 and is stereospecifically inhibited by the L-arginine analogue N G-monomethyl-L-arginine.11
Impairment of EDRF activity has been documented in essential systemic hypertension12 and in coronary artery disease.13 , 14 Loss of pulmonary endothelium-dependent relaxation has been demonstrated in rats with chronic hypoxic pulmonary hypertension.15 Preliminary data also suggest that such impairment occurs in patients with Eisenmenger's syndrome16 and in patients with cystic fibrosis who are in chronic respiratory failure.17 However, it is not known whether the seventy of lung disease or the degree of hypoxemia and hypercapnia contributes to this impaired vasoreactivity of pulmonary arteries, nor is it known whether the vasodilator responses to pharmacologic stimuli in vitro and the characteristic histologic abnormalities of the pulmonary arteries of patients with chronic obstructive lung disease are in any way related.
Combined heart—lung transplantation, a treatment for end-stage lung disease,18 including cystic fibrosis,19 allows in vitro study of isolated pulmonary arteries from explanted lungs.16 , 17 We have therefore assessed the pharmacologic responses and histologic changes observed in isolated pulmonary arteries obtained from 22 patients undergoing heart—lung transplantation for end-stage cystic fibrosis, emphysema, or bilateral bronchiectasis associated with purulent chronic bronchitis. Control pulmonary arteries were obtained from 15 patients undergoing thoracic surgery for lung carcinoma.
Methods
Subjects
We studied 22 patients with severe chronic obstructive lung disease and 15 control patients with no evidence of chronic lung disease. The patients with chronic disease underwent heart—lung transplantation, and the controls had lobectomy or pneumonectomy for lung carcinoma. Their clinical data are shown in Table 1Table 1
Clinical Characteristics and Preoperative Lung Function and Arterial Blood Gas Values of the Study Groups.*. The last results of pulmonary-function tests and arterial blood gas measurements obtained before surgery were taken into account for analysis (Table 1). The last preoperative evaluation was performed two weeks to five months before surgery in the patients with chronic lung disease, and during the week before the operation in the control patients who underwent lobectomy.In Vitro Study
Immediately after lung excision, tissue was placed in cold (4°C) Krebs—Ringer bicarbonate solution equilibrated with 95 percent oxygen and 5 percent carbon dioxide, and transported to the laboratory for dissection.16 , 17
Within half an hour of removal of the lungs, the lobar, segmental, and subsegmental pulmonary arteries were dissected free, cleaned of excess fat and connective tissue, and cut into rings. When measured after dissection, these rings were 3 to 5 mm long, with an external diameter of 1.2 to 3.4 mm. Pairs of adjacent rings were cut from the middle part of pulmonary-artery segments, and the endothelium was carefully removed from one ring of each pair by gentle rubbing with a pipe cleaner inserted into the lumen.16 , 17 Rings with and without endothelium were then mounted over fine rigid wires, in organ chambers filled with 20 ml of Krebs—Ringer buffer continuously bubbled with 95 percent oxygen and 5 percent carbon dioxide and maintained at 37°C by an outer water bath warmed by a recirculating heater (Circulator C-400, Techne Ltd., Cambridge, United Kingdom). Changes in isometric tension were recorded with a force transducer (Category No. 52–9529, Harvard Bioscience, South Natick, Mass.) with use of a two-channel chart drive recorder (PM 8252A, Philips, Eindhoven, the Netherlands).
The rings were progressively stretched until the optimal point of the length—tension relation was reached. Each ring was then allowed to equilibrate in the bath for at least 90 minutes (range, 90 to 180), during which the fluid in the bath was changed every 15 minutes.
After equilibration, all rings were preincubated with indomethacin (10–5 M) for 30 minutes before study, to inhibit the synthesis of cyclooxygenase products of arachidonic acid. Thereafter indomethacin was present in the bath throughout the experiment. Phenylephrine dichloride (10–6 M) was added to cause submaximal precontraction of the rings, thus giving a stable plateau of tension. The endothelium-dependent vasodilators acetylcholine dichloride and adenosine diphosphate were then added at increasing concentrations (10–10 to 10–5 M) to the preparation of rings with and without endothelium, which were studied in pairs. Two pairs of rings from each of the first 12 control patients (Patients 23 through 34) (one ring with and one without endothelium) were studied on each occasion, one pair being exposed to acetylcholine and the other to adenosine diphosphate. A total of 32 pairs of rings from the 22 patients with chronic obstructive lung disease were challenged with acetylcholine, and 24 pairs of rings from 15 of the 22 (Patients 1 through 15) were challenged with adenosine diphosphate. To assess the reproducibility of the vascular responses to pharmacologic agents, we studied two or three pairs of rings of similar sizes from different parts of both lungs from the same patient, for 10 of the 22 patients with chronic lung disease. Sodium nitroprusside at a concentration of 10–4 M — a value previously determined to produce maximal relaxation in a series of preliminary experiments — was added to the bath at the end of all experiments.
The effect of the specific inhibitor of nitric oxide synthesis, N G-monomethyl-L-arginine,11 was studied in 10 patients with chronic lung disease (Patients 13 through 22) and 7 control patients (Patients 31 through 37). This inhibitor (10–4 M) was added, after the addition of phenylephrine (10–6 M), to one ring from each pair from the same patient. After 10 minutes, both rings were challenged with acetylcholine (10–10 to 10–5 M) and sodium nitroprusside (10–4 M), as described above.
The drugs were diluted in distilled water, except for indomethacin, which was dissolved in 50 percent ethanol. Except for the N G-monomethyl-L-arginine, which was donated by Wellcome Research Laboratories (Beckenham, Kent, United Kingdom), all the drugs were purchased from Sigma Chemical (Poole, Dorset, United Kingdom), and solutions were freshly prepared before use.
While the investigators were conducting the in vitro studies, they were not blinded to the patients' diagnoses but were unaware of the severity of disease as well as the results of the preoperative blood gas measurements and lung-function tests.
Histologic Review
After the pharmacologic tests, all the rings were fixed in 10 percent neutral buffered formaldehyde, processed overnight in a cytocentrifuge (Shandon Hypercenter Runcorn, Cheshire, United Kingdom), and embedded in paraffin wax. Transverse sections (5 μm) were stained with hematoxylin and eosin and Perls elastic—van Gieson stain, mounted in Distrene 80 (dibutylphthalate-xylene), and placed under coverslips.
All sections of paraffin wax—embedded tissue were examined by light microscopy at high-power magnification. The wall of each ring was examined. In addition, the control pulmonary arteries were evaluated for microscopical evidence of spread of carcinoma to the vascular rings.
The morphologic characteristics of pulmonary vascular rings from 12 patients with chronic obstructive lung disease (Patients 1 through 12) were assessed with a projecting microscope and a magnetized grid coupled to an image-analysis system (Reichert-Jung Mop-3). A transverse section of each ring was projected onto the grid. The crenated outline of the internal elastic lamina was traced, and its length calculated. The areas of the intima and media were measured with the cursor. In addition, the length of the internal elastic lamina (in millimeters) and two external diameters were measured. Changes in the intima were calculated by dividing the area of intima by the total wall area, and expressed as percentages.
All histologic reviews were performed by one investigator, who was unaware of the patients' diagnoses as well as the results of the in vitro studies.
Statistical Analysis
Results were expressed as the degree of absolute tension (in grams) during precontraction in response to phenylephrine. Relaxation in response to different vasodilators was expressed both as absolute tension (in grams) and as the percentage of relaxation from precontraction in response to phenylephrine. Maximal relaxation was considered to be the greatest reduction in tone obtained with a given agent.
The pharmacologic responses of the rings with or without endothelium, and those of the rings treated or untreated with N G-monomethyl-L-arginine, from the same patient were compared with the t-test for paired values. The vascular responses to acetylcholine and adenosine diphosphate observed in the rings with endothelium from both study groups were compared with the responses in the rings without endothelium, by means of analysis of variance for repeated measures, followed by a multiple range test if the F value indicated significant differences among group means.20 The values for maximal relaxation obtained with acetylcholine, adenosine diphosphate, and sodium nitroprusside in pulmonary arterial rings from both study groups were compared by t-test for unpaired values.
The relation between the area of intima, expressed as a percentage of the total area of vessel wall, and its corresponding maximal relaxation in vitro in response to either acetylcholine or adenosine diphosphate was assessed by linear regression analysis, as was the relation between preoperative values for the partial pressure of arterial oxygen (PaO2), the partial pressure of arterial carbon dioxide (PaCO2), and the forced expiratory volume in one second (FEV1) in each patient, and maximal relaxation of pulmonary vascular rings in response to acetylcholine and adenosine diphosphate. Subsequently, a multiple stepwise regression analysis was performed to evaluate the covariates independently related to maximal relaxation with acetylcholine and adenosine diphosphate.20
All data are expressed as means ±SEM. All calculated P values are two-tailed. A P value below 0.05 was considered to indicate statistical significance.
Results
Only one patient with chronic obstructive lung disease (Patient 7) was not in hypoxic respiratory failure with severe airflow obstruction (Table 1). This patient with cystic fibrosis was nonetheless accepted for heart—lung transplantation because he had had two consecutive life-threatening episodes of pneumonia.
Pharmacologic Responses
Portions of the data on the first three patients (Patients 1, 2, and 3) have been published in a preliminary report.17
Among the pulmonary arterial rings from the control patients, the absence of endothelium was associated with a greater absolute level of tension induced by phenylephrine (10–6 M) than was the presence of endothelium (1.59 ± 0.21 vs. 1.28±0.18g, P<0.01) (Table 2Table 2
Vascular Responses of Pulmonary Arterial Rings to Phenylephhne and Vasodilators.). However, among the patients with chronic obstructive lung disease there was no difference in response between the rings with and those without endothelium (2.19±0.16 g and 2.22±0.18 g, respectively) (Table 2). When the rings with intact endothelium were compared, those from patients with chronic lung disease had a greater tension than those from controls (P<0.05) (Table 2). When rings without endothelium were compared, no significant difference between the groups was apparent.In rings with intact endothelium from the patients with chronic obstructive lung disease, measurement of the reproducibility of the relaxation in response to acetylcholine and adenosine diphosphate in 10 patients demonstrated intrasubject coefficients of variation of 11.9±1.9 percent (range, 2 to 22 percent). Rings without endothelium showed no relaxation and even showed contraction with high doses (10–6 to 10–5 M) of acetylcholine (P<0.001) (Fig. 1Figure 1
Responses of Pulmonary Arterial Rings with (Upper Panels) and without (Lower Panels) Endothelium to Cumulative Doses of Acetylcholine in a Control Subject and Patients with Bilateral Bronchiectasis, α1-Antitrypsin Deficiency, and Cystic Fibrosis. and 2Figure 2
Endothelium-Dependent Relaxation in Rings without (Open Symbols) and with (Closed Symbols) Endothelium in Response to Cumulative Doses of Acetylcholine and Adenosine Diphosphate in Control Patients (Circles) and Patients with Chronic Obstructive Lung Disease (Squares).). Endothelium-dependent relaxation in response to acetylcholine was reduced in pulmonary arterial rings from patients with chronic disease as compared with those from controls (Fig. 1 and 2 and Table 2) (maximal relaxation, 41.3±4.8 percent vs. 81.3±3.9 percent; P<0.001), as was relaxation in response to adenosine diphosphate (Fig. 2 and Table 2) (maximal relaxation, 49.4±5.5 percent vs. 85.3±2.6 percent; P<0.001).Expressing the tension developed in the rings in absolute values gave similar results. The lowest tension achieved with acetylcholine (1.16±0.1 g) and adenosine diphosphate (0.88±0.08 g) was significantly greater (P<0.01) in rings from patients with chronic lung disease than the lowest tension achieved in control rings (maximal relaxation, 0.24±0.06 g in response to acetylcholine and 0.16±0.03 g in response to adenosine diphosphate). By contrast, the lowest tension that was obtained with the endothelium-independent vasodilator sodium nitroprusside was similar in the rings from the patients with chronic lung disease (0.19±0.04 g) and the control patients (0.12± 0.04 g).
There was a larger intersubject variation in the maximal relaxation with acetylcholine and adenosine diphosphate among patients with chronic obstructive lung disease (range, 8 to 89 percent) than among controls (range, 62 to 100 percent) (Fig. 3Figure 3
Maximal Relaxation of Pulmonary Arterial Rings in Response to Acetylcholine, Adenosine Diphosphate, and Sodium Nitroprusside in Each Control Patient and Each Patient with Chronic Obstructive Lung Disease.). Sodium nitroprusside relaxed to the same extent all pulmonary arterial rings with or without endothelium in both study groups (Fig. 3 and Table 2).N G-monomethyl-L-arginine had no effect on the tension that developed after rings without endothelium were treated with phenylephrine (10–6 M), but significantly increased tension further (P<0.01) in rings with intact endothelium from control patients. No significant rise in tension occurred in rings with intact endothelium from patients with chronic lung disease when these rings were treated with N G-monomethyl-L-arginine. The level of tension in control rings treated with this agent (1.91 ±0.4 g) was comparable to the level in untreated rings from the patients with chronic lung disease (1.84±0.23 g, P not significant) (Table 3Table 3
Effects of Inhibition of EDRF (Nitric Oxide) Synthesis on Vascular Responses of Pulmonary Arterial Rings to Phenylephrine and Vasodilators.). In both study groups, N G-monomethyl-L-arginine significantly (P<0.01) reduced relaxation in response to acetylcholine but had no effect on relaxation in response to sodium nitroprusside (Table 3). The degree of impairment of endothelium-dependent relaxation in response to acetylcholine caused by N G-monomethyl-L-arginine in control rings (38.6±6.7 percent) was similar to that in untreated rings from patients with chronic lung disease (44.7±5.9 percent, P not significant) (Table 3).Physiologic Correlates
The average maximal relaxation in response to acetylcholine and adenosine diphosphate in each patient with chronic obstructive lung disease correlated directly with the preoperative PaO2 (r = 0.68, P<0.01) and inversely with the preoperative PaCO2 (r = -0.55, P<0.01) but not with the FEV1 (r = 0.19, P not significant) (Fig. 4Figure 4
Maximal Relaxation of Intact Pulmonary Arterial Rings in Response to Acetylcholine and Adenosine Diphosphate, in Relation to Pretransplantation Values for PaO2, PaCO2, and FEV1 in the Patients with Chronic Obstructive Lung Disease.). Multiple regression analysis indicated that the PaO2 and FEV1 were covariates independently related to endothelium-dependent relaxation. Together these two variables accounted for 52 percent of the variance in maximal relaxation in response to acetylcholine and adenosine diphosphate in the patients with chronic disease; by itself, PaO2 accounted for most of the variance (R2 = 46 percent).Histologic Correlates
Histologic examination confirmed the presence of the endothelial layer in all vascular rings in which care had been taken not to damage the intimal surface, and the absence of endothelium was confirmed in all rings in which the endothelial cells had been intentionally removed. No carcinomatous spread to vascular rings was seen in the control pulmonary arteries.
Morphometric measurements showed a significant inverse relation between the degree of intimal thickening of a ring and its ability to relax in response to either acetylcholine (n = 19) or adenosine diphosphate (n = 17) (r = -0.60, P<0.001) (Fig. 5Figure 5
Maximal Relaxation of Pulmonary Arterial Rings in Relation to intimal Thickening.).Discussion
This study confirms our preliminary data17 and extends the results obtained in 3 patients with cystic fibrosis17 to a group of 22 patients with chronic obstructive lung disease, including cystic fibrosis, emphysema, and bilateral bronchiectasis. Furthermore, we found that impairment of endothelium-dependent pulmonary-artery relaxation in vitro was related to preoperative levels of hypoxemia and hypercapnia but not to the severity of airways obstruction caused by the diseases. We also found a significant correlation between the degree of intimal fibromuscular thickening and the reduced in vitro endothelium-dependent relaxation of pulmonary vascular rings from patients with chronic obstructive lung disease.
Rings from patients with chronic lung disease developed a greater tension in response to phenylephrine than rings from controls. This could reflect supersensitivity of vascular smooth muscle to phenylephrine in patients with chronic lung disease. However, the difference between the two study groups in their response to phenylephrine was seen only in rings whose endothelium was intact. Removal of the endothelium resulted in the development of a significantly greater tension in response to phenylephrine in the rings from controls but not in the rings from patients with chronic lung disease. The same result was achieved when rings were treated with the specific inhibitor of EDRF (nitric oxide) synthesis, N G-monomethyl-L-arginine.11 Inhibition of EDRF (nitric oxide) synthesis significantly increased the tension that developed after phenylephrine treatment in control rings but not in rings from the patients. As a result, after inhibition of EDRF production there was little difference between the two groups in the level of tension. It is recognized that release of EDRF may act as a brake on any rise in tension in normal pulmonary vessels.21 , 22 Our observations in the control rings support this view and, furthermore, indicate that impaired EDRF activity could account for the increased tension in rings from patients with chronic lung disease.
Impairment of EDRF-mediated relaxation of pulmonary arteries from patients with chronic lung disease is also indicated by the results of the studies on relaxation. Rings from control patients that had intact endothelium showed the same degree of relaxation with the endothelium-dependent vasodilators acetylcholine and adenosine diphosphate and the endothelium-independent vasodilator sodium nitroprusside.23 By contrast, physical removal of endothelium from control rings or inhibition of EDRF (nitric oxide) synthesis with N G-monomethyl-L-arginine eliminated or markedly reduced relaxation in response to acetylcholine and adenosine diphosphate but left relaxation in response to sodium nitroprusside unaffected. The same pattern of impaired relaxation in response to acetylcholine and adenosine diphosphate but not in response to sodium nitroprusside was seen in the rings with intact endothelium from patients with chronic lung disease. The physical or functional, integrity of the endothelium is therefore an important determinant of vascular responsiveness to both vasoconstrictor and vasodilator agents.21 22 23
The impairment of pulmonary-endothelium—dependent relaxation may result from failure of endothelial cells to synthesize or release EDRF, limitation of the diffusion of EDRF through the remodeled intima, or inability of the underlying vascular smooth muscle to relax with EDRF. The latter seems unlikely since sodium nitroprusside relaxed all pulmonary vascular rings that failed to respond to acetylcholine (Fig. 1) or adenosine diphosphate. This relaxation was independent of the presence of the endothelium23 and, more important, was similar in the rings from the controls and those from the patients with chronic obstructive lung disease (Fig. 3, right panel). Sodium nitroprusside relaxes vascular smooth muscle by releasing nitric oxide close to or within smooth-muscle cells.24 , 25 Nitric oxide has been identified with EDRF9 and termed "endothelium-derived nitric oxide."26 Like exogenous nitric oxide generated by sodium nitroprusside, endogenous endothelium-derived nitric oxide induces vasorelaxation by activating soluble guanylate cyclase and, as a result, increasing the level of cyclic guanosine monophosphate within vascular smooth muscle.25 , 26 EDRF is now considered by many authors to be the endogenous nitrovasodilator.27 28 29
The thickening of the intima of pulmonary arterial rings from patients with chronic obstructive lung disease could serve as a physical barrier preventing EDRF released by endothelial cells from reaching the underlying vascular smooth muscle. Since nitric oxide is a highly diffusible gas,30 however, thickening of the intima might delay relaxation but would be unlikely to reduce its magnitude. intimal thickening alone is therefore unlikely to act as a serious barrier to the diffusion of EDRF. A more likely explanation is that the reduced endothelium-dependent relaxation results from impairment of the synthesis or release (or both) of EDRF from pulmonary endothelial cells.
The features common to different causes of chronic obstructive lung disease are airways obstruction, chronic hypoxemia, and hypercapnia. EDRF-mediated pulmonary-artery relaxation in response to pharmacologic stimuli is reduced in experimental chronic hypoxia.15 Similarly, exposure to hypoxia for 30 minutes impairs the release of EDRF from cultured bovine pulmonary endothelial cells stimulated with bradykinin.31 Although circumstantial evidence suggests that EDRF activity is enhanced during acute hypoxic pulmonary vasoconstriction,32 33 34 35 36 disturbance of endothelial-cell metabolism in chronic hypoxia is also likely. For example, pulmonary uptake of propranolol is reduced in patients with emphysema,37 and in endothelial cells cultured under conditions of chronic hypoxia, the production of thrombomodulin is suppressed and a novel activator of factor X is formed.38 One could therefore speculate that impairment of the synthesis of EDRF could result from the metabolic effects of chronic hypoxia.
Although our results were obtained in large conduit pulmonary vessels, which may behave differently from small pulmonary resistance arteries, recent evidence suggests that impairment of relaxation of large conduit vessels may in itself contribute to the rise in vascular resistance.39
intimal thickening of the pulmonary arteries is a common feature of secondary pulmonary hypertension in chronic obstructive lung disease.5 , 6 The correlation between the degree of impairment of endothelium-dependent relaxation and the degree of intimal thickening (Fig. 5) suggests that chronic hypoxemia may either stimulate production of an endothelium-derived growth factor or, alternatively, decrease synthesis of an inhibitor of cell proliferation. It has recently been suggested that nitric oxide may act as an inhibitor of cell proliferation and mitogenesis.40 Thus, any impairment of the synthesis or release of nitric oxide from endothelial cells might lead to an increase in the activity of growth factors. This might link the impairment of endothelium-dependent pulmonary-artery relaxation with the structural changes in pulmonary arteries in chronic obstructive lung disease.
Supported by grants (1871066 and 90/36) from the British Heart Foundation and by a travel grant from the Fondation Maurice Rapin.
We are indebted to Mr. Ben Milstein for editorial comments, to Dr. Linda Sharpies, Ph.D. (Medical Research Council Biostatistic Unit, Cambridge, United Kingdom), for statistical advice, to Dr. Salvador Moneada, F.R.S. (Wellcome Research Laboratories, Kent, United Kingdom) for the gift of N G-monomethyl-L-arginine and helpful advice, and to Professor Alain Lockhart, M.D. (Cochin Medical School, Paris), for stimulating discussions while this work was in progress.
Source Information
From the Departments of Respiratory Physiology (A.T.D.-X., T.W.H., J.P.-Z., G.C., A.Y.B.), Histopathology (C.A.C.), and Cardiothoracic Surgery (S.R.L., F.C.W., J.W.), Papworth Hospital, Cambridge, United Kingdom. Address reprint requests to Dr. Higcnbottam at the Department of Respiratory Physiology, Papworth Hospital, Papworth Everard, Cambridge CB3 8RE, United Kingdom.
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