Ann Thorac Surg 1997;64:414-420
© 1997 The Society of Thoracic Surgeons
Original Articles: Cardiovascular
L-Arginine Prevents Cyclosporin A-Induced Pulmonary Vascular Dysfunction
Patrick Mathieu, MD,
Michel Carrier, MD,
Jocelyn Dupuis, MD, PhD,
Jim Ryan, MD, PhD,
L. Conrad Pelletier, MD
Departments of Medicine and Surgery, Montreal Heart Institute, Montreal, Quebec, Canada
Accepted for publication February 3, 1997.
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Abstract
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Background. Cyclosporin A is known to alter endothelium-dependent responses to different agonists. Few data are available concerning the effect of cyclosporin A on the pulmonary vascular bed.
Methods. The endothelium-dependent responses to acetylcholine (20 µg), bradykinin (5 µg), and substance P (5 µg) were investigated in a dog model of left lung autoperfusion at constant flow.
Results. The vasodilator response to bradykinin and substance P was significantly decreased with cyclosporin A (20 mg) administration. The average decreases in pulmonary arterial pressure with bradykinin were 5.4 ± 1.5 mm Hg and 2.4 ± 0.4 mm Hg before and after cyclosporin A administration, respectively (p = 0.04). The average decreases in pulmonary arterial pressure with substance P were 4.4 ± 1.0 mm Hg and 1.8 ± 0.5 mm Hg before and after cyclosporin A administration, respectively (p = 0.04). The responses to acetylcholine and the endothelium-independent relaxing agent nitroglycerin were not significantly affected by cyclosporin A. The effects of cyclosporin A on endothelium-dependent responses to bradykinin and substance P were overcome by the administration of L-arginine (200 mg/kg intravenously). The decreased response to bradykinin and substance P after cyclosporin A administration was not significantly affected by indomethacin, a cyclooxygenase inhibitor. The pulmonary angiotensin-converting enzyme activity was also measured using [3H]benzoyl-phenylalanyl-glycyl-proline, an inactive angiotensin-converting enzyme substrate. There was an average [3H]benzoyl-phenylalanyl-glycyl-proline hydrolysis of 54% ± 2% and 55% ± 2% before and after cyclosporin A administration, respectively (not significant).
Conclusions. The present study suggests that cyclosporin A selectively decreases endothelium-dependent responses to bradykinin and substance P without affecting the cyclic guanosine monophosphate-dependent pathway in the canine pulmonary vascular bed. The decreased endothelium-dependent responses to bradykinin and substance P are not related to increased angiotensin-converting enzyme activity. The toxic effect of cyclosporin A on endothelium-dependent responses is reversible by the administration of L-arginine, a source of substrate for nitric oxide.
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Introduction
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Cyclosporin A (CyA) represents a significant advance in human organ transplantation. Despite its outstanding antirejection properties, CyA has considerable toxic effects on the vascular network. It has been extensively studied in the renal and peripheral circulation. In the rat renal artery, the isolated rat aorta, human subcutaneous vessels, and canine resistance coronary arteries [1], CyA has been shown to impair endothelium-dependent relaxation. Moreover, CyA induced direct endothelial injury in cultured bovine endothelial cells [2]. In vitro CyA has been shown to induce angiotensin-converting enzyme (ACE) release from endothelial cells, and in vivo to increase ACE serum activity in patients receiving CyA therapy [3].
In recent years accumulating evidence about the importance of nitric oxide (NO)-mediated vasodilation has been demonstrated. Endothelial cells produce NO from L-arginine and activate a soluble guanyl cyclase, in turn increasing cyclic guanosine monophosphate in vascular smooth muscle, which causes relaxation [4]. Nitric oxide has a significant role in the regulation of pulmonary vascular tone in the normal lung [5]. Damage of the endothelium with consequent loss of NO regulation could be detrimental as a decreased production of NO has been described in patients with pulmonary hypertension [6].
In this study, we hypothesized that CyA causes acute endothelial dysfunction in pulmonary arterial resistance vessels. First, we examined the effect of acute CyA administration in vivo in the canine pulmonary vascular bed. Second, we studied the response to endothelium-dependent and endothelium-independent vasodilators, with the hypothesis that the vasodilator effect of nitroglycerin, acetylcholine, bradykinin, and substance P is impaired by CyA. Further insight on the mechanism of CyA-induced endothelial dysfunction was attained using the NO precursor, L-arginine, with the hypothesis that vasodilation would be restored. Third, we also examined the effect of acute CyA administration on ACE activity by using [3H]benzoyl-phenylalanyl-glycyl-proline ([3H]BPGP), a pharmacologically inactive ACE substrate, to probe pulmonary ACE activity with the hypothesis that ACE activity is increased by CyA.
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Material and Methods
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All animals were treated in accordance with the "Guide for the Care and Use of Laboratory Animals," published by the National Institutes of Health (NIH publication 85-23, revised 1985). Mongrel dogs weighing 20 to 35 kg were anesthetized with sodium pentobarbital (30 mg/kg, IV), and artificially ventilated (Ohio Medical Products, Madison, WI) at 10 to 12 cycles/min. A sternotomy was performed and the left pulmonary artery and the femoral artery were isolated. After anticoagulation with heparin (3 mg/kg intravenously), a retrograde cannula was introduced in the femoral artery and connected to the circuit tubing including a heat exchanger, an occlusive roller pump, and a depulsator. Autologous blood maintained at 37°C was pumped at constant flow into the left pulmonary artery after cannulation and proximal ligation of the artery. The right pulmonary artery, the left auricle, and the right femoral artery were cannulated for pressure monitoring (Fig 1
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Fig 1. . Technique of isolated perfusion of pulmonary artery in dogs. Autologous blood is pumped from the femoral artery through a heat exchanger and a depulsator into the isolated left pulmonary artery.
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Perfusion flow of the left pulmonary artery was adjusted by controlling the pump speed at the beginning of each experiment to obtain a mean pulmonary perfusion pressure equal to mean right pulmonary pressure. For the study of endothelial-dependent and endothelial-independent responses to vasodilators, a perfusion of phenylephrine (5–20 µg·kg-1·min-1) was started in the circuit tubing to elevate mean pulmonary arterial pressure to between 25 and 30 mm Hg. Mean pulmonary arterial pressure was elevated to ensure an optimal response to vasodilators. Changes in pulmonary perfusion pressure reflected changes in pulmonary arterial resistance.
Blood samples were withdrawn during the experiment to measure blood pH, oxygen tension, and carbon dioxide tension. Blood pH was maintained between 7.3 and 7.4 by bicarbonate infusion as needed.
Drugs were infused directly in the pulmonary arterial inflow, proximal to the insertion of the pulmonary artery cannula and to the site of perfusion pressure monitoring. Drugs were injected as a bolus, and changes in perfusion pressure were recorded.
In nine dogs, the endothelium-independent vasorelaxation was studied with nitroglycerin administration at a dose of 5 mg. In six dogs, the endothelium-dependent relaxation was studied with acetylcholine (20 µg), bradykinin (5 µg), and substance P (5 µg). The drugs were injected as individual boluses, and a period of stabilization was allowed between injections. The injections were done after turning off the ventilator at the end of expiration to ensure a vascular response in zone 3 of West; after reaching maximal response the ventilator was turned on, and a period of time was allowed to restore initial pulmonary vascular pressure before the next injection. These injections were repeated in the same animal after CyA administration in the left lung perfusion system at a dose of 20 mg. At the end of CyA injection, left auricle blood samples were withdrawn for determination of CyA serum levels, measured by the fluorescence polarization immunoassay technique [7].
In another six dogs, the vasodilator responses to nitroglycerin (5 mg), acetylcholine (20 µg), bradykinin (5 µg), and substance P (5 µg) were repeated as just described, before and after administration of cremophor, the CyA vehicle. The amount of cremophor injected was equivalent to that given in the CyA study.
The pulmonary vascular response to nitroglycerin (5 mg), bradykinin (5 µg), and substance P (5 µg) were tested in five dogs before and after CyA (20 mg) administration with indomethacin (100 mg, IV), a cyclooxygenase inhibitor. In six dogs, the response to these vasodilators was studied before and after CyA (20 mg) administration with L-arginine (200 mg/kg intravenously), a source of substrate for NO.
In the fifth series of experiments, vasodilator responses to nitroglycerin (5 mg), acetylcholine (20 µg), bradykinin (5 µg), and substance P (5 µg) were compared in six dogs before and after the administration of the NO synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME) (100 mg/kg, IV), and with L-NAME and L-arginine (200 mg/kg, IV). L-NAME and L-arginine were administered as slow boluses to the left pulmonary artery.
In the sixth series of experiments, pulmonary ACE activity was studied before and after CyA administration (20 mg) in 6 dogs. The same model was used, with the additional insertion of a cannula in the aortic root, which was connected to a Masterflex roller pump. At the beginning of each experiment, the perfused lung flow was adjusted to 1,040 mL/min and there was no infusion of vasopressor. The pulmonary ACE activity was measured using the single bolus indicator-dilution technique with [3H]BPGP, an inactive ACE substrate. At the end of expiration, the ventilator was turned off and a radioactive bolus of 24 µCi of [3H]BPGP in 5 mL of autologous blood was rapidly flushed into the left pulmonary artery, proximal to the insertion of the pulmonary artery cannula. Simultaneously, the sampling pump (2 mL/s) and the collecting rack (1.5 tubes/s) were started, and the samples were collected over a period of 40 seconds. A second similar experiment was performed 10 minutes after intrapulmonary injection of CyA (20 mg).
Sample Collection and Preparation
Each collecting tube contained 1.5 mL of stop solution (0.15 mol/L NaCl, 3 x 10-3 mol/L Na2 EDTA, and 1 x 10-3 mol/L 1,10-phenanthroline, pH adjusted to 6.8 to 8 by 1.0 N NaOH), which blocked the minor amount of plasma ACE activity present in the outflow samples. Immediately after each experiment, the tubes were centrifuged at 3,000 rpm for 10 minutes, after which 300 µL of supernatant was then added to a 20-mL scintillation vial with 1 mL of 0.1 N HCl and 1 mL of toluene-omnifluor (4 g omnifluor [Dupont-New England Nuclear, Boston, MA] per liter of reagent grade toluene). The vials were capped and inverted 20 times before being assayed for ß-radiation. The contents resolved themselves into two phases, the toluene phase floating on top of the water phase. At the acid pH, the organophilic radioactive product was extracted into the counting phase, the organic solvent containing the scintillants, while the unhydrolyzed substrate remained in the aqueous or "noncounting" phase. The vials were then reopened and 15 mL of aqueous scintillation cocktail was added (Ready Safe; Beckman, Fullerton, CA); they were then vigorously shaken by hand before being counted for a second time. A single phase resulted. The tritium activity assayed was then that corresponding to the total.
ACE Kinetics
Samples were analyzed for [3H]BPGP and the labeled hydrolysis product [3H]benzoyl phenylalanine by use of the toluene extraction procedure outlined above, as originally described by Ryan [8]. Pulmonary ACE activity was determined by measuring percent [3H]BPGP hydrolysis during a single transit time. The first-order kinetic parameter Amax/Km for BPGP hydrolysis was also computed as previously described [9], providing a measure of the ratio of the reacting enzymatic mass to the Km for the substrate. Angiotensin-converting enzyme substrates containing a proline group can exhibit both cis and trans conformations. It has been suggested that only the trans conformer is hydrolyzable by ACE so that single-pass hydrolysis may be limited depending on the hydrolysis rate and the conformers' respective proportions. Such a limitation has been shown for benzoyl-Phe-Ala-Pro using double-isolated lung experiments but not for BPGP when looking at second-pass pulmonary hydrolysis in vivo [9]. Nuclear magnetic resonance spectroscopic data indicate that BPGP exhibits a 23% cis conformer [10]. We consequently also computed a corrected or true Amax/Km to account for a possibly nonreacting fraction of 23% of the substrate.
Drugs
All drugs were kept frozen and a working solution was prepared frequently. The following drugs were used: acetylcholine, bradykinin, substance P, indomethacin, cremophor, L-arginine, L-NAME (Sigma Chemical Co, St. Louis, MO), CyA (Sandoz, Montreal, Quebec, Canada), and nitroglycerin (Omega, Montreal, Quebec, Canada). Dilutions were made in normal saline solution. Substance P was kept in polyethylene containers. Contact with glass or polystyrene was avoided because substance P is absorbed by these materials.
Data Analysis
The data are presented as mean changes in pulmonary perfusion pressure, means ± standard deviation. Responses represent peak changes. Angiotensin-converting enzyme kinetic parameters are expressed as means ± standard deviation. The data were analyzed using a one-way analysis of variance and Scheffé's F test or a paired t test. Statistical significance was considered when p was less than 0.05.
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Results
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Effect of Cyclosporin A on Endothelium Vasodilation
In the first group of 9 dogs, the endothelium-independent response to nitroglycerin was not significantly affected by CyA; the mean decreases in pulmonary arterial pressure were 6.7 ± 0.9 mm Hg and 5.0 ± 0.8 mm Hg (p = 0.12), respectively, before and after CyA administration. The endothelium-dependent response to acetylcholine was also not affected by CyA; the mean decreases in pulmonary arterial pressure were 2.9 ± 0.4 mm Hg and 3.1 ± 0.8 mm Hg (p = 0.89), respectively, before and after CyA administration. However, the endothelium-dependent responses to bradykinin and substance P were significantly decreased after CyA. The average decreases in pulmonary arterial pressure with bradykinin were 5.4 ± 1.5 mm Hg and 2.4 ± 0.4 mm Hg (p = 0.04), respectively, before and after CyA administration. The decrease in pulmonary arterial pressure with substance P averaged 4.4 ± 1.0 mm Hg before and 1.8 ± 0.5 mm Hg after CyA (p = 0.04) (Fig 2). The left atrial pressure was unchanged after the administration of vasodilators (Table 1). Cyclosporin blood level in the left auricle obtained 2 minutes after bolus injection averaged 1,016 ± 76 nmol/L. In a second group of 6 dogs, the responses to nitroglycerin, an endothelium-independent agent, and to acetylcholine, bradykinin, and substance P, causing endothelium-dependent vasorelaxation, were not affected by cremophor, the CyA vehicle (Fig 3).
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Fig 2. . Influence of cyclosporin A (CyA) on decreases in pulmonary arterial pressure in response to nitroglycerin (NTG; 5 mg, n = 9), acetylcholine (Ach; 20 µg, n = 6), bradykinin (BK; 5 µg, n = 6), and substance P (SP; 5 µg, n = 6) under conditions of elevated tone. Responses were compared before (control) and after CyA (20 mg) administration. (*p < 0.05 versus control).
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Fig 3. . Influence of cremophor (cyclosporin A [CyA] vehicle) on decreases in pulmonary arterial pressure in response to nitroglycerin (NTG; 5 mg), acetylcholine (Ach; 20 µg), bradykinin (BK; 5 µg), and substance P (SP; 5 µg) under conditions of elevated tone. Responses were compared before (control) and after cremophor administration (n = 6; p = not significant).
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Effect of Cyclooxygenase Inhibition
In a third group of 5 dogs, the vasodilator responses to bradykinin, substance P, and nitroglycerin was studied in the presence of CyA with indomethacin, a cyclooxygenase inhibitor. The response to nitroglycerin was not significantly affected. However, the endothelium-dependent responses to bradykinin and substance P were decreased after CyA administration with indomethacin. The decrease in pulmonary arterial pressure with bradykinin averaged 5.9 ± 1.5 mm Hg and 1.9 ± 0.2 mm Hg (p = 0.04), respectively, before and after CyA and indomethacin injection. With substance P, the decrease in pulmonary arterial pressure averaged 5.9 ± 1.3 mm Hg and 2.2 ± 0.3 mm Hg (p = 0.02), respectively, before and after CyA and indomethacin administration (Fig 4).
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Fig 4. . Decrease in pulmonary arterial pressure to nitroglycerin (NTG; 5 mg), bradykinin (BK; 5 µg), and substance P (SP; 5 µg) before (control) and after cyclosporin A (CyA; 20 mg) administration with indomethacin (100 mg) (n = 5). (*p < 0.05 versus control.)
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Effect of L-Arginine
The endothelium-dependent response to bradykinin and substance P was resumed after CyA administration with L-arginine. The mean decrease in pulmonary arterial pressure with bradykinin averaged 5.5 ± 1.3 mm Hg and 4.0 ± 0.7 mm Hg (p = 0.33), respectively, before and after CyA and L-arginine injection. Substance P-induced decrease in pulmonary arterial pressure averaged 5.3 ± 1.0 mm Hg and 6.0 ± 1.3 mm Hg (p = 0.22), respectively, before and after CyA and L-arginine. The endothelium-independent response to nitroglycerin was not affected (Fig 5).
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Fig 5. . Decrease in pulmonary arterial pressure to nitroglycerin (NTG; 5 mg), bradykinin (BK; 5 µg), and substance P (SP; 5 µg) before (control) and after cyclosporin A (CyA) (20 mg) administration with L-arginine (200 mg/kg) (n = 6) (p = not significant).
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In a group of 6 dogs, the response to vasodilators was studied in the presence of L-NAME, an inhibitor of NO synthase, and L-NAME injected with L-arginine. The responses to acetylcholine, bradykinin, and substance P were significantly inhibited by L-NAME, and resumed after the administration of L-arginine. The vasodilator response to nitroglycerin was not affected by L-NAME (Fig 6).
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Fig 6. . Decrease in pulmonary arterial pressure to nitroglycerin (NTG; 5 mg), acetylcholine (Ach; 20 µg), bradykinin (BK; 5 µg), and substance P (SP; 5 µg) before (control) and after L-NAME (100 mg/kg) and after L-NAME with l-arginine (200 mg/kg) (n = 6). (*p < 0.01 versus control; **p < 0.01 versus L-NAME.)
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Effect of Cyclosporin A on ACE Activity
Angiotensin-converting enzyme activity was not affected by short-term administration of CyA. There was an average [3H]BPGP hydrolysis of 54% ± 2% and 55% ± 2% (p = 0.83), respectively, before and after CyA administration. The first-order kinetic parameter Amax/Km was 10.4 ± 0.8 mL/s and 10.6 ± 0.8 mL/s (p = 0.89), respectively, before and after CyA. And the true Amax/Km, corrected for a possibly nonreacting BPGP conformer, was 21.4 ± 1.6 mL/s and 21.8 ± 1.6 mL/s (p = 0.85), respectively, before and after CyA administration.
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Comment
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Endothelium-derived relaxing factor NO is involved in the regulation of basal arterial tone. The dilator action of NO has been shown to contribute to the maintenance of low-resting pulmonary tone in humans [11]. Cyclosporin A has been shown to alter the NO-mediated vasodilation in nonpulmonary vascular bed [1]. The present study was designed to test the short-term effect of CyA on endothelial function of the pulmonary vascular bed in vivo. The results showed that acute administration of CyA impairs bradykinin- and substance P-induced vasorelaxation in pulmonary arterial resistance vessels under conditions of elevated tone. Rego and colleagues [12] have demonstrated that CyA acts directly on the vascular smooth muscle and decreases cyclic guanosine monophosphate-mediated vasodilation in the rat aorta. However, in our model, the cyclic guanosine monophosphate-mediated vasorelaxation to the endothelium-independent agent, nitroglycerin, was not significantly impaired after CyA administration. The decreased response to bradykinin- and substance P-mediated vasorelaxation does not seem to be related to the ability to produce NO, because the acetylcholine-induced vasorelaxation was not affected by CyA. Acetylcholine-induced relaxation has been shown to be an endothelium-dependent process in the pulmonary vascular bed, and is related to the release of NO [13]. Gallego and coworkers [14] reported that the vasorelaxation to the endothelium-dependent receptor-independent agent, Ca2+ ionophore, was not affected by the presence of CyA in isolated rat femoral arteries, therefore suggesting that the NO-forming system was not impaired. It has been hypothesized that CyA could affect the cell membrane and disrupt transducing mechanisms because of its lipophilic characteristics [15]. In this study, the inhibition of agonist-induced vasorelaxation seen with CyA could be related to a specific defect of the receptor-mediated mechanism that transduces the signal of bradykinin and substance P to the NO-forming system. An alternate hypothesis is that CyA decreased bradykinin- and substance P-induced vasorelaxation by interfering with agonist binding to their respective receptors. Gitter and associates [16] have demonstrated in human lymphoblastoid cell culture and in guinea pig lung that CyA acts as a specific tachykinin receptor antagonist. Tachykinin receptors (NK-1) appear to mediate the substance P endothelium-dependent vasorelaxation [17]. However, this hypothesis is difficult to sustain in our model since the bradykinin- and substance P-mediated vasodilation were restored in the presence of L-arginine.
The role of L-arginine in reversing the effect of CyA on bradykinin- and substance P-mediated vasodilation suggests that CyA decreases production of NO with bradykinin and substance P, which could be recovered by the presence of L-arginine. Gallego and colleagues [14] have also reported a CyA-induced endothelial injury in the rat renal and femoral artery, which was overcome by L-arginine administration. It has been shown that administration of L-arginine, the substrate for NO synthase, could restore the NO system when it is damaged by a pathologic process [18] or inhibited pharmacologically [19]. In this study, vasodilator responses induced by acetylcholine, bradykinin, and substance P were inhibited with the NO synthase inhibitor, L-NAME, and were restored after L-arginine administration, indicating that the vasodilation was at least partly due to NO production.
Cyclosporin A was also shown to induce renal vasoconstriction in the dog through the release of thromboxane [20]. Yaris and associates [21] have reported that the inhibitory effect of CyA on endothelium-dependent relaxation in the rat aorta was overcome by indomethacin, a cyclooxygenase inhibitor. The cyclooxygenase pathway is a source of contracting factors such as thromboxane A2 and prostaglandin H2, which could interfere with the effect of NO. In spontaneously hypertensive rats, the impaired responses to endothelium-dependent relaxing agents are explained by simultaneous release of a prostanoid endothelium-derived contracting factor, in addition to the normal release of NO by agonist stimulation [22]. In our model, indomethacin did not decrease the inhibitory effect of CyA on the bradykinin- and substance P-mediated vasodilation, indicating that cyclooxygenase products were not significantly involved in this process.
Cyclosporin A concentrate for intravenous infusion is dissolved in an oil-based vehicle, cremophor, because it is hydrophobic. Cremophor has been shown to have vasoactive properties, inducing vasoconstriction in the isolated rabbit jugular vein [23]. Mankad and coworkers [24] have demonstrated in the isolated rat heart that cremophor caused a reduction of endothelium-dependent vasorelaxation. However, in our model cremophor did not affect the vasodilator response to agonists, indicating that the decreased response to bradykinin and substance P was directly related to CyA.
The endothelial cells of the lung play an important role in transforming angiotensin I to angiotensin II through ACE activity. In vitro, CyA has been shown to induce elevation of ACE release from endothelial cells, and in vivo to increase ACE serum activity in patients receiving CyA [3]. It was hypothesized that CyA-induced hypertension might be related to increased ACE activity. Angiotensin-converting enzyme is also involved in the hydrolysis of bradykinin and substance P [25]. As we had demonstrated a decreased response to the bradykinin- and substance P-mediated vasodilation in the pulmonary vascular bed after CyA, we hypothesized that an increase in ACE activity might be involved. To test this hypothesis, we probed pulmonary ACE activity with an indicator-dilution technique using [3H]BPGP, an inactive ACE substrate. Under constant flow conditions, CyA did not affect either the percent of hydrolysis of [3H]BPGP or the first-order kinetic parameter, Amax/Km. The determinable parameter Amax/Km is a function of available ACE mass and activity. Available ACE mass is predominantly a function of the pulmonary capillary area that is perfused, which in turn is flow-dependent. Since the flow was constant before and after CyA administration, we can assume that Amax/Km represents ACE activity. A true Amax/Km was also calculated because 23% of [3H]BPGP is in a cis isomer conformation, a form that may not be hydrolyzed by ACE. As expected, the true Amax/Km was also unchanged after CyA administration. Thus, according to our model, acute administration of CyA did not affect pulmonary ACE activity.
The observed decreases in pulmonary arterial pressure in response to the agonists used in this study can seem like rather small changes; they represent in the control group a range of 2.9 to 6.7 mm Hg. However, when expressed in percentage from the baseline value, these changes represent a range of 10% to 21% decrease in pulmonary arterial pressure. The pulmonary circulation is a low pressure system in which small changes can have significant hemodynamic effects. Another potential limitation of this study is related to the use of a sequential drug administration, in which an order effect could have influenced the results. The initial administration of an agonist might have affected the results with another agonist. As the same order was used and a period of stabilization and washout of the drugs with pulmonary blood flow was observed, we maintain that the results are valid but are interpreted cautiously.
The present study investigated the short-term effect of CyA administration on endothelial-dependent vasorelaxation in the canine pulmonary vascular bed under conditions of elevated tone. According to our model, CyA selectively impaired the endothelium-dependent vasorelaxation to bradykinin and substance P, without affecting the cyclic guanosine monophosphate-dependent pathway in smooth muscles. The toxic effect of CyA on endothelium-mediated vasorelaxation was prevented with the administration of L-arginine but not with indomethacin, a cyclooxygenase inhibitor. The decreased response to bradykinin- and substance P-mediated vasodilation was not related to an increase in pulmonary ACE activity. Whereas NO-mediated vasodilation appears to play a significant role in the regulation of pulmonary vascular tone in normal lung [5], a decreased production of NO has been described in patients with pulmonary hypertension [6]. As pulmonary hypertension is a common feature among heart transplant candidates, any deleterious effect of CyA on pulmonary artery reactivity could affect the prognosis during the immediate postoperative period. However, the extent to which the findings of this study relate to the clinical situation remains to be established.
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Footnotes
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Address reprint requests to Dr Carrier, Departments of Medicine and Surgery, Montreal Heart Institute, 5000 Belanger St, Montreal, PQ H1T 1C8, Canada.
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References
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Abstract
Introduction
