Short-term Pulmonary Vasodilation With l-Arginine in Pulmonary Hypertension
Background Endothelial dysfunction may contribute to the pathogenesis of pulmonary hypertension through impaired production of the endothelium-derived vasodilator nitric oxide (NO). l-Arginine, the substrate for NO synthase (NOS), has a vasodilatory effect in systemic vascular beds and can correct abnormal endothelium-dependent vasodilation. It has been suggested that these two effects of l-arginine are mediated through NOS metabolism and enhanced NO production. Therefore, we assessed the short-term pulmonary hemodynamic effects of exogenous l-arginine in patients with pulmonary hypertension of various origins.
Methods and Results During continuous hemodynamic monitoring, 10 subjects with pulmonary hypertension (mean pulmonary artery pressure [PAP], 54±5 mm Hg [mean±SEM]) received a 30-minute control infusion of hypertonic saline followed by a 30-minute infusion of 500 mg/kg of l-arginine. The hemodynamic effects of l-arginine were compared with those of prostacyclin titrated to maximally tolerated doses. The hemodynamic response to l-arginine was also studied in 5 subjects with heart failure but without pulmonary hypertension (mean PAP, 20±2 mm Hg) and 5 healthy control subjects. In subjects with pulmonary hypertension, infusion of l-arginine reduced mean PAP by 15.8±3.6% (P<.005) and pulmonary vascular resistance (PVR) by 27.6±5.8% (P<.005) compared with decreases of 13.0±5.5% (P<.005) and 46.6±6.2% (P<.005), respectively, with prostacyclin. l-Arginine infusion also increased the mean plasma level of l-arginine from 59±6 μmol/L to 10 726±868 μmol/L (P<.005), which was associated with a significant increase in the plasma level of l-citrulline, the immediate product of NOS metabolism of l-arginine. Moreover, the peak plasma level of l-citrulline correlated significantly with the reductions in mean PAP (r=.71, P<.05) and PVR (r=.70, P<.05), consistent with vasodilation mediated by NOS metabolism of exogenous l-arginine and increased NO production. l-Arginine also had a modest hypotensive effect in healthy control subjects and reduced systemic vascular resistance in subjects with heart failure in the absence of pulmonary hypertension. However, only small reductions in absolute pulmonary vascular resistance were observed in this latter group in response to l-arginine that did not reach significance.
Conclusions An exaggerated short-term pulmonary vasodilatory response to l-arginine in patients with pulmonary hypertension suggests a relative impairment in pulmonary vascular endothelial NO production that may contribute to increased pulmonary vascular tone and thus be important in the pathophysiology of pulmonary hypertension.
Endothelial dysfunction is postulated to contribute significantly to the pathogenesis of pulmonary hypertension through several mechanisms,1 2 including an imbalance between the release of vasoconstrictor agents such as endothelin-13 and vasodilator substances such as prostacyclin and endothelium-derived nitric oxide (NO).4 5 In vascular endothelium, NO is produced by the enzyme NO synthase (NOS), which oxidizes the terminal guanidino nitrogen atom of the amino acid l-arginine, releasing l-citrulline.6 The importance of the endogenous l-arginine–NO pathway in the regulation of vascular tone has been demonstrated by the use of competitive, l-arginine–analogue inhibitors of NOS such as NG-monomethyl-l-arginine.7 8 In addition, the blunted endothelium-dependent systemic vasodilation seen in vascular disorders such as that associated with hypercholesterolemia9 may be overcome by administration of exogenous l-arginine, presumably by substrate-loading of NOS and enhanced local endothelial NO production.10 11 Although a stereospecific dilator effect is evident in normal blood vessels,12 the hemodynamic actions of exogenous l-arginine may be more pronounced in vascular beds affected by endothelial dysfunction.10 11
We hypothesized that parenteral l-arginine would have a significant short-term pulmonary vasodilatory effect in patients with pulmonary hypertension, the magnitude of which would depend on the ability of the pulmonary vascular endothelium to metabolize l-arginine through the NOS pathway. The aim of the present study was to examine the short-term hemodynamic effects of l-arginine administration in patients with pulmonary hypertension resulting from a variety of causes.
Patients with documented pulmonary hypertension (mean pulmonary artery pressure [PAP] ≥25 mm Hg and pulmonary vascular resistance [PVR] ≥3 mm Hg · L−1 · min−1) undergoing pulmonary artery catheterization for clinical indications unrelated to the present study were eligible. Patients were excluded if their pulmonary hemodynamic status was considered critical, as defined by cardiac index (CI) ≤1.5 L · min−1 · m−2 and mixed venous oxygen saturation ≤50%. They were also excluded if there was evidence of significant hepatic or renal dysfunction (serum transaminases more than fourfold normal levels, cirrhosis, coagulopathy, or serum creatinine ≥200 μmol/L). The study was approved by the respective institutional ethics committees, and informed consent was obtained from all study subjects.
Ten subjects (6 women, 4 men 52±5 [mean±SEM] years of age) were enrolled in the study. Table 1⇓ summarizes their baseline characteristics. The study population included 4 subjects with pulmonary hypertension secondary to chronic ischemic cardiomyopathy and congestive heart failure (CHF), 3 subjects with primary pulmonary hypertension as defined by the NHLBI Primary Pulmonary Hypertension Registry,13 2 subjects with pulmonary hypertension related to progressive systemic sclerosis, and 1 subject with recurrent pulmonary thromboembolism and biventricular heart failure. Baseline hemodynamic values included a mean PAP of 54±5 mm Hg and a mean PVR of 11.9±1.8 mm Hg · L−1 · min−1. Seven subjects were on maintenance oral cardiovascular medications, and the doses of these were kept constant throughout the study period (Table 1⇓). Although subject 1 was not on any long-term cardiovascular medications, he was studied while in short-term biventricular failure and receiving intravenous inotropes, including 5 μg · kg−1 · min−1 dobutamine, 2.0 μg · kg−1 · min−1 dopamine, and 2.5 μg · kg−1 · min−1 amrinone, the doses of which remained constant throughout the study period.
Blood pressure (BP) was monitored continuously by means of an indwelling radial or femoral artery catheter. A 7.5F, balloon-tipped, thermodilution catheter was positioned in the pulmonary artery for measurement of PAP, pulmonary capillary wedge pressure (Pcw), right atrial pressure (Pra), and cardiac output (CO) in all subjects except subject 4, in whom pulmonary vascular pressures were measured through an end-hole catheter without thermodilution sensors and CO was determined with expired gas analysis and direct Fick calculations. Standard formulas were used to calculate CI, systemic vascular resistance (SVR), and either pulmonary vascular resistance (PVR=[mean PAP−Pcw]/CO) or total pulmonary resistance (TPR=mean PAP/CO) if the wedge position could not be reliably maintained (subjects 1, 3, 9, and 10). The Pcw of these 4 subjects was measured at baseline (Table 1⇑). Data presented in the text and figures under the heading of PVR thus represent a mixture of actual PVR in 6 subjects and TPR in the other 4 subjects. There were no differences in the timing and magnitude of the resistance response to l-arginine infusion whether the data were analyzed with a mixture of PVR and TPR data, only TPR data in all subjects, or only PVR data in those 6 subjects in whom this information was available.
After insertion of the monitoring catheters, subjects were permitted to rest during a 30-minute baseline period. Then, 2 mL/kg hypertonic saline (3.6%, 1200 mOsm/L, pH 7.0) was infused into a central vein over a 30-minute control period. Subsequently, an identical volume of l-arginine hydrochloride (500 mg/kg, 250 mg/mL, 1200 mOsm/L, pH 5.0 to 6.5; Sabex) was administered into a central vein over a similar 30-minute interval, with continuous clinical and hemodynamic monitoring during a 2-hour recovery period.
Two hours after termination of the l-arginine infusion, 9 of 10 subjects received infusions of prostacyclin (Flolan, Burroughs-Wellcome). Prostacyclin was administered into a central vein at an initial dose of 1 ng · kg−1 · min−1, with subsequent progressive increments (2, 4, 8, 12, 16, and 20 ng · kg−1 · min−1) every 10 to 15 minutes until a maximal tolerated dose was reached. End points included systemic hypotension (fall in mean BP by ≥20%), excessive tachycardia (heart rate ≥140 beats per minute), or symptoms of chest pain, worsening dyspnea, headache, or dizziness.
Arterial and mixed venous blood samples were tested before and after the hypertonic saline infusion, every 10 minutes during the l-arginine infusion, and every 30 minutes during the recovery period. Samples were centrifuged at 1200g for 15 minutes at 4°C, and the plasma was removed and frozen at −20°C until analyzed. After deproteinization with 50% sulfosalicylic acid, the plasma concentrations of free l-arginine, l-citrulline, and l-ornithine were determined by high-performance liquid chromatography with an amino acid analyzer (119CL, Beckman Instruments Inc). Arterial and mixed venous blood samples were also tested regularly during the protocol for blood gas analysis and determination of serum electrolytes, urea, creatinine, and glucose.
Study Control Subjects
Two sets of control subjects also received 30-minute infusions of l-arginine hydrochloride (500 mg/kg). The control CHF group consisted of 5 subjects (age, 47±4 years; P=NS versus pulmonary hypertensive group) with heart failure but without pulmonary hypertension, defined by a mean PAP ≤25 mm Hg and PVR ≤2.0 Wood units. Baseline hemodynamics included a mean PAP of 20±2 mm Hg, Pcw of 12±1 mm Hg, PVR of 1.5±0.2 Wood units, and CI of 2.59±0.21 L · min−1 · m−2. The second control group consisted of 5 healthy subjects (age, 34±1 years; P<.05 versus both the pulmonary hypertensive group and the control CHF group) who underwent noninvasive monitoring of BP during l-arginine infusion.
Data are expressed as mean±SEM. A repeated-measures ANOVA (sigmastat, Jandel Scientific) was used to analyze serial hemodynamic and metabolic data over time, and a post hoc paired t test was applied when appropriate to evaluate for significant differences between conditions and individual time points. Correlations between hemodynamic and metabolic changes were performed with linear regression analysis by the least-squares method. A two-tailed value of P<.05 was considered statistically significant.
Hemodynamic Effects of l-Arginine in Subjects With Pulmonary Hypertension
Fig 1⇓ shows the time course of the pulmonary and systemic hemodynamics during the administration of hypertonic saline and l-arginine. Hypertonic saline had no significant hemodynamic effects. In contrast, l-arginine infusion produced substantial decreases in pulmonary and systemic arterial pressures and resistances, accompanied by a slight increase in CO (P<.05 by repeated-measures ANOVA for all parameters). l-Arginine had no effect on Pcw and Pra. The peak effects of l-arginine infusion on pulmonary and systemic hemodynamics in individual subjects occurred at 40±8 and 33±3 minutes, respectively, after initiation of the infusion and gradually resolved within 30 minutes of the peak effect (Table 2⇓). There was no evidence of any rebound vasoconstrictive effect during the recovery period.
There was no significant relation between the baseline severity of pulmonary hypertension and the magnitude of the pulmonary vasodilatory response to l-arginine, nor was there a relation between baseline mean BP or SVR and the systemic vasodilatory response. However, a correlation existed between basal PVR and SVR (r=.51, P<.05) and between the magnitude of the pulmonary and systemic vasodilatory responses to l-arginine (r=.64, P<.05).
Hemodynamic Effects of l-Arginine in Control Subjects
In control subjects with CHF but without pulmonary hypertension (Table 3⇓), l-arginine infusion was associated with reductions in mean BP and SVR (P<.05), with a peak effect at 27±3 minutes. An increase in CO and slight decreases in mean PAP and PVR were also observed; however, these changes did not reach statistical significance. The magnitude of the systemic vasodilatory response to l-arginine was not significantly different between subjects with and without pulmonary hypertension. l-Arginine infusion also produced a significant fall in mean BP in the control group of healthy subjects, with a peak effect at 32±7 minutes (Table 3⇓).
Comparison of Peak Hemodynamic Effects of l-Arginine and Prostacyclin in Subjects With Pulmonary Hypertension
Of the 10 subjects, 9 underwent short-term vasodilator challenges with prostacyclin to a mean maximal dose of 13.6±1.2 ng · kg−1 · min−1. There was a constant order of administration so that these 9 subjects first received l-arginine and then received prostacyclin after a 2-hour recovery period. Comparison of the peak hemodynamic effects of l-arginine and prostacyclin in these subjects revealed changes of a similar magnitude in mean PAP and BP but a greater increase in CO with prostacyclin and thus substantially greater reductions in PVR and SVR (Fig 2⇓). The hemodynamic effects of prostacyclin were transient, resolving within 15 minutes of cessation of the infusion.
Subjects were divided into two groups that were based on the origin of the pulmonary hypertension. Group A included the 5 subjects with pulmonary hypertension associated with a primary vascular abnormality, ie, primary pulmonary hypertension and scleroderma-associated pulmonary hypertension (subjects 3, 5, 6, 9, and 10); group B included the 5 subjects with pulmonary hypertension secondary to left ventricular failure or pulmonary thromboembolic disease (subjects 1, 2, 4, 7, and 8). Although there was variation in the individual hemodynamic responses to l-arginine in the group of 10 subjects as a whole, there was less interindividual variation within subgroups A and B. The subjects in group A were younger (39±5 versus 64±4 years, respectively; P<.05) and had more severe pulmonary hypertension than the subjects in group B (PVR, 15.7±2.4 versus 8.0±1.7 mm Hg · L−1 · min−1, respectively; P<.05). Although prostacyclin produced comparable reductions in mean PAP, BP, PVR, and SVR and increases in CO in both groups (Fig 3⇓), l-arginine had strikingly greater pulmonary hemodynamic effects in group B than in group A subjects (change in PVR, −40±8% versus −15±3%, respectively; P<.05). Thus, in group B subjects, the pulmonary vasodilatory responses to l-arginine and prostacyclin were similar, whereas in group A subjects, only a modest effect was seen with l-arginine relative to that with prostacyclin.
The mean baseline plasma l-arginine concentration was 59±6 μmol/L for the pulmonary hypertensive group, with 4 of 10 subjects falling below the fifth percentile of the normal range for our laboratory (54 to 134 μmol/L).14 During l-arginine infusion, the mean plasma level increased to a peak value of 10 726±868 μmol/L (P<.005) at 30 minutes and then rapidly fell (6246±745 μmol/L at 35 minutes and 848±106 μmol/L at 150 minutes) during the recovery period. There were no significant differences between systemic arterial and mixed venous plasma l-arginine levels at baseline, during l-arginine infusion, or during the recovery period.
After l-arginine administration, the plasma l-citrulline level increased from 25.5±4.9 μmol/L at baseline to a peak of 55.7±9.3 μmol/L (P<.005) 74±8 minutes after the beginning of the infusion. A much greater change was seen in the plasma l-ornithine level, which increased from 79.4±8.2 μmol/L at baseline (normal range for our laboratory, 32 to 100 μmol/L)14 to a peak value of 1821±148 μmol/L (P<.005) at 64±5 minutes. There was no significant correlation between the peak levels of l-ornithine and l-citrulline (r=−.46, P=NS).
Baseline mean PAP and PVR did not correlate with baseline plasma levels of l-arginine, l-citrulline, or l-ornithine. Of the three amino acids, only the baseline plasma levels of l-arginine and l-citrulline showed significant relations with the peak pulmonary vasodilatory responses to l-arginine infusion (Fig 4⇓). Furthermore, the reductions in both mean PAP and PVR with l-arginine correlated significantly with the peak plasma l-citrulline concentration but not with peak plasma levels of either l-arginine or l-ornithine (Fig 5⇓).
During titration to a maximal tolerated dose of prostacyclin, all 9 subjects with pulmonary hypertension developed side effects such as headache, dizziness, flushing, chest pain, or worsening dyspnea. All of these were mild and resolved rapidly after termination of the infusion. In comparison, l-arginine produced no side effects in any of the 10 subjects with pulmonary hypertension or the 10 control subjects.
Although l-arginine infusion produced no significant change in mean Pao2 in subjects with pulmonary hypertension, slight increases were observed in serum potassium (3.9±0.1 versus 4.9±0.2 mmol/L, P<.005), urea nitrogen (7.0±1.4 versus 9.6±1.4 mmol/L, P<.005), and blood glucose (7.1±0.3 versus 9.3±0.8 mmol/L, P<.01) from baseline to after l-arginine infusion, respectively. Neither hypertonic saline nor l-arginine infusion had any significant effect on serum sodium or serum osmolarity.
This study demonstrates that parenteral l-arginine can have a significant short-term pulmonary vasodilatory effect in patients with pulmonary hypertension of different origins. In many patients, l-arginine was equally as effective as prostacyclin, one of the most potent pulmonary vasodilators in clinical use. Yet, in contrast to prostacyclin, the beneficial hemodynamic effects of l-arginine were achieved without associated side effects.
Endothelial cells play an important role in the regulation of local vascular tone through release of a variety of vasoactive mediators. One of the most potent endogenous vasodilators, endothelium-derived NO, is produced by NOS through oxidation of the amino acid l-arginine.6 In the pulmonary circulation, NO release from the endothelium has been implicated in the maintenance of a characteristically low resting vascular tone,15 ventilation-perfusion matching during normoxic ventilation, and modulation of hypoxic pulmonary vasoconstriction.16 17 Consequently, an impairment of NO production resulting from endothelial dysfunction may contribute to the pathogenesis of pulmonary hypertension.5 Indeed, endothelium-dependent pulmonary vasodilation has been found to be attenuated in an animal model of hypoxia-induced pulmonary hypertension.18 Furthermore, inhaled exogenous NO has a significant pulmonary vasodilatory effect in the setting of pulmonary hypertension in animal models19 20 and humans,21 22 possibly overcoming a relative deficiency of endogenous production.
Administration of excess l-arginine, the substrate for NOS, restores endothelium-dependent vasodilatory responses in hypoxia-induced pulmonary hypertension in rabbits and protects against the development of pulmonary hypertension if administered before exposure to hypoxia.18 In the study of Eddahibi et al,18 a lack of activity of d-arginine, the biologically inactive enantiomer, suggests that exogenous l-arginine exerted its hemodynamic effects through a stereospecific, enzyme-mediated mechanism, consistent with its metabolism by NOS to increase endogenous NO production. However, in other studies, the vascular effects of l-arginine were not limited to abnormal vascular beds, and the stereospecificity of the effects of l-arginine may be lost at higher doses.23 24
In the present study, l-arginine produced a fall in mean BP in healthy subjects and systemic vasodilation in subjects with CHF in the absence of pulmonary hypertension. These findings are consistent with those of earlier reports on the systemic vascular effects of l-arginine in healthy subjects.23 25 Systemic vascular disorders such as hypercholesterolemia are associated with abnormalities of endothelial function, including a blunted response to endothelium-dependent vasodilators.9 In these disorders, l-arginine has a more pronounced vasodilatory effect than in normal vessels and normalizes impaired endothelium-dependent responses in both animal models10 11 and humans.26
In patients with pulmonary hypertension of various origins, we observed significant systemic and pulmonary vasodilation with l-arginine infusion. The peak pulmonary vascular response was characterized by a significant reduction in PAP in association with a rise in CO, resulting in a substantial decrease in PVR. Although the degree of systemic vasodilation with l-arginine was similar in subjects with and without pulmonary hypertension, l-arginine had only a small pulmonary vascular effect in control subjects with CHF but without pulmonary hypertension. A critical function of endogenous NO is the optimization of the conductance characteristics of a vascular bed in response to changes in the hemodynamic state.27 Thus, the exaggerated pulmonary vascular response to l-arginine in subjects with pulmonary hypertension suggests an inappropriately low basal level of endothelial NO production in these patients, with reduced pulmonary vascular conductance.
In the present study, infusion of l-arginine resulted in a substantial rise in plasma l-arginine to supraphysiological levels. The majority of this exogenous l-arginine was clearly metabolized through the urea cycle, given the large increase in plasma l-ornithine, the immediate product of l-arginine metabolism through this pathway, and the increase in blood urea nitrogen. A significant increase in plasma l-citrulline also was observed. The lack of correlation between peak plasma levels of l-ornithine and l-citrulline suggests that the rise in plasma l-citrulline was not merely the result of l-arginine metabolism through the urea cycle. Furthermore, positive correlations between the magnitude of the pulmonary vasodilatory response to exogenous l-arginine and both baseline and peak plasma levels of l-citrulline but not l-ornithine suggest a relation between plasma l-citrulline and NO production. Thus, the short-term pulmonary vasodilatory effect of exogenous l-arginine in patients with pulmonary hypertension may have resulted from its specific role as a substrate for endothelial NOS with enhanced generation of NO in the pulmonary vasculature.
It is also possible that some of the vascular effects of l-arginine are mediated through other endothelium- or NO-independent mechanisms such as the release of histamine24 or a nonspecific effect of pH.28 Although alkaline solutions of l-arginine, d-arginine, and other amino acids can produce direct vasodilation in vitro, the hemodynamic effects we observed are not likely to be simply mediated by an increase in pH because the l-arginine hydrochloride solution used in our protocol was slightly acidic (pH 5.0 to 6.5).
In 4 of 10 subjects with pulmonary hypertension, baseline plasma levels of l-arginine were below the fifth percentile of the normal range for our laboratory,14 consistent with similar observations in an animal model of experimental pulmonary hypertension.18 It has been suggested that a relative deficiency of the l-arginine pool might contribute to the pathogenesis of pulmonary hypertension.18 However, a simple deficiency of l-arginine as the cause of decreased NO production is improbable, given the finding of a direct correlation between baseline plasma l-arginine and the magnitude of the pulmonary hemodynamic response to exogenous l-arginine: patients with the lowest baseline plasma l-arginine showed the least rather than the greatest pulmonary vasodilation.
Although a statistically significant pulmonary vasodilatory response to l-arginine was observed in the study population as a whole (Fig 2⇑), there was marked interindividual variation, with some subjects showing a response comparable to that with prostacyclin and other subjects showing a minimal response. When the subjects with pulmonary hypertension were divided in a post hoc analysis into groups based on the origin of the pulmonary hypertension, substantial pulmonary vasodilation in response to l-arginine was seen in patients with pulmonary hypertension secondary to heart failure. An exaggerated pulmonary vascular response to l-arginine in these patients is consistent with a defect in basal NO production that may be overcome by excess substrate. This defect may be due in part to such abnormalities as a defect in the transport of l-arginine into endothelial cells, resulting in a reduction of intracellular l-arginine availability11 or the presence of an endogenous antagonist of the NOS pathway.29
In contrast, patients with primary pulmonary hypertension or scleroderma-associated pulmonary hypertension showed a minor degree of pulmonary vasodilation with l-arginine, with some patients showing no response, consistent with a previous report.30 The demonstration of an intact pulmonary vasodilatory response to prostacyclin, an agent acting directly on smooth muscle cells, argues against a fixed structural abnormality of the pulmonary vasculature as the reason for vascular unresponsiveness to l-arginine in these patients. These findings suggest that there may be fundamental differences in the biosynthesis of NO in patients with pulmonary hypertension of different origins.
In conclusion, we have demonstrated in the present report that exogenous l-arginine has a potent, beneficial short-term pulmonary hemodynamic action in some patients with pulmonary hypertension. This hemodynamic effect may be mediated in part through increased endogenous NO production as reflected by increased plasma levels of l-citrulline. In certain patients with pulmonary hypertension, l-arginine may have an important clinical role as a short-term pulmonary vasodilator because it was equally effective and yet better tolerated than prostacyclin. The availability of oral preparations of l-arginine raises the possibility that long-term supplementation may have a beneficial effect in these patients, providing a novel approach to the treatment of pulmonary hypertension. However, the safety of l-arginine administration, particularly in patients with compromised renal function, will need to be carefully explored in future studies.
We wish to acknowledge the funding support of the following agencies: Canadian Lung Association (S.M.), Fonds de la Recherche en Santé de Québec (D.J.S., D.L.), Medical Research Council of Canada (MT11620, D.J.S.), and l’Association Pulmonaire du Québec (R.D.L.). We gratefully acknowledge the technical support provided by Dr Charles R. Scriver, his laboratory staff, and specifically Keo Phommarinh, as well as the efficient and pleasant cooperation of the nurses of the cardiac and intensive care units of the Royal Victoria and Jewish General hospitals.
- Received February 13, 1995.
- Accepted March 13, 1995.
- Copyright © 1995 by American Heart Association
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