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Cardiovascular Research 1999 43(1):228-236; doi:10.1016/S0008-6363(99)00059-0
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Copyright © 1999, European Society of Cardiology

Adenosine plasma concentration in pulmonary hypertension

Alain Y. Saadjiana,d,*, Franck Paganellia, Martine L. Reynaud Gaubertb, Samuel Levya and Régis P. Guieuc

aCardiology Department, C.H.U Nord, 13915 Marseille cedex 20, France
bPneumology Department, C.H.U Nord, 13915 Marseille cedex 20, France
cCentre National de la Recherche Scientifique: UMR 6560 and Biochemistry Department, C.H.U Nord, 13915 Marseille cedex 20, France
dInstitut National de la Santé et de la Recherche Médicale, C.H.U Nord, 13915 Marseille cedex 20, France

* Corresponding author. Tel.: +33-04-9196-8684; fax: +33-04-9196-2162

Received 28 September 1998; accepted 11 December 1998


   Abstract
Top
 Abstract
1 Patients
 2 Study design
 3 Method
 4 Results
 5 Discussion
 References
 
Objective: In this study, we sought to appreciate the role of adenosine in the regulation of pulmonary vascular tone, especially in the case of clinical pulmonary hypertension, by investigating the relationship between endogenous plasma adenosine levels and pulmonary artery vasoconstriction. Methods: Adenosine plasma concentrations, were measured simultaneously in the distal right pulmonary artery and in the femoral artery, both at steady state (room air) and during pure oxygen inhalation. Three clinical situations were considered: (1) normal hemodynamics [7 control subjects, mean pulmonary artery pressure (MPAP)=18.5±1 mm Hg], (2) moderate pulmonary hypertension secondary to chronic obstructive pulmonary disease (COPD), (8 patients, MPAP=31±3 mm Hg), (3) severe primary pulmonary hypertension (PPH), (8 patients, MPAP=70±5 mm Hg). Results: In every instance, adenosine evaluated by HPLC was higher in the pulmonary than in the systemic circulation. For room air, adenosine plasma concentrations were significantly lower in COPD (0.49±0.16 µmol l–1) and PPH patients (0.45±0.14 µmol l–1) than in controls (1.26±0.12 µmol l–1). During O2 administration, adenosine plasma concentrations all decreased but more so in COPD and PPH patients. The significant correlations between adenosine plasma concentrations and both pulmonary vascular resistance and PvO2, in controls, were not found in COPD or PPH patients. Conclusion: The adenosine plasma concentrations in the pulmonary circulation of PPH and COPD patients are low, and may contribute to pulmonary artery hypertension.

KEYWORDS Adenosine; Pulmonary circulation; Hemodynamics; Hypoxia/anoxia; Endothelial function

Adenosine, a powerful vasodilating nucleoside, is released during spontaneous or experimental tissue hypoxia and ischemia [1]. Adenosine release is tightly related to local oxygen tension [2]. Also adenosine metabolites appear to play a part in local vasoregulation and possibly in the physiological control of blood pressure [3].

On the other hand, exogenous i.v. adenosine is an effective vasodilator in primary pulmonary hypertension, causing a substantial reduction in pulmonary vascular resistance associated with a significant increase in cardiac output [4–10]. However, given the practical difficulties in assaying adenosine in clinical settings, there is little information on the possible role of endogenous adenosine in the regulation of normal and diseased pulmonary circulation. These difficulties are related essentially to the very short half-life of adenosine. The degradation of adenosine to inosine, and the uptake of adenosine by the red cells are very fast, both in vitro and in vivo [11–13]. Special sampling techniques with a stop solution preventing re-uptake of adenosine by the erythrocytes were developed to allow reliable adenosine assay [14–17].

In this study, we sought to appreciate the role of adenosine in the regulation of the pulmonary vascular tone, especially in the case of clinical pulmonary hypertension, by investigating the relationship between the endogenous plasma adenosine levels and the pulmonary artery vasoconstriction. To this end, we studied plasma adenosine concentrations in the pulmonary and systemic circulations relative to the hemodynamic condition at steady state and during pure oxygen inhalation. Three clinical situations were considered: (1) normal hemodynamics (control subjects), (2) moderate pulmonary hypertension [patients with chronic obstructive pulmonary disease (COPD) with hypoxic pulmonary vasoconstriction], (3) severe primary pulmonary hypertension (PPH).


   1 Patients
Top
 Abstract
 1 Patients
2 Study design
 3 Method
 4 Results
 5 Discussion
 References
 
Adenosine plasma concentrations and hemodynamic variables were evaluated in 23 subjects: eight patients suffered from pulmonary hypertension secondary to COPD, and eight patients were considered as having PPH. These patients were studied in our cardiac catheterization laboratory as part of a standard evaluation of their pulmonary and heart disease. The eight patients with pulmonary artery hypertension (PAH) secondary to COPD (mean pulmonary artery pressure >20 mm Hg) had functional tests showing evidence of respiratory impairment (Table 1). All complained of dyspnea and fatigue on moderate exertion but were clinically stable and had been free of broncho-pulmonary infection, acute respiratory distress, and right ventricular failure for at least one month prior to the study. At the time of investigation, none was treated with vasodilators, long-acting theophylline, β2 agonists, diuretics, or digitalis. Long-term domiciliary oxygen therapy, indicated in three patients, was discontinued 3 h before investigation. All the patients were in sinus rhythm, with no clinical, ECG, X-ray, or echographic evidence of left ventricular dysfunction. The eight patients with PPH were referred to our institution for evaluation of the pulmonary vascular response to nitric oxide inhalation and for prostacyclin intravenous infusion in order to determine whether they should be enrolled in a lung transplantation program or/and in a chronic prostacyclin infusion procedure [8]. The evaluation included clinical history (six out of the eight PPH patients had a previous history of anorexigen medication by isomeride), physical examination, chest radiography and computed tomography scan, pulmonary function testing, and cardiac catheterization. Their conditions were defined on the basis of the criteria used in the National Institutes of Health Registry on PPH [18]. They all had severe symptomatic disease (NYHA class III or IV) while receiving diuretics, digoxin, and vasodilators (Nifedipine, Urapidil). Vasodilators were discontinued 24 h before the investigation, and oxygen therapy indicated in one patient, was discontinued 3 h before the investigation.


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  		Table 1 Patients: Morphometric and respiratory parameters

 
Adenosine levels were also assessed in seven subjects who underwent cardiac catheterization and coronary angiography for atypical chest pain. The right and left hemodynamics as well as the left ventricular and coronary artery angiography were normal. These subjects were considered the controls. In these subjects blood samples for adenosine assay were taken at least 20 min after completion of the diagnostic procedure. In these untreated control subjects, the investigation was performed in clinically stable conditions: no pain was reported during the procedure. These patients had no ST-segment depression at rest and during standardized bicycle exercise. In this group, the thoracic pain has been related to an esophageal spasm in one patient and to esophagitis with hiatal hernia in two other patients (demonstrated by esophageal manometry, pH-metry and fibroscopy). In four patients no cause was found in spite of exhaustive tests, including, Thallium-201 stress imaging and ergonovine test. Considering the psychological context, the thoracic discomfort was attributed to anxiety (psychogenic chest pain).

The protocol was approved by our institutional ethics committee. Informed consent was obtained from all patients. The investigation conforms with the principles outlined in the Declaration of Helsinki.


   2 Study design
Top
 Abstract
 1 Patients
 2 Study design
3 Method
 4 Results
 5 Discussion
 References
 
Hemodynamic parameters, blood gases, and adenosine plasma levels were simultaneously measured in all patients both in the distal right pulmonary artery and in the systemic circulation. These measurements were made at steady state while they inhaled room air (FiO2=0.21) and after a 30-min inhalation of pure O2 through a non-rebreathing face mask (FiO2=1). Room air or oxygen was administered in randomized blinded order.


   3 Method
Top
 Abstract
 1 Patients
 2 Study design
 3 Method
4 Results
 5 Discussion
 References
 
3.1 Hemodynamics and blood gases
Heart rate was monitored continuously by electrocardiography, and blood pressure was measured either with a 4F Teflon catheter introduced in the right femoral artery (patients with pulmonary artery hypertension) or with the catheter used for the left ventricular angiography (Judkins 7F, Bard) positioned in the femoral artery (control subjects). Right heart catheterization was done via the right femoral vein with a 7F flow-directed balloon-tipped thermodilution catheter (Spectramed, Oxnard, CA). For pulmonary blood sampling the catheter was pushed in a distal pulmonary artery in the most peripheral location allowing an easy blood withdrawal and sampling. Intravascular pressures were measured relative to atmospheric pressure with a zero reference point at the mid-axillary line by two Gould-Statham P23 ID pressure transducers (Hato Rey, Puerto Rico) and an EVR Physiologic Monitoring System (PPG Biomedical Systems, Pleasantville, NY). Pressures were measured during apnea at the end of expiration. Cardiac output was determined by the thermodilution technique (Spectramed device) and expressed as the mean of four consecutive determinations that differed less than 10%. Arterial and mixed venous O2 tension (PaO2, PvO2), arterial carbon dioxide tension (PaCO2), and pH were determined with a Radiometer BMS 3 MK2 blood gas analyzer (Copenhagen, Denmark) and SaO2 and SvO2 with a Radiometer OS M2 device.

Derived hemodynamic variables were calculated as follows:

• Pulmonary vascular resistance (dynes cm–5 s)=mean pulmonary artery pressure–pulmonary artery wedge pressurex80/cardiac output;
• Systemic vascular resistance (dynes cm–5 s)=mean arterial pressurex80/cardiac output.

3.2 Plasma adenosine assay
Sample collection and treatment have been described [16,17,19,20]. Briefly, since specific precautions are required, because of the biological short half-time of adenosine, the lumens of the catheters were washed and filled with a solution made from 1 ml of papaverine and 1 ml of dipyridamole and injected through the lateral entry of a three-way stopcock. Papaverine was added along with dipyridamole to increase the inhibition of adenosine uptake by red blood cells. Immediately after, 3 ml of blood was sampled through the axial entry of the stopcock, in an ice cold syringe containing 6 ml of the stopping solution described above in order to prevent both adenosine uptake by the red cells and deamination into inosine by plasma adenosine deaminase (ADA). The stopping solution was composed of 0.2 mM dipyridamole, 4.2 mM ethylenediaminetetraacetic acid disodium (Na2 EDTA), 5 mM 9-erythro (2-hydroxy-3 nonyl) adenine (EHNA), 79 mM a, β-methylene adenosine-5'-diphosphate (AOPCP), heparin sulfate 1 IU ml–1, and 0.9% NaCl. We checked that the proportion between blood sample and stopping solution was correct (one volume of blood for two volumes of stopping solution) by measuring hematocrits (mean values 44%±3; mean values of the hematocrits with stopping solution 17.6%±5). The sample plus stopping solution was centrifuged at 2500 g for 10 min, and the supernatant was deproteinized by adding 2 ml of 70% perchloric acid before a second centrifugation (2500 g for 10 min). The supernatant was lyophilized and redissolved in 1 ml of 50 mM sodium phosphate buffer (pH 4). The resulting solutions were filtered by centrifugation in a Millipore Ultrafree-MC 0.45-µm filter before being chromatographed.

Samples were analyzed by HPLC (Kratos HPLC 4000) with a 1-ml loop. Absorbance was measured at 254 nm, and eluted peak areas were measured with a Shimatzu Chromatopac C-RCA integrator. Plasma adenosine was assayed by reversed-phase HPLC on a Merck LI Chrospher C18 columns (250x4 mm). The column was equilibrated with 50 mM sodium phosphate buffer (pH 4). The sample was injected and was eluted with a methanol gradient (0% to 46% methanol in 40 minutes) at a flow-rate of 1 ml min–1. Adenosine was identified by elution time and after incubation with adenosine deaminase, which increases the inosine peak and decreases the adenosine peak. Adenosine was quantified by comparing these peak areas with those given by known quantities of adenosine. In these conditions, the sensitivity threshold was 10 pM injected in 1 ml. Adenosine (crystallized, 99% pure), adenosine deaminase (calf intestine, specific activity 200 IU/mg), and dipyramidole were from Boehringer Mannheim (France); inosine (99% pure), AOPCP, deoxycoformycine from Sigma; and EHNA from Burroughs Welcome.

3.3 Statistical analysis
Data were expressed as mean±SEM and analyzed by one- and two-way ANOVA followed by a paired bilateral t-test.


   4 Results
Top
 Abstract
 1 Patients
 2 Study design
 3 Method
 4 Results
5 Discussion
 References
 
4.1 Hemodynamics (Table 2)
4.1.1 Steady state (room air)
Cardiac output was similar in control subjects and COPD patients, but it was much lower in PPH patients. Mean pulmonary artery pressure and pulmonary vascular resistance were significantly higher in COPD and PPH patients than in controls (p<0.01 and p<0.0001, respectively). Mean pulmonary artery wedge pressure and mean arterial systemic pressure did not differ in the three groups.


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  		Table 2 Hemodynamics in the three groups of patients

 
4.1.2 Effect of 100% oxygen inhalation
During O2 inhalation, heart rate decreased significantly and similarly in the three groups: –8±1.5% in controls, –8±1% in patients with PPH and –10.6±1.6% in patients with COPD. In controls and in patients with PPH, supplemental oxygen resulted in a slight but non significant decrease in cardiac output: –3.4±3.8% and –4±3% respectively. Conversely, in patients with COPD the decrease was strong: –15.6±3.1% (p<0.001), and significantly different from the two other groups (p<0.05). In controls, as well as in patients with PPH, mean pulmonary artery pressure was not significantly affected by oxygen inhalation. In COPD patients, acute administration of oxygen resulted in a small but significant decrease in mean pulmonary artery pressure (p<0.001) (Table 2).

4.2 Blood gases (Table 3)
Blood gases at steady state and their modifications during oxygen inhalation are displayed in Table 3.


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  		Table 3 Blood gases in the three groups of patients.

 
4.3 Adenosine plasma concentrations (Fig. 2)
4.3.1 Steady state (room air)
In the three groups, adenosine plasma levels were significantly higher in the distal pulmonary artery samples than in the systemic arterial ones (Figs. 1 and 2Go). Pulmonary adenosine plasma concentrations were significantly lower in the patients with PAH than in controls (–60% in COPD, p<0.005 and –70% in PPH, p<0.001). This was also the case for systemic arterial samples but at a lower level (Fig. 2). In controls, pulmonary adenosine plasma concentrations were linearly correlated with PvO2 (r=–0.880; p<0.01) and pulmonary vascular resistance (r=0.940; p<0.002). Conversely, these variables were not correlated in the two groups of patients with PAH (Figs. 3 and 4Go).


Figure 2
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  		Fig. 2 Mean values (±SEM) of adenosine plasma concentrations in the pulmonary and the femoral artery during base line conditions (room air) and during 100% oxygen inhalation.

 

Figure 1
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  		Fig. 1 Individual variations of adenosine plasma concentrations before and during oxygen inhalation. Black symbols: distal pulmonary artery concentrations; open symbols: femoral artery concentration. Control subjects are represented by dots, patients suffering from COPD by squares, and patients with PPH by triangles.

 

Figure 3
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  		Fig. 3 Relationship between PvO2 and pulmonary artery adenosine concentration in seven control subjects, eight patients with chronic obstructive pulmonary disease (COPD), and eight patients with primary pulmonary hypertension (PPH).

 

Figure 4
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  		Fig. 4 Relationship between pulmonary vascular resistance and pulmonary artery adenosine concentration in seven control subjects, eight patients with chronic obstructive pulmonary disease (COPD), and eight patients with primary pulmonary hypertension (PPH).

 
4.3.2 Effects of 100% oxygen inhalation
Inhalation of oxygen resulted in a significant decrease in pulmonary and systemic adenosine plasma levels in all the subjects but at a lower level in the systemic circulation. In three patients with PPH and in one with COPD, adenosine level was very low and remained almost unchanged during oxygen inhalation (Fig. 1).


   5 Discussion
Top
 Abstract
 1 Patients
 2 Study design
 3 Method
 4 Results
 5 Discussion
References
 
The main findings of this study are as follows:

1. In every instance, adenosine plasma concentration was higher in the distal pulmonary arteries than in the systemic circulation.
2. In room air conditions, the systemic and pulmonary adenosine plasma concentrations were lower in COPD and PPH patients than in controls.
3. During acute O2 administration, adenosine plasma concentrations were all lowered but most in patients with PAH.
4. The correlations observed in control subjects between adenosine plasma concentration and pulmonary vascular resistance and between adenosinemia and PvO2, were not found in COPD and PPH patients.

The reproducibility of sample collection and adenosine assay was previously checked [17]: given its very short half-life, the means by which adenosine is assayed is crucial to the accuracy of the data. In the present study the interindividual variation of adenosine concentration in controls was narrow (Fig. 2), suggesting that both sampling and assay were highly reproducible.

That our control subjects were investigated because they complained of thoracic pain, raises the question of whether they can be considered a valid control group. Indeed, among patients who undergo coronarography because of a chest pain syndrome, 10% to 30% have a normal appearing coronary artery (Syndrome X) [21,22]. In this syndrome, the chest pain may be due to the inappropriate constriction of small coronary artery vessels and the pain may occur even in the absence of ischemia, as a consequence of adenosine release in response to inappropriate pre-arteriolar constriction or because of the increased stimulation of the algogenic nervous A1 receptor by the adenosine release [21,23]. Furthermore, adenosine was proposed to be a messenger of angina pain [24]. In four control subjects, a syndrome X cannot be, formally eliminated since no cause explaining the thoracic pain was found in these patients. However these subjects had negative ergonovine test, normal exercise test, and normal Thallium-201 stress imaging. Note also that the investigation and sample collections were done in the absence of chest pain. Furthermore, as mentioned above, the standard deviation in plasma adenosine concentrations in the whole control group was small and there is no evidence for interindividual variations in adenosine concentration in this group. Moreover, adenosine plasma concentrations in control subjects were in the same range as those in healthy volunteers [15,19,20].

That pulmonary adenosine concentrations were higher than the arterial ones raises the question of the main site of adenosine release in our patients. The very short half-life of adenosine in blood and presumably in the interstitial spaces (few seconds) [11,13] argues against the hypothesis that the adenosine in the blood samples withdrawn from the distal pulmonary arteries was released in the whole circulation (mixed venous blood). On the contrary, it supports the assumption that the adenosine measured in these conditions is released essentially locally or up-stream, near the sampling site, by the pulmonary vascular endothelium. It has also been shown that in the absence of circulating blood, rabbit lung is able to extract adenosine in vitro; however, this mechanism is of little significance in vivo, where blood cells appear to be primarily responsible for such removal [25]. Thus, that adenosine levels were lower in the systemic than in the pulmonary circulation can be explained simply by the fast metabolism of adenosine [1,11]. The low pulmonary adenosine concentration in the patients with PAH would account for the even lower systemic level. This low systemic concentration, in room air conditions, may contribute to the rise in systemic resistance, particulary in PPH patients.

Because oxygen inhalation reduced adenosine level in all samples, the question arises whether blood oxygen could alter the assay for adenosine or adenosine half-life rather than affecting adenosine production in vivo. However, there is no evidence that PaO2 has any effect on adenosine uptake and on its half-life because adenosine crosses into the red blood cells via an equilibrative transporter recently cloned [26]. This facilitated diffusion system is not oxygen dependent. Much evidence indicates that cellular adenosine formation increases when tissue metabolic rate increases or tissue blood flow and O2 delivery decreases, especially when O2 consumption exceeds oxygen supply in tissues highly dependent on oxidative phosphorylation [1,2]. Since adenosine production is tightly related to local O2 tension [27], it is very likely that increasing PaO2 and PvO2 by pure oxygen inhalation may result in a decreased adenosine level.

Adenosine is an endogenous nucleoside whose vasodilatator effects have been examined by exogenous continuous infusions in normal volunteers [28–30]. The continuous intravenous administration of adenosine in healthy subjects induces a decrease in the systemic vascular resistance and an increase in pulmonary blood flow without significant changes in systemic pressure [29]. Such beneficial effects of exogenous adenosine administration in refractory PPH have been widely investigated, and no adverse systemic hemodynamic effects were reported [5–9]. Little is known about the physiological role of endogenous adenosine in the control of pulmonary vascular resistance. There is more evidence now that the A2b (but not A2a) receptor mediates adenosine-induced vasodilation [31,32] and that A1 mediates adenosine-induced vasoconstriction possibly via the release of thromboxane A2 [33]. The vasodilation/vasoconstriction pulmonary response to adenosine is a tone-dependent phenomenon [34]. However, it is not clear how endogenous adenosine acts in the regulation of pulmonary blood flow and in hypoxic pulmonary vasoconstriction. Although it was demonstrated that exogenous adenosine blunted hypoxic pulmonary vasoconstriction [35], the role of endogenous adenosine in hypoxic pulmonary vasoconstriction was both suggested [36] and excluded [37]. However, as previously and strongly suggested for the systemic circulation [3], the correlation between the pulmonary vascular resistance and the adenosine concentration in the pulmonary artery suggests that adenosine may play a part in the regulation of pulmonary vascular tone.

We found a low adenosine plasma concentration in the pulmonary circulation in both COPD and PPH patients. Since adenosine has a higher affinity for A1 than for A2b receptors [38,39], low adenosine concentration is likely to stimulate A1 more than A2b receptors and might contribute to the pulmonary vasoconstriction in those patients. Conversely, this may explain why administration of exogenous adenosine can activate A2b receptors and thus induce vasodilation [31,32].

The correlation between adenosinemia and pulmonary vascular resistance in room air conditions disappeared during O2 inhalation, probably because adenosine concentration decreased under the affinity constant of low affinity A2b receptors, whose activation produces vasodilation. The lack of action of adenosine on pulmonary vascular resistance in these conditions may be compensated by the vasodilating effects of O2. Besides, it must be kept in mind that many other substances are implicated in vasodilation/vasoconstriction regulation.

Hypoxic and ischemic conditions are associated with the release of adenosine, both in vitro and in vivo [1,2,27,40]. Therefore, tissue ischemia due to either low flow (PPH) or hypoxia (COPD) should result in high adenosine release. Besides, it has been experimentally shown on normal canine lung tissue that acute alveolar hypoxia resulted in a large increase in adenosine release [41]. On the contrary and surprisingly, in the present study, the patients suffering from PAH (PPH and COPD) had, relative to controls, significantly lower adenosine plasma levels. Moreover, whereas adenosine was correlated with PvO2 in controls – which is not unexpected because adenosine release is tightly related to local oxygen tension – no correlation was found for PPH and COPD patients. In these patients, a pulmonary endothelial cell dysfunction or alteration could explain the low adenosine plasma concentrations and the lack of correlation with PvO2. Endothelial dysfunction in PAH has been well documented [42], but its background is far from clear. Impairment of endothelium-dependent pulmonary vasodilation in PPH [43] and increase [44] or decrease [45] in nitric oxide synthase (NOS III) expression by hypoxia were demonstrated. Interestingly, PAH is associated with increased endothelin-I release and endothelin-converting enzyme-I expression [45]. Moreover, NO-dependent relaxation in monocrotaline-induced PAH is reversed by endothelin A receptor antagonist [46], suggesting that endothelin-I plays an important role in causing endothelial dysfunction in PAH. Thus, it cannot be excluded that an increased level of endothelin-I may participate in the altered responsiveness of endothelial cell to O2 inhalation in PPH and COPD patients. Yet, experimental studies on animals and isolated vessels suggested that elevated pulmonary arterial pressure may, over time, promote and accelerate pulmonary vascular wall damage [47]. Since adenosine is released by endothelial cells [48], one can hypothesize that the abnormal pulmonary vascular endothelium injured by a chronic PAH [4] becomes unable to release enough adenosine to stimulate A2b receptors. In three patients with PPH and one with COPD, O2 inhalation had no effect on adenosine concentration probably because their adenosinemia was already very low, in room air condition, suggesting a strong alteration in pulmonary endothelial system. It was also recently reported that adenosine produced by smooth muscle cells, via A2b receptors, may be a local anti-growth agent. So, the decrease in local adenosine concentration may contribute to the abnormal deposition of extra-cellular matrix protein and participate in several disease states such as systemic hypertension and atherosclerosis [49]. Similarly, the low adenosine concentration we found in both PPH and COPD patients, may participate in PAH.

Low adenosine concentration may also be the result of an increased adenosine deaminase activity as suggested for some vaso-occlusive diseases, or because of release of adenosine deaminase by damaged erythrocytes [50]. In this perspective, the evaluation of adenosine deaminase activity in patients with PAH would be an interesting field of investigation.

Time for primary review 22 days.


   References
Top
 Abstract
 1 Patients
 2 Study design
 3 Method
 4 Results
 5 Discussion
 References
 

  1. Shryock J.C., Belardinelli L. Adenosine and adenosine receptors in the cardiovascular system: biochemistry, physiology, and pharmacology. Am J Cardiol (1997) 79(12A):2–10.[ISI][Medline]
  2. Bardenheuer H., Schrader D. Supply to demand ratio for oxygen determines formation of adenosine by the heart. Am J Physiol (1986) 250:H173–H180.[ISI][Medline]
  3. Schlüter H., Offers E., Bruggemann G., et al. Diadenosine phosphates and the physiological control of blood pressure. Nature (1994) 367:186–188.[CrossRef][Medline]
  4. Reeves J.T., Groves B.M., Weir E.K. Adenosine and selective reduction of pulmonary vascular resistance in primary pulmonary hypertension. Circulation (1991) 84:1437–1438.[Free Full Text]
  5. Morgan J.M., McCormack D.G., Griffiths M.J.D., et al. Adenosine as a vasodilator in primary pulmonary hypertension. Circulation (1991) 84:1145–1149.[Abstract/Free Full Text]
  6. Schrader B.J., Inbar S., Kaufmann L., Vestal R.E., Rich S. Comparison of the effects of adenosine and nifedipine in pulmonary hypertension. JACC (1992) 19:1060–1064.[Abstract]
  7. Inbar S., Schrader B.J., Kaufmann L., Vestal R.E., Rich S. Effects of adenosine in combination with calcium channel blockers in patients with primary pulmonary hypertension. JACC (1993) 21:413–418.[Abstract]
  8. Nootens M., Schrader B.J., Kaufmann L., et al. Comparative acute effects of adenosine and prostacyclin in primary pulmonary hypertension. Chest (1995) 107:54–57.[CrossRef][ISI][Medline]
  9. Kneussl M.P., Lang I.M., Brenot F.P. Medical management of primary pulmonary hypertension. Eur Respir J (1996) 9:2401–2409.[Abstract]
  10. Fullerton D.A., Jones S.D., Grover F.L., McIntyre R.C. Jr. Adenosine effectively controls pulmonary hypertension after cardiac operations. Ann Thorac Surg (1996) 61:1118–1123.[Abstract/Free Full Text]
  11. Klabunde R.E., Althouse D.G. Adenosine metabolism in dog whole blood: effects of dipyridamole. Life Sci (1981) 23:2631–2641.
  12. Klabunde R.E. Dipyridamole inhibition of adenosine metabolism in human blood. Eur J Pharmacol (1983) 93:21–26.[CrossRef][ISI][Medline]
  13. Moser G.H., Schrader J., Deussen A. Turnover of adenosine in plasma of human and dog blood. Am J Physiol (1989) 256:C799–C806.[ISI][Medline]
  14. Shryock J.C., Boykin M.T., Hill J.A., Bellardinelli L. A new method for sampling blood for measurement of plasma adenosine. Am J Physiol (1990) 258:H1232–H1239.[ISI][Medline]
  15. Ontyd J., Schrader J. Measurement of adenosine, inosine and hypoxanthine in human plasma. J Chromatogr (1984) 307:404–409.[ISI][Medline]
  16. Guieu R., Sampieri F., Bechis G., Rochat H. Use of HPLC to measure circulating adenosine levels in migrainous patients. Clin Chim Acta (1994) 227:185–194.[CrossRef][ISI][Medline]
  17. Guieu R., Paganelli F., Sampieri F., et al. The use of HPLC to evaluate the variations of blood coronary adenosine levels during percutaneous transluminal angioplasty. Clin Chim Acta (1994) 230:63–68.[CrossRef][ISI][Medline]
  18. Rich S., Dantzker D.R., Ayers S.M., et al. Primary pulmonary hypertension: A prospective study. Ann Intern Med (1987) 107:216–223.[CrossRef][ISI][Medline]
  19. Guieu R., Sampieri F., Bechis G., Rochat H. Adenosine in painful legs and moving toes syndrome. Clin Neuropharmacol (1994) 5:460–469.
  20. Guieu R., Peragut J.C., Roussel P., et al. Adenosine and neuropathic pain. Pain (1996) 68:1–5.[CrossRef][ISI][Medline]
  21. Maseri A., Crea F., Kaski J.C., Crake T. Mechanisms of angina pectoris in syndrome X. J Am Coll Cardiol (1991) 17:499–506.[ISI][Medline]
  22. Cannon R.O., Camici P.G., Epstein S.E. Pathophysiological dilemma of syndrome X. Circulation (1992) 85:883–892.[Free Full Text]
  23. Rosano G.M., Lindsay D.C., Poole-Wilson P.A. Syndrome X: an hypothesis for cardiac pain without ischaemia. Cardiologia (1991) 36:885–895.[Medline]
  24. Lagerqvist B., Sylven C., Helmius G., Waldenstrom A. Effects of exogenous adenosine in a patient with transplanted heart. Evidence for adenosine as a messenger in angina pectoris. Ups J Med Sci (1990) 95:137–145.[ISI][Medline]
  25. Catravas J.D. Removal of adenosine from the rabbit pulmonary circulation, in vivo and in vitro. Circ Res (1984) 54:603–611.[Abstract/Free Full Text]
  26. Griffiths M., Beaumont N., Yao S., et al. Cloning of a human nucleoside transporter implicated in the cellular uptake of adenosine and chemotherapeutic drugs. Nature Med (1997) 3:89–93.[CrossRef][ISI][Medline]
  27. Sollevi A. Cardiovascular effects of adenosine in man; possible clinical implications. Prog Neurobiol (1986) 27:319–349.[CrossRef][ISI][Medline]
  28. Watt A.H., Routledge P.A. Adenosine stimulates respiration in man. Br J Clin Pharmacol (1985) 20:503–506.[ISI][Medline]
  29. Bush A., Busst C.M., Clarke B., Barnes P.J. Effect of infused adenosine on cardiac output and systemic resistance in normal subjects. Br J Clin Pharmacol (1989) 27:165–171.[ISI][Medline]
  30. Reid P.G., Fraser A.G., Watt A.H., Henderson A.H., Routeledge P.A. Acute haemodyamic effects of intravenous infusion of adenosine in conscious man. Eur Heart J (1990) 11:1018–1028.[Abstract/Free Full Text]
  31. Pearl R.G. Adenosine produces pulmonary vasodilatation in the perfused rabbit lung via A2 receptor. Anest Analg (1994) 79:46–51.[Abstract/Free Full Text]
  32. Haynes J., Obiako B., Thomson W.J., Downey J. Adenosine-induced vasodilatation: receptor characterization in pulmonary circulation. Am J Physiol (1995) 268:H1862–H1868.[ISI][Medline]
  33. Biaggioni I., King L.S., Enayat N., Robertson D., Newman J.M. Adenosine produces pulmonary vasoconstriction in sheep: evidence for thromboxane A2 prostaglandins endoperoxidase receptor activation. Circ Res (1989) 65:1516–1525.[Abstract/Free Full Text]
  34. Cheng D.Y., Dewitt B.J., Suzuki F., Neely C.F., Kadowitz P.J. Adenosine A1 and A2 receptors mediate tone dependent responses in feline pulmonary vascular bed. Am J Physiol (1996) 270:H200–H207.[ISI][Medline]
  35. Jolin A., Helset E., Tollali T., Bjertnaes L.J. Adenosine modulates vascular resistance and fluid filtration in isolated rat lungs. Acta Anaesthesiol Scand (1992) 36:400–405.[ISI][Medline]
  36. Thomas T., Marshall J.M. The role of adenosine in hypoxic pulmonary vasoconstriction in the anaesthetized rat. Exp Physiol (1993) 78:541–543.[Abstract]
  37. Jolin A., Kjaeve J., Helset E., et al. Evidence against endogenously released adenosine as modulator of the pressor response to hypoxia in isolated rat lungs. Acta Anaesthesiol Scand (1992) 36:449–453.[ISI][Medline]
  38. Pelleg A., Porter S. The pharmacology of adenosine. Pharmacotherapy (1990) 10:157–174.[ISI][Medline]
  39. Olsson R.A., Pearson J.D. Cardiovascular purinoreceptors. Physiol Rev (1990) 70:761–845.[Free Full Text]
  40. Feigl E.O. Coronary Physiology. Physiol Rev (1983) 63:1–205.[Abstract/Free Full Text]
  41. Mentzer R.M. Jr., Rubio R., Berne R.M. Release of adenosine by hypoxic canine lung tissue and its possible role in pulmonary circulation. Am J Physiol (1975) 229:1625–1631.[Abstract/Free Full Text]
  42. Lopes A.A., Maeda N.Y., Bydlowski S.P. Abnomalities in circulating von Willebrand factor and survival in pulmonary hypertension. Am J Med (1998) 105:21–26.[CrossRef][ISI][Medline]
  43. Brett S.J., Gibbs J.S.R., Pepper J.R., Evans T.W. Impairment of endothelium-dependent pulmonary vasodilation in patients with primary pulmonary hypertension. Thorax (1996) 51:89–91.[Abstract]
  44. Le Cras T.D., Tyler R.C., Horan M.P., et al. Effects of chronic hypoxia and altered hemodynamics on endothelial nitric oxide synthase expression in the adult rat lung. J Clin Invest (1998) 101:795–801.[ISI][Medline]
  45. Giaid A. Nitric oxide and endothelin-1 in pulmonary hypertension. Chest (1998) 114:208S–212S.[CrossRef][ISI][Medline]
  46. Priè S., Duncan J.S., Dupuis J. EndothelinA receptor blockade improves nitric oxide-mediated vasodilation in monocrotaline-induced pulmonary hypertension. Circulation (1998) 97:2169–2174.[Abstract/Free Full Text]
  47. Parks W.C., Mecham R.P., Crouch E.C., Orton E.C., Stenmark K.R. Response to lobar vessels to hypoxic pulmonary hypertension. Am Rev Respir Dis (1989) 140:1455–1457.[ISI][Medline]
  48. Pearson J.D., Gordon J.L. Vascular endothelium and smooth muscle cells in culture selectively release adenine nucleotides. Nature (1979) 281:384–386.[Medline]
  49. Dubey R.K., Gillespie D.G., Mi Z., Jackson E.K. Adenosine inhibits growth of human aortic smooth muscle cells via A2b receptors. Hypertension (1998) 31(part 2):516–521.[Abstract/Free Full Text]
  50. Jackson E.K., Koelher M., Mi Z., et al. Possible role of adenosine deaminase in vaso-occlusive diseases. J Hypertens (1998) 17:19–29.[ISI]

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