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Departments of 1Pharmacological and Physiological Science and 2Chemistry, School of Medicine, Saint Louis University, St. Louis, Missouri 63104
Submitted 6 December 2002 ; accepted in final form 8 April 2003
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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adenosine-5' triphosphate; red blood cell
We reported previously that 1) ATP is released from rabbit RBCs as they traverse the pulmonary circulation (29) and 2) RBCs that are capable of releasing ATP were a requisite component in the perfusate of isolated rabbit lungs to demonstrate the participation of NO as a determinant of vascular resistance (31, 33). In the work presented here, we present evidence that ATP, in the absence of RBCs, is capable of promoting NO synthesis in the pulmonary circulation of the rabbit. Thus we determined the effect of ATP infused into the circulation of isolated rabbit lungs on vascular resistance. Moreover, we present evidence that the major mechanism by which ATP acts in the rabbit lung is via the stimulation of endogenous NO synthesis. The role of the RBC as a stimulus for endogenous NO synthesis was investigated by comparing the effect of the administration of NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthesis, on pressure-flow relationships in lungs perfused with either native rabbit RBCs or rabbit RBCs treated with glibenclamide, an inhibitor of ATP release (30). Finally, we used a mixture of apyrases that metabolize ATP to AMP (15, 22) to examine the contribution of ATP released from non-RBC sources in the lung to pulmonary vascular resistance.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Incubation of RBCs with glibenclamide. Washed RBCs were incubated with glibenclamide at a final concentration of either 10 or 100 µM for 60 min. After incubation, the cells were centrifuged at 500 g at 4°C for 10 min, and the supernatant was discarded. The cells were then washed three times, as described above, to remove any residual glibenclamide (30).
Deformability of RBCs. Rabbit RBCs were subjected to mechanical deformation using the St. George's Blood Filtrometer (Carri-Med; Dorking, UK) (30, 31). This device develops a 3-cmH2O pressure gradient across a vertically mounted filter. A 13-mm diameter polycarbonate filter (Nucleopore) with 9.53-mm exposed surface diameter and average pore size of 5 µm was placed in the filter chamber. Proximal to the filter, the chamber and the open-ended capillary tube were filled with either PSS or PSS containing RBCs to achieve a hematocrit of 10%. Flow was prevented by an outflow channel tap. For calibration, PSS was passed through the filter resulting in movement of the air-fluid meniscus. The time taken for the fluid to pass four fiberoptic detectors was recorded digitally. The process was repeated until coefficients of variance between runs were 1% or less. Deformability of RBCs was determined by passing cells suspended in PSS through the filters. The filtration rate of the RBC suspension relative to PSS alone, RBC transit time (RCTT), was calculated as described previously (30, 31).
Isolated perfused rabbit lungs. Rabbits were anesthetized,
ventilated, and exsanguinated as described above. The heart and lungs were
removed en block during continuous ventilation. Catheters were placed in the
main pulmonary artery and the left atrium. The lungs and heart were suspended
in a humidified chamber maintained at 37°C and ventilated with 15%
O2-6% CO2, balance N2. Blood was removed from
the lungs by perfusion with 300 ml of PSS [in mM: 118.3 NaCl, 4.7 KCl, 2.5
CaCl2, 1.2 MgSO4, 1.2 KH2PO4, 25.0
NaHCO3, 0.026 Na-EDTA, and 11.1 glucose and 5% hetastarch (Baxter
Healthcare, Deerfield, IL)] in a nonrecirculating fashion. Lungs were then
perfused at 100 ml/min with a recirculating volume of PSS of 125 ml. In some
studies, washed rabbit RBCs were added to the perfusate to achieve a final
hematocrit of 
20%. Pulmonary arterial pressure (Ppa), left
atrial pressure (Pla), and airway pressure (Paw) were
recorded continuously. Pla was set to a pressure of 2–3 mmHg
with a screw clamp. Pulmonary microvascular pressure (Pmv) was
determined by the double-occlusion method
(32), i.e., the arterial and
venous cannulas were simultaneously occluded with electronically controlled
solenoid pinch valves that cause minimal fluid displacement. Occlusions were
maintained for 3 to 5 s, and the resulting equilibration pressure in the
pulmonary arterial and venous catheters was recorded. Lungs were perfused
under zone III conditions (Ppa > Pla >
Paw). Samples of perfusate were analyzed for pH and O2
and CO2 tensions under control and experimental conditions (pHOx
blood gas analyzer, Nova Biomedical; Waltham, MA).
Generation of pressure-flow curves in isolated perfused rabbit lungs. After hemodynamic stability was achieved under baseline conditions (flow rate of 100 ml/min, minimum of 30 min after establishment of hemodynamic and blood gas stability), perfusate flow rate was reduced to 50 ml/min and then increased to 100, 200, and 300 ml/min, sequentially. Within 10 s of each change in flow rate, after Pla was adjusted to 2–3 mmHg, both Ppa and Pmv were recorded. Flow rate was then returned to 100 ml/min. The effect of L-NAME and ATP on total pulmonary vascular resistance was examined by plotting the pressure drop across the circulation (Ppa – Pla) as a function of flow rate. To determine the effects of L-NAME and ATP on the intrapulmonary distribution of vascular resistance, the effects of these agents on the upstream (arterial) and downstream (venous) component of total pulmonary resistance were determined by plotting Ppa – Pmv (upstream pressure difference) and Pmv – Pla (downstream pressure difference) as a function of flow rate.
Measurement of ATP. ATP was measured by the luciferin-luciferase technique (6, 9, 29, 30), which utilizes the ATP concentration dependence of light generated by the reaction of ATP with firefly tail extract. Sensitivity was augmented by addition of synthetic D-luciferin to the extract. Glibenclamide, at the concentrations used in this study, does not alter the sensitivity of the assay for authentic ATP (30). The addition of apyrase grade VII to luciferin-luciferase resulted in a small decrease in baseline activity of the reagents and a 40% decrease in the sensitivity of the assay for ATP. However, this property of apyrase did not prevent the detection of ATP standards.
Passage of RBCs through microbore glass tubing. ATP release from RBCs was stimulated by their passage through microbore glass tubing as described previously (7, 35). Briefly, RBCs (7% hematocrit) were passed through fused silica microbore tubing (Polymicro Technologies; Phoenix, AZ) having a length of 50 cm and an inside diameter of 25 µm with the use of a syringe pump equipped with a removable 500-µl syringe (Hamilton, Fisher Scientific). The linear rate of the RBCs through the tubing was 5.5 cm/s. After passage through the deformation tubing, the RBC sample was mixed with luciferin-luciferase at a tee with an internal volume of 29 nl (Upchurch Scientific; Oak Harbor, WA). The chemiluminescence resulting from the reaction of RBC-derived ATP with luciferin-luciferase was measured by a photomultiplier tube encased in a light-excluding box. Data acquisition was performed using a computer and was analyzed with a program written in-house with the LabWindows/CVI software package (National Instruments; Austin, TX). ATP released from RBCs was quantified by comparison to light emission recorded in response to the passage of ATP standards through the system.
Preparation of reagents. Glibenclamide (Sigma; St. Louis, MO) was prepared as a 0.01 M stock solution by adding 49 mg of glibenclamide to a solution containing 2 ml NaOH and 7.94 ml of dextrose in distilled water (50 mg/ml) and heating it slowly to 52°C. ATP (Sigma or Calbiochem; La Jolla, CA) solutions were prepared in PSS immediately before use as standards in the luciferin-luciferase assay or for infusion in isolated lung studies. Apyrase (fraction VII, Sigma) was dissolved in distilled deionized water to produce a stock solution containing 1 U/µl. The stable thromboxane A2 analog U-46619 (Sigma) was prepared as a stock solution of 1 mg/1 ml ethanol. This stock solution was diluted in 0.9% saline (5 µl of stock solution in 2,950 µl saline) for infusion into the perfusate of isolated lungs.
Statistical methods. Statistical significance between experimental
periods was determined with an analysis of variance. In the event that the
F ratio indicated that changes had occurred, a least significant
difference test was used to identify individual differences. The slope of the
pressure-flow relationship in isolated lungs was determined by regression
analysis. A value of P 
0.05 was considered to be statistically
significant.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Effect of L-NAME on ATP-induced decreases in vascular resistance in isolated lungs perfused with PSS. To examine the mechanism by which ATP produced vasodilation in the pulmonary circulation, ATP infusion was repeated in the presence of the inhibitor of endogenous NO synthesis L-NAME. After a minimum of 30 min to achieve hemodynamic and blood gas stability (at a flow rate of 100 ml/min, pH 7.45 ± 0.01, PCO2 32.0 ± 0.7 mmHg and PO2 132.6 ± 4.5 mmHg), L-NAME was added to the perfusate to achieve a concentration of 100 µM (n = 8). In agreement with our previous studies (31–33), L-NAME was without effect on vascular resistance in lungs perfused with PSS. After an additional 45 min, vascular tone was increased by the infusion of the thromboxane mimetic U-46619. Infusion of U-46619 resulted in a value for Ppa – Pla of 25.5 ± 0.9 mmHg, Ppa – Pmv of 17.2 ± 0.8 mmHg, and Pmv – Pla of 8.3 ± 0.3 mmHg. These values were not different from those in studies in which ATP was infused in the absence of L-NAME (Table 1). The decreases in total (Ppa – Pla) and arterial (Ppa – Pmv) resistance produced by 300 nM ATP were significantly inhibited, but not eliminated, by pretreatment with L-NAME (Fig. 1).
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Effect of L-NAME on pressure-flow relationships in isolated lungs perfused with PSS containing washed RBCs. To demonstrate that, in the presence of rabbit RBCs, endogenous NO is a determinant of pulmonary vascular resistance, pressure-flow curves were generated before and 45 min after the addition of L-NAME (100 µM, n = 5) to the perfusate of isolated rabbit lungs. Lungs were perfused with PSS containing washed rabbit RBCs (hematocrit 22 ± 1%, pH 7.38 ± 0.01, PCO2 44.7 ± 0.9 mmHg and PO2 142.4 ± 2.4 mmHg). The administration of L-NAME resulted in an increase in total pulmonary vascular resistance at all flow rates studied (Ppa – Pla, Fig. 2A) and an increase in the slope of the pressure-flow relationship (P < 0.01) reflecting a decrease in pulmonary vascular caliber (increase in resistance). The majority of the increase in pulmonary vascular resistance following L-NAME was in the arterial segment of the circulation, i.e., the pressure-flow relationship defined by plotting Ppa – Pmv (upstream pressure drop) as a function of flow rate demonstrated increases in pressure at all flow rates studied (Fig. 2B) as well as a shift in the slope of the relationship (P < 0.01) in response to administration of L-NAME. The slope of the pressure-flow relationship for the venous component of the circulation (Pmv – Pla vs. flow rate) was not altered by addition of L-NAME to the perfusate.
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Effect of glibenclamide on RBC deformability and ATP release. To confirm that incubation of rabbit RBCs with glibenclamide results in inhibition of deformation-induced ATP release in the absence of changes in RBC deformability, washed RBCs (7–10% hematocrit) were incubated with glibenclamide (10 µM) for 30 min. The cells were then washed three times to remove glibenclamide from the suspending medium (30). RBC deformability was determined by passage through filters with an average pore size of 5 µm using the St. George's Blood Filtrometer. RBCs incubated with glibenclamide did not release ATP in response to mechanical deformation produced by passage of RBCs through microbore silica tubing (Fig. 3A). Importantly, the RCTT, a measure of RBC deformability, was not altered by incubation of the cells with glibenclamide at concentrations of 10 µM (Fig. 3B) or 100 µM (RCTT 5.6 ± 0.7).
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Effect of L-NAME on pressure-flow relationships in isolated lungs perfused with PSS containing washed RBCs incubated with glibenclamide. To establish that ATP release from RBCs is a requisite for the stimulation of endogenous NO synthesis in isolated rabbit lungs, pressure-flow curves were generated before and 45 min after L-NAME (100 µM) in lungs perfused with PSS containing washed rabbit RBCs that had been incubated with glibenclamide. RBCs were incubated with 10 or 100 µM glibenclamide for 30 min and washed as described above. In studies in lungs perfused with PSS containing RBCs incubated with 10 µM glibenclamide (n = 4), the hematocrit was 20 ± 1%, and pH and gas composition of the perfusate were the following: pH 7.44 ± 0.01, PCO2 34.4 ± 0.4 mmHg, and PO2 119.8 ± 0.7 mmHg. In the case of RBCs incubated with 100 µM glibenclamide (n = 5), the hematocrit was 21 ± 1%, and pH and gas composition of the perfusate were the following: pH 7.41 ± 0.01, PCO2 44.5 ± 0.9 mmHg, and PO2 142.6 ± 0.6 mmHg. The effect of L-NAME on total vascular resistance as well as the arterial component of that resistance in both glibenclamide-treated groups was attenuated compared with lungs perfused with RBCs that were not exposed to glibenclamide. The glibenclamide-associated differences in the total pressure drop across lung (Ppa – Pla) and the pressure drop across the arterial segment of the circulation (Ppa – Pmv) at the highest flow rate studied (300 ml/min) are depicted in Fig. 4A. Importantly, in the group treated with 100 µM glibenclamide, the effects of L-NAME on the pressure-flow relationship was entirely prevented (Fig. 4B).
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Effect of apyrase on ATP-induced decreases in vascular resistance and pressure-flow relationships in isolated lungs perfused with PSS. To determine whether ATP released from endothelial cells in response to increases in perfusate flow rate contribute to vascular resistance, apyrase VII (8 U/ml) was added to the perfusate of isolated rabbit lungs perfused with PSS in the absence of RBCs (n = 6). When added to a solution containing 1 µM ATP, this concentration of apyrase was sufficient to reduce measurable ATP to undetectable levels in the luciferin-luciferase assay within 15 s. In support of the hypothesis that this concentration of apyrase VII was sufficient to metabolize ATP produced by the lung, 45 min after the addition of apyrase to the perfusate of isolated rabbit lungs, infusion of ATP (300 µM) was without effect on pulmonary vascular resistance (n = 6, Fig. 1). To establish that, in the absence of RBCs that release ATP, increases in perfusate flow rate alone were not a sufficient stimulus for endogenous ATP release in the isolated lung, pressure-flow curves were generated before and 45 min after the addition of apyrase to isolated lungs perfused with PSS (pH 7.46 ± 0.01, PCO2 33.1 ± 0.9 mmHg, and PO2 128.6 ± 0.9 mmHg). Apyrase was without effect on the pressure-flow relationship (n = 5, Fig. 5).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Formed elements present in the lumen of blood vessels, namely RBCs, have been shown to release ATP in response to physiological stimuli such as reduced oxygen tension (1, 6, 9) and/or mechanical deformation (30, 31). Previously, we reported (31, 33) that RBCs that release ATP in response to these stimuli, cells from healthy humans and rabbits, are a required component of the perfusate of isolated rabbit lungs to demonstrate endogenous NO synthesis. Indeed, the only component of whole blood that was required for the stimulation of endogenous NO synthesis was the RBC, i.e., in the presence of plasma containing normal numbers of platelets and leukocytes there was no effect of L-NAME on vascular resistance in the absence of RBCs from rabbits or healthy humans (31, 33). Importantly, the addition from RBCs of dogs, cells that do not release ATP in response to physiological stimuli (31), did not result in the stimulation of endogenous NO synthesis in isolated rabbit lungs (31).
If RBC-derived ATP is an important determinant of endogenous NO synthesis in the rabbit pulmonary circulation, then it must be shown that the infusion of ATP into that circulation results in NO-dependent vasodilation. Although ATP has been reported to be a pulmonary vasodilator in several species, there are few reports of the effects of ATP infusion on vascular resistance in the intact rabbit pulmonary circulation. To address this important issue, we infused ATP in isolated perfused rabbit lungs to determine the smallest concentration that produced an effect on vascular resistance. Infusion of ATP at a concentration of 300 µM resulted in a reduction in total pulmonary vascular resistance (Table 1), and this effect was confined to the upstream (arterial) vascular segment. ATP has been reported to produce vasodilation via stimulation of the endothelium to produce NO (5, 8, 11, 12, 16), arachidonic acid metabolites (13, 23), and possible other endothelium-derived relaxing factors (36). The majority of the effect of ATP to reduce vascular resistance was inhibited by L-NAME suggesting that, under these experimental conditions, ATP acts largely, but not entirely, through stimulation of NO synthesis (Fig. 1).
To demonstrate that rabbit RBCs stimulate NO synthesis in the intact pulmonary circulation, we determined that, in the presence of rabbit RBCs that release ATP in response to physiological stimuli, the addition of an inhibitor of endogenous NO synthesis, L-NAME, resulted in a shift in the pressure-flow relationship consistent with a decrease in vascular caliber (increase in Ohmic resistance, Fig. 2A) (32, 33). This effect of L-NAME was confined to the upstream (arterial) segment of the pulmonary vasculature (Fig. 2B), i.e., the segment of the pulmonary circulation affected by the administration of ATP (Table 1). The concentration of ATP (300 nM) that produced reductions in Ppa – Pla and Ppa – Pmv in the work presented here is comparable to the amounts of ATP measured in the effluent of isolated rabbit lungs perfused with PSS containing washed rabbit RBCs (29).
To establish that the property of rabbit RBCs responsible for the stimulation of endogenous NO synthesis in the isolated rabbit lung is the ability of that cell to release ATP, we performed additional studies in which rabbit RBCs were incubated with glibenclamide, an agent that inhibits deformation-induced ATP release from this cell type (30). Glibenclamide (10 µM) inhibited ATP release from RBCs in response to passage through microbore glass tubing (Fig. 3), i.e., in response to a deforming stimulus, as had been reported previously (30). Here we demonstrate that when RBCs treated with glibenclamide were added to the perfusate of isolated lungs, the effect of L-NAME to increase vascular resistance was inhibited in a concentration-dependent fashion (Fig. 4A). Indeed, at the highest concentration of glibenclamide, the L-NAME-induced shift in the pressure-flow relationship was abolished (Fig. 4B).
It has been suggested that, in addition to the RBC, the endothelium itself
may be an important source of ATP released into the vascular lumen in vivo.
Although endothelial cells in culture have been shown to release ATP in
response to the application of shear force
(3,
4), it was also reported that
increasing perfusate flow rate (endothelial shear stress) in isolated lungs of
rabbits (33) and rats
(37) did not stimulate
endogenous NO synthesis in the absence of RBCs that release ATP in response to
physiological stimuli (9), even
when perfusate viscosity was increased to that of blood with dextran
(33,
37). In addition, it was
demonstrated that, in the isolated rabbit lung, increments in perfusate flow
rate resulted in increases in ATP in the lung effluent solely in lungs
perfused with sufficient numbers of rabbit RBCs (HCT 
20%), i.e., in
PSS-perfused lungs no flow-induced ATP release was detected
(29). To address this issue in
another fashion, in the work presented here, we added enzymes (apyrases) to
the perfusate (PSS) of isolated rabbit lungs that metabolize ATP to AMP
(15,
22). It would be anticipated
that, if endothelial ATP is released in response to increases in flow rate,
the addition of apyrase would result in an increase in vascular resistance.
The enzyme mixture chosen was apyrase grade VII. This mixture of apyrases was
chosen because it has a low ATPase-to-ADPase ratio, i.e., the end product
resulting from the reaction of ATP with this mixture is AMP
(15,
22). This is important because
ADP is also capable of activating endothelial purinergic receptors resulting
in the release of EDRFs, whereas AMP does not possess that property. We
determined that the addition of apyrase VII, at a concentration sufficient to
metabolize micromolar amounts of ATP (8 U/ml), was without effect on
pressure-flow relationships in isolated rabbit lungs perfused with PSS
(Fig. 5). These studies,
coupled with those in which RBCs incapable of ATP release were added to the
perfusate of isolated lungs, strongly suggest that ATP derived from the
endothelium is not a major determinant of vascular resistance in the isolated
perfused rabbit lung.
In summary, the results of the work presented here demonstrate that ATP, via its ability to stimulate endogenous NO synthesis, is a pulmonary vasodilator in the intact pulmonary circulation of the rabbit. In addition, we present strong support for the hypothesis that RBC-derived ATP, released in the intact pulmonary circulation in response to a physiological stimulus, is a major determinant of endogenous NO synthesis in the lung. Indeed, both infused ATP and RBC-derived ATP appear to act at the same site in the pulmonary circulation, i.e., arterial (upstream) segment. Finally, the finding that inclusion of enzymes that metabolize ATP and ADP in the perfusate of isolated lungs perfused with PSS had no effect on pressure-flow relationships suggests that ATP released from the endothelium is not a major determinant of vascular resistance in this experimental model.
The finding that ATP released from RBCs is an important determinant of pulmonary vascular resistance coupled with reports that deformation-induced ATP release is deficient in RBCs of humans with some forms of pulmonary hypertension (34) suggests that RBC-derived ATP may be an important determinant of vascular resistance in the pulmonary circulation and that defects in the ability of the RBC to stimulate endogenous NO synthesis may contribute to human disease.
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DISCLOSURES |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Different from respective control value (P <
0.01).
