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J Appl Physiol 82: 852-858, 1997;
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Journal of Applied Physiology
Vol. 82, No. 3, pp. 852-858, March 1997
PULMONARY CIRCULATION AND LUNG FLUID BALANCE

Segmental pulmonary vascular responses to ATP in rat lungs: role of nitric oxide

Tawfic S. Hakim, Lara Ferrario, Jeffrey C. Freedman, Robert E. Carlin, and Enrico M. Camporesi

Departments of Surgery, Anesthesiology, and Physiology, State University of New York Health Science Center, Syracuse, New York, 13210

ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES

ABSTRACT

Hakim, Tawfic S., Lara Ferrario, Jeffrey C. Freedman, Robert E. Carlin, and Enrico M. Camporesi. Segmental pulmonary vascular responses to ATP in rat lungs: role of nitric oxide. J. Appl. Physiol. 82(3): 852-858, 1997.---ATP exhibits vascular pressor and depressor responses in a dose- and tone-dependent manner. The vascular site of ATP-induced contraction or dilation has not previously been characterized. Using the vascular occlusion technique, we investigated the effects of ATP in isolated rat lungs perfused with autologous blood (hematocrit = 20%) and described its action during resting and elevated tone in terms of changes in resistances of the small and large arteries and veins. During resting tone, ATP (10-5 M)

purines; adenosine 5'-triphosphate; pulmonary vascular resistance; thromboxane; segmental resistance; occlusion; hypoxia; endothelium-derived relaxing factor

INTRODUCTION

MANY CELLS IN THE LUNG, including endothelial cells, mast cells, erythrocytes, platelets, and vascular smooth muscle, have high concentrations of ATP that can be released by cell injury or other pathophysiological stimuli (12, 13). At least two classes of ATP purinoceptors (P2x and P2y) and two adenosine purinoceptors (A1 and A2) have been described in the pulmonary vessels (13, 26, 32). Activation of P2x receptors on smooth muscle cell causes contraction, whereas activation of P2y receptors on endothelial cells causes nitric oxide release and vasodilation. In general, injection of ATP or adenosine into the pulmonary circulation at resting conditions causes contraction, but under conditions of elevated tone, purinergic agonists cause dilation (30, 31). Prior characterization of the responses to ATP is strongly based on studies using isolated vessels (8, 14, 26). Arteries and veins exhibit marked heterogeneous physiological and pharmacological responses (8, 23). Therefore, responses observed in isolated vessels cannot necessarily predict the response of the entire pulmonary vasculature. The effects of ATP have also been investigated by using intact animals and isolated lungs. In adult lungs, ATP usually causes vasoconstriction (29, 30, 34), whereas ATP causes dilation in newborn lung (22, 40). Studies that utilized the isolated lungs to characterize the responses to purinergic stimulation have focused primarily on the effects of adenosine (19, 28, 31, 33, 38, 42, 43). A few have examined the effect of exogenous ATP in isolated lungs (10, 18, 38), and one study separated the responses in terms of vessels upstream or downstream from the capillary bed (10).

The present study was designed to characterize the site of constriction or dilation induced by ATP and to separate the responses in terms of large and small vessels. By using a combination of the arterial, venous, and double-occlusion principles, we are able to describe the site of constriction or dilation as being either in large or small arteries or in veins. In addition, the role of nitric oxide production on vascular responses to ATP was investigated.

METHODS

Isolated perfused lung preparation. Male Sprague-Dawley rats weighing 438 ± 57 (SD) g were anesthetized by intraperitoneal injection of pentobarbital sodium (50 mg/kg). The animals were intubated and ventilated with a control gas mixture of 35% O2-5% CO2 in N2 (tidal volume = 3.5 ml and respiratory rate = 30 breaths/min) by using a rodent ventilator (model 683, Harvard Apparatus, South Natick, MA). The animals were heparinized (1,000 U/kg) and exsanguinated via a catheter placed in the carotid artery. While animals were bleeding, a total of 30 ml of 5% dextrose in lactated Ringer (Baxters, Deerfield, IL) was injected slowly into the animal to expand the blood volume. A total of 40 ml of diluted blood [hematocrit (Hct), 20 ± 3%] was exsanguinated from the animals. Twenty milliliters were used to prime the perfusion system, which was kept at 38°C. The chest was opened, and two cannulas connected to the perfusion system were placed, one into the left atrium and the other into the pulmonary artery, through an incision in the right ventricle. Positive end-expiratory pressure of 1.5 Torr was applied. After ensuring that there was no air in the perfusion circuit, blood flow into the pulmonary artery was initiated by using a roller pump (Cole-Parmer Instrument, Chicago, IL) and was then increased gradually to provide an arterial pressure between 10 and 15 mmHg. Thereafter, flow was kept constant. Venous pressure was set between 0 and 1 mmHg relative to the top of the lung, such that the lung was in zone 3 condition. Blood pH was maintained between 7.34 and 7.45 by the addition of NaHCO3 into the reservoir.

Pulmonary arterial (Ppa) and venous (Ppv) pressures were measured from side ports in the cannulas (Gould Statham transducers P23 ID, Quincy, IL) and recorded on a chart recorder (8890A, Hewlett-Packard, Andover, MA). Because the perfusion rate and Ppv were kept constant, changes in Ppa were indicative of changes in pulmonary vascular resistance (PVR). Airway pressure was also recorded.

The concepts of the vascular occlusion techniques have been discussed previously (15, 16). In this study, partitioning of PVR into four segments was accomplished by using a modified analysis approach, as described in detail recently (17) and summarized below. A three-way solenoid valve was used as a means to rapidly stop the flow into the pulmonary artery, and a hemostat was used to stop the venous outflow by clamping the tube. Ventilation was stopped in expiration during the vascular occlusion measurement. Double occlusion (DO) was performed by activating the solenoid valve and clamping the outflow tubing simultaneously. The duration of each DO was 10 s, which allowed the arterial and venous pressures to equilibrate. During the DO period, the pressure signals were stored on a computer for off-line analysis. The arterial and venous pressure tracings from each DO were analyzed, as previously described in detail (17). Briefly, five pressures were calculated from each DO: Ppa, small arterial pressure (Ppa'), capillary pressure (Pc), small venous pressure (Ppv'), and Ppv. Ppa and Ppv were averaged from the 5 s before occlusion. The pressure traces after DO consisted of a rapid change followed by a slow phase. Because these traces are similar to those obtained during a single arterial or a single venous occlusion, they were analyzed as such. A stretch of data between 0.1 and 1.0 s after occlusion was fitted to an exponential curve and extrapolated back toward the instant of occlusion. Ppa' and Ppv' were identified as the breakpoint between the rapid phase and the fitted exponential curve from the slow phase. Pc was calculated from the mean pressure after Ppa and Ppv had equilibrated (7, 16). Based on these five pressures (Ppa, Ppa', Pc, Ppv', and Ppv), the pulmonary vasculature was divided into four pressure gradients across the large arteries (Delta Ppa = Ppa - Ppa'), small arteries (Delta Ppa' = Ppa' - Pc), small veins (Delta Ppv' = Pc - Ppv'), and large veins (Delta Ppv = Ppv' - Ppv). By dividing each pressure gradient by the flow rate, the resistances (R) of the large arteries (Ra), small arteries (Ra'), small veins (Rv'), and large veins (Rv) were calculated. In addition, total PVR [PVR = (Ppa - Ppv)/flow rate] was calculated.

Experimental protocol. After 20 min of stabilization during ventilation with the control gas mixture, baseline (BL) Ppv and blood gases were measured. The lungs were then ventilated with an isocapnic hypoxic gas mixture of 0-3% O2 for up to 15 min. The hypoxic pulmonary vasoconstriction (HPV) reached its peak within 5 min. After a new steady Ppa value during hypoxia was reached, ATP (final concentration = 10-5 M; Sigma Chemical, St. Louis, MO) was added into the reservoir. After a new steady Ppa was reached, ventilation with the control gas mixture was resumed. ATP (10-5 M) was then injected again into the reservoir during normoxic conditions. DO were done during BL, hypoxia, ATP-induced vasodilation in hypoxic conditions, BL again, and during ATP-induced contraction in normoxic conditions. After recovery from ATP, as indicated by return of Ppa to basal level, blood in the perfusion system was removed, the system was washed with saline and refilled with the remaining 20 ml of fresh blood, reestablishing perfusion in <3 min. Flow rate was set to provide a normal Ppa, as during the first perfusion period. After a steady state during the second perfusion period was reached, DO was done, and Nomega -nitro-L-arginine (L-NNA; Sigma Chemical), a nitric oxide synthase inhibitor, was then added into the reservoir (final concentration: 5.4 × 10-4 M). After 30 min, DO was repeated, and HPV was induced. The effect of ATP was tested for its capacity to cause vasodilation during hypoxia. After recovery and during normoxia, ATP-induced contraction was obtained. DO were obtained during each condition. Before and after L-NNA, ATP-induced contraction was transient, and occlusion was done at peak contraction. Effluent blood-gas values during normoxia were PO2 = 247 ± 17 Torr, PCO2 = 40 ± 3 Torr, pH 7.42 ± 0.05, and during hypoxia they were 24 ± 10 Torr, 41 ± 3 Torr, and pH 7.39 ± 0.07, respectively. In this group, there were a total of 17 rats. Seven were treated exactly as described above, and six were pretreated with indomethacin and then studied as above. The remaining four were studied as above by using the nonhydrolyzable form of ATP (ATPgamma S; Sigma Chemical) (6).

Because hypoxia causes a very localized constriction, primarily in the precapillary segment, we also used a thromboxane mimetic (U-46619; Sigma Chemical) to elicit a more generalized constriction. U-46619 was added 0.25 µg at a time to give about the same increase in Ppa as with hypoxia. In this group, DO were done during BL, during U-46619-induced contraction, and during ATP-induced relaxation after constriction with U-46619. After recovery from U-46619 and ATP, the blood was removed and replaced with fresh blood, and flow was reestablished. When Ppa became stable, occlusion was done, and L-NNA was added. After 30 min, U-46619-induced contraction and ATP-induced relaxation were tested. U-46619 was again added 0.25 µg at a time. The dose of U-46619 required to elicit the necessary response after L-NNA was smaller than before L-NNA. DO were done as before. This group included a total of 12 rats. Six were studied as described above, and the remaining six were pretreated with indomethacin and studied as described above. In both groups, indomethacin (1 mg) was injected intravenously into the rat before bleeding, and 0.5 mg was added to the reservoir after priming the perfusion system.

Statistical analysis. The results are presented as means ± SE. Statistical analysis was performed by using analysis of variance for repeated measures, and Fisher's paired least-significant difference (PLSD) test was used as a post hoc test for multiple comparisons. The repeated measurements during the first and second period of perfusion were compared separately. The ATP-induced contraction before and after L-NNA was tested with a paired Student's t-test. P < 0.05 was considered significant.

RESULTS

The basic hemodynamic parameters are shown in Table 1. The flow rate as well as Ppa, Pc, and Ppv during BL conditions are given for each perfusion period in the two groups. The number of experiments in each period is also shown. In the first group of 17 animals, 15 were also studied during the second perfusion period; in the second group, 10 of 12 were also studied during the second perfusion period.

Table 1. Flow rates and pressures during baseline conditions for both perfusion periods in 2 groups of experiments

Condition n Flow Rate, ml/min Ppa, mmHg Pc, mmHg Ppv, mmHg
Group 1 
  Period 1  17 21.5 ± 1.4  10.5 ± 0.5  3.9 ± 0.1  0.4 ± 0.1 
  Period 2  15 18.3 ± 1.0  10.9 ± 0.5  3.9 ± 0.2  0.3 ± 0.1 
Group 2 
  Period 1  12 18.8 ± 1.6  10.6 ± 0.5  3.7 ± 0.2  0.4 ± 0.1 
  Period 2  10 16.4 ± 1.0  11.9 ± 0.7  3.5 ± 0.3  0.3 ± 0.1
Values are means ± SE; n, no. of experiments. Ppa, pulmonary arterial pressure; Pc, double-occlusion capillary pressure; Ppv, pulmonary venous pressure.

ATP with and without indomethacin and effect of ATPgamma S. Because ATP is metabolized rapidly during transit through the lung (20), we included a group of experiments using the nonhydrolyzable ATPgamma S. In addition, because of the reported role of prostaglandins associated with ATP-induced vascular changes in some vascular beds, we included a group of experiments in which the lungs were pretreated with the cyclooxygenase inhibitor indomethacin to inhibit prostaglandin synthesis. There was no significant difference in the effects of ATP and ATPgamma S or between the effect of ATP with and without indomethacin. Furthermore, the sites of the responses were similar. Small differences due to indomethacin were observed only after L-NNA: when indomethacin was present, ATP-induced contraction was attenuated and the HPV was potentiated. Because of the insignificant difference, all experiments with ATP, ATPgamma S, and with or without indomethacin were combined. Indomethacin treatment had no significant effect on total or segmental resistance. L-NNA treatment caused a significant increase in total resistance, as described below.

ATP-induced contraction. As shown in Figs. 1 and 2, injection of ATP during resting tone caused transient vasoconstriction where the total PVR increased from 523 ± 57 to 605 ± 62 mmHg · l-1 · min (P < 0.05).
Fig. 1. Total pulmonary vascular resistance in rat lungs during baseline (BL) and at peak contraction after ATP injection before and after treatment with Nomega -nitro-L-arginine [L-NNA (LNA)]. Bars are SE. * P < 0.05 compared with BL value.
[View Larger Version of this Image (31K GIF file)]

Fig. 2. Segmental vascular resistance for 4 conditions shown in Fig 1. Each segment is compared with its BL value. * P < 0.05 compared with its BL value.
[View Larger Version of this Image (24K GIF file)]

ATP-induced vasodilation during hypoxia. As shown in Figs. 3 and 4, before L-NNA, hypoxia caused PVR to rise from 544 ± 58 to 843 ± 90 mmHg · l-1 · min, and when ATP was added PVR fell to 571 ± 82 mmHg · l-1 · min (92% reversal of HPV, P < 0.05). The increase in PVR during hypoxia and the subsequent dilation after ATP were primarily due to changes in resistance of the small arterial segment from 189 ± 33 to 413 ± 68 to 204 ± 49 mmHg · l-1 · min, with minimal changes in the other segments. After L-NNA, HPV was enhanced with PVR rising from 812 ± 100 to 1,797 ± 178 mmHg · l-1 · min, falling to 1,375 ± 237 mmHg · l-1 · min after ATP (42% reversal of HPV, P < 0.05). The enhanced hypoxic response after L-NNA was primarily due to an enhanced response in the small arteries (from 310 ± 61 to 1,127 ± 114 mmHg · l-1 · min) and partially due to enhancement in the response of the large arterial and small venous segments. The ATP-induced dilation after L-NNA was present in the arterial segment, whereas the dilation in the small arterial segment was attenuated compared with before L-NNA. Before and after L-NNA, ATP-induced relaxation was usually preceded by a small and transient contraction.
Fig. 3. Total pulmonary vascular resistance during hypoxic vasoconstriction (H) and after ATP-induced vasodilation before and after L-NNA. * Difference from preceding value, P < 0.05.
[View Larger Version of this Image (36K GIF file)]

Fig. 4. Segmental vascular resistance during conditions shown in Fig. 3. Changes in resistance of each segment are shown separately for large arteries (A), small arteries (B), small veins (C), and large veins (D). * Significant change compared with preceding value, P < 0.05.
[View Larger Version of this Image (33K GIF file)]

ATP-induced vasodilation in U-46619-contracted lungs. As shown in Figs. 5 and 6, U-46619 caused an increase in resistance due to even increases in all four segments. In contrast to the consistently observed ATP-induced vasodilation during hypoxia, the ATP-induced dilation after U-46619 was small and inconsistent. The response to U-46619 was enhanced markedly after L-NNA. Before and after L-NNA, ATP caused a small decrease in PVR that did not reach statistical significance. However, on examining the segmental resistances, we found that ATP dilated the large arteries but did not affect the other segments significantly. As in the previous group, the ATP-induced relaxation was preceded by a small and transient vasoconstriction.
Fig. 5. Total pulmonary vascular resistance at BL, during U-46619 (U4)-induced contraction, and after ATP-induced relaxation with and without L-NNA. * Significant change compared with preceding value, P < 0.05.
[View Larger Version of this Image (32K GIF file)]

Fig. 6. Segmental vascular resistance for conditions in Fig 5. Resistance of each segment is shown separately for large arteries (A), small arteries (B), small veins (C), and large veins (D). * Significant change from preceding value, P < 0.05. 
[View Larger Version of this Image (34K GIF file)]

DISCUSSION

The results of the present study confirm previous data on the effects of ATP on total vascular resistance but extend these findings by showing which vessels are responsible for the changes in resistance. L-NNA caused a significant increase in resting tone, suggesting that basal tone in rat lungs is regulated by basal production of NO. As previously reported, nitric oxide synthesis

During hypoxia, ATP caused nearly total reversal of HPV (92%) which was markedly attenuated after L-NNA (42%). ATP-induced vasodilation was attenuated by L-NNA in the small arteries but not in the large arteries. The contractile response to U-46619 was almost evenly distributed among all segments and was potentiated in all segments except in the large veins. U-46619-induced vasoconstriction was not reversed consistently by ATP. This result contrasts with other reports in which ATP has been shown to cause significant, although small, vasodilation in rat lungs perfused with blood-free solutions (10) and contrasts with studies on isolated vessel rings (8, 14, 26). The U-46619-induced constrictions in the large arteries and veins were partially reversed by ATP; however, U-46619-induced constriction in the small vessels was not affected by ATP. Eichinger and Walker (10) reported in isolated rat lungs a much more impressive reversal of U-46619 action by ATP. The concentration of U-46619 that was necessary in this study was one-half to one-third that used by these investigators and was even smaller after L-NNA. The fact that they used lungs perfused with blood-free solution may have attenuated the contraction after U-46619 and potentiated the dilation after ATP. The concentration of ATP was approximately similar. The response to U-46619 after L-NNA was enhanced, as others have reported (38).

The reason for the differences in ATP action during hypoxia and after U-46619 is not clear. Hypoxia may affect endothelial cell function by diminishing Ca2+ entry due to depolarization (41), consequently leading to diminished nitric oxide synthesis and endothelium-dependent relaxation (27). During hypoxia, ATP can cause repolarization of the endothelial cell, and increase calcium entry via "leak" channels (4, 9, 21). Increase in intracellular calcium would increase nitric oxide production, leading to vasodilation and reversal of hypoxic vasoconstriction. In contrast, U-46619 leads to smooth muscle contraction and at the same time would cause endothelial cells to hyperpolarize via membrane receptors (21), causing an increase in Ca2+ influx and NO production. Therefore, addition of ATP is not likely to cause further hyperpolarization in the endothelial cells, and thus ATP was not very effective as a dilator.

The increases and decreases in segmental vascular resistance due to nucleotide injection have seldom been measured. One study examined the vasodilatory effect of ATP in terms of vessels upstream and downstream from the capillaries (10). All other studies have examined the effect of nucleotides on isolated vessels (8, 14, 26) or on total resistance of isolated lungs (19, 28, 33, 37). Previous studies, however, have shown that main branches of pulmonary vessels exhibit NO-mediated dilation on stimulation with ATP (8, 14, 26). This study does not refute these findings; however, it does suggest that the role of the large vessels and their purinergic receptors is of minimal importance to the total resistance of the lung. Previous results on intact or isolated lungs were also interpreted in terms of the different types of purinergic receptors, but the location of such receptors could not be inferred from such previous studies. The present study offers this new information on isolated lungs. It should be noted that the responses in rat lungs to ATP, hypoxia, U-46619, and L-NNA occurred primarily in the small arterial segment. This may be different in other animal species in which the large pulmonary arteries and veins are more responsive to vasoactive agents, such as in rabbits (2), pigs (5, 36), dogs (15), and lambs (11).

In summary, the present study extends previous knowledge about the vascular effects of ATP on the pulmonary vasculature and shows that in isolated rat lungs the site of dilatory and constrictor action of ATP was primarily in the small arteries. These findings suggest that P2x and P2y purinoceptors are predominant in the small arterioles of rat lungs. Purinoceptors in other vessels contribute very little to regulation of PVR. Studies that use isolated vessel rings from main branches of the arterial tree do not necessarily reflect the overall change in PVR in the isolated perfused lung or the intact animal.

ACKNOWLEDGEMENTS

This work was supported by a grant from the Hendricks Foundation of New York State.

FOOTNOTES

Address for reprint requests: T. S. Hakim, Dept. of Surgery, SUNY Health Science Center, 750 East Adams St., Syracuse, NY 13210 (Email: hakimt{at}mailbox.hscsyr.edu).

Received 3 May 1996; accepted in final form 1 November 1996.

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