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J Appl Physiol 82: 1084-1090, 1997;
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Journal of Applied Physiology
Vol. 82, No. 4, pp. 1084-1090, April 1997
PULMONARY CIRCULATION AND LUNG FLUID BALANCE

Hypoxic vasoconstriction in pulmonary arterioles and venules

Simon C. Hillier1, Jacquelyn A. Graham1, Christopher C. Hanger1, Patricia S. Godbey1, Robb W. Glenny4, and Wiltz W. Wagner Jr.1,2,3

1 Department of Anesthesia, 2 Department of Physiology/Biophysics, and 3 Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202; and 4 Departments of Medicine and of Physiology and Biophysics, University of Washington, Seattle, Washington 98195

ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES

ABSTRACT

Hillier, Simon C., Jacquelyn A. Graham, Christopher C. Hanger, Patricia S. Godbey, Robb W. Glenny, and Wiltz W. Wagner, Jr. Hypoxic vasoconstriction in pulmonary arterioles and venules. J. Appl. Physiol. 82(4): 1084-1090, 1997.---Pulmonary microvessels (<70 µm) lack a complete muscular media. We tested the hypothesis that these thin-walled vessels do not participate in the hypoxic pressor response. Isolated canine lobes were pump perfused at precisely known microvascular pressures. A videomicroscope, coupled to a computerized image-enhancement system, permitted accurate diameter measurements of subpleural arterioles and venules, with each vessel serving as its own control. While vascular pressure was maintained constant throughout the protocol, hypoxia caused an average reduction of 25% of microvessel diameters. The constriction was reversed when nitric oxide was added to the hypoxic gas mixture. The nitric oxide reversal, combined with a lack of lobar blood flow redistribution as measured by fluorescent microspheres, shows that the constriction was active. This response suggests the unexpected potential for active intra-acinar ventilation-perfusion matching.

pulmonary circulation; nitric oxide; pulmonary microcirculation; videomicroscopy; hypoxic pulmonary vasoconstriction; dogs

INTRODUCTION

HYPOXIA-INDUCED CONSTRICTION of pulmonary vessels has been shown by a variety of techniques to occur in small muscular pulmonary arteries with diameters >100 µm (1, 4, 13, 18). Pulmonary arterioles <100 µm tend to have either no media at all or only a scattering of smooth muscle cells (15, 17). This characteristic makes it difficult to histologically distinguish pulmonary arterioles from pulmonary venules. It has long been assumed that, lacking obvious equipment for constriction, pulmonary arterioles and venules are passive (6, 20). This reasonable function-follows-form idea, plus the technical difficulties of directly studying vasoconstriction in such small vessels, has left the question unanswered as to whether pulmonary arterioles and venules constrict with hypoxia. To investigate this question, we measured luminal diameters by using computer-enhanced videomicroscopic images of the pulmonary microcirculation (10, 12), which was perfused at precisely known microvascular pressures. By comparing the diameter of individual vessels at the same perfusion pressures during normoxia and hypoxia, shifts in the pressure-diameter relationship could be used to directly determine whether active vessel narrowing had occurred. Nitric oxide was then added to the inhaled hypoxic gas mixture to reverse any hypoxia-induced microvascular response and thereby demonstrate whether active microvascular contraction was elicited by hypoxia.

METHODS

Experimental preparation. Healthy mongrel dogs [n = 12, weight 23.3 ± 2.9 (SD) kg] were anesthetized with intravenous pentobarbital sodium (30-40 mg/kg), intubated, and mechanically ventilated with room air by using a Harvard 607D animal respirator. After heparinization (1,000 U/kg) and intravenous administration of meclofenamate (5 mg/kg freshly dissolved in saline; Sigma Chemical, St. Louis, MO), the animals were rapidly exsanguinated through a 3-mm-internal-diameter cannula in the left carotid artery. The first 150 ml of exsanguinate were replaced with 150 ml of 10% Dextran 70 in saline solution (5). The first 600 ml of blood were used to prime the perfusion circuit. After exsanguination, the left thoracic wall was removed and the left upper lobe was excised to gain surgical access to the left lower lobe. The left lower lobar artery was secured around a 6-mm-internal-diameter Teflon fluorinated ethylene polypropylene (FEP) cannula. Throughout the surgical procedure the left lower lobe was kept inflated to 5 cmH2O. The left lower lobe bronchus was clamped, and the lobe was excised along with a cuff of the left atrium. The lobe was placed on a microscope stand and, after the bronchus was cannulated, was ventilated with a 6% CO2-17% O2-77% N2 gas mixture. A tidal volume of 100 ml resulted in peak airway pressures of <10 cmH2O. End-expiratory pressure was set at 2.5 cmH2O. The left atrial cuff was secured around a 9-mm-internal-diameter Teflon FEP cannula, and the lobe was perfused with autologous heparinized whole blood [hematocrit = 33.3 ± 2.8% (SD)]. The perfusion circuit (Fig. 1) consisted of a calibrated roller pump (model 7522-10, Masterflex) and a windkessel to dampen pump pulsations and to act as a bubble trap. These were coupled in series with a high-capacity filter to remove circulating microaggregates (model 4C7700, Fenwal; 20-µm pore size) and a heat exchanger (model HE-100, Bentley), which was warmed by a constant-temperature circulating water bath (model 1267-62, Cole-Parmer) to maintain the perfusate temperature at 37°C. Blood drained from the lobe into a venous reservoir. The vertical height of the venous reservoir relative to the lobe could be adjusted to control pulmonary venous pressure (Fig. 1). Pulmonary arterial and venous pressures were measured via polyethylene catheters (length 40 cm, ID 1.19 mm, OD 1.70 mm) that were threaded via the arterial and venous cannulas so that their tips were just within the lobar artery and lobar vein. Pressure transducers (model P23 XL, Statham) were zeroed at the level of the surface of the lung where vessel diameters were being measured. The outputs from the transducers were amplified (model 13-G4615-52, Gould) and directed to an analog-to-digital board (model C10-DA508-PGA, Computer Boards) in a microcomputer (Dell 486; 50 MHz).
Fig. 1. Schematic illustration of experimental setup. VCR, videocassette recorder; Ppa, pulmonary arterial pressure; Ppv, pulmonary venous pressure; TV, television.
[View Larger Version of this Image (30K GIF file)]

Videomicroscopic technique. A 1.3-cm2 area on the diaphragmatic surface of the lobe was held stationary against a transparent window by a vacuum ring that prevented motion (26). The lobe was also suspended from above by two ligatures that were attached to the lobar edges with spring-backed paper clips to prevent the lobe from falling away from the observation window. The subpleural pulmonary microcirculation was observed and videotaped through the window with a Leitz Ultropak surface-illuminating microscope (final magnification ×618-957) coupled to a charge-coupled device television camera (model TM 840, Videoscope) and an SVHS video recorder (model AG 7300, Panasonic). Illumination was provided by a 200-W mercury arc lamp filtered to prevent tissue damage with a combination of dichroic infrared-reflecting filters and broadband-pass ultraviolet-absorbing filters. A narrowband-pass interference filter was used to illuminate the lung only with the mercury green line (546 nm). This wavelength is absorbed by hemoglobin, thereby increasing the contrast between the red blood cells and the surrounding tissue (25). A subpleural arteriole and venule (both <70 µm ID) were videotaped during the experimental protocol for later determination of vessel diameter.

Data acquisition. In the previous description from our laboratory of canine pulmonary microvascular distensibility under normoxic conditions (12), microvascular diameter was measured over the physiological pressure range (5-30 mmHg) in each individual preparation. The present study was designed to compare microvascular diameters during normoxia and hypoxia. Hypoxia, however, tended to cause visible perivascular edema, particularly when microvascular pressures were elevated. Because the edema interfered with our ability to accurately measure microvascular diameter, data collection was abbreviated by measuring microvascular diameter at only one or two microvascular pressures. This protocol limited the duration of exposure of the lobe to hypoxia and to elevated microvascular pressure.

Before each period of data collection, the lobe was continuously perfused at a flow of 350 ml/min. The inspired gas composition was adjusted and sodium bicarbonate was added to the venous reservoir to maintain blood gases at the required values: PO2 >100 Torr during normoxia and PO2 30-40 Torr during hypoxia. The PCO2 (~35 Torr) and pH (~7.40) were held constant. Preparations were considered acceptable only if pulmonary arterial pressure increased by at least 50% during hypoxia at a perfusion rate of 350 ml/min. During each measurement, respiratory movement was briefly arrested by occluding the bronchial cannula at an end-expiratory pressure of 2.5 cmH2O, and the pump flow was transiently reduced to 15-50 ml/min. The low flow rate caused the arteriovenous pressure gradient to diminish to <3 mmHg, permitting us to control microvascular pressure to within ±1.5 mmHg of the desired value. The process of adjusting the height of the venous reservoir during low flow to achieve the required microvascular pressure never took >2 min and resulted in a constant microvascular pressure during the period of data collection.

In each lobe, one or two microvascular pressures were selected from the 5- to 10-mmHg range (low pressure) and/or the 15- to 20-mmHg range (high pressure) and were held constant for each experimental condition. The microvascular pressure was set by adjusting the vertical height of the venous reservoir, and, when steady state was reached, the microvessels were video recorded for later determination of vessel diameter.

Nitric oxide. In four of the preparations, microvascular diameters were remeasured during the addition of nitric oxide to the hypoxic gas mixture to reverse the pressor response while constant hypoxic blood-gas values were maintained. The nitric oxide was diluted in the inspired gas to a final concentration of 40 parts per million as measured by an electrochemical monitor (Sensor-Stik model 4586, Exidyne Instrumentation Technologies, Exton, PA).

Vessel diameter measurement. The technique used for measuring vessel diameters has been described in detail elsewhere (10, 12). Briefly, once equilibrium was established at each pressure, the vessel was videotaped for 10 s. At a later time, vessel diameter was determined from the videotape by using a computer-assisted image-analysis system. To optimize vessel definition, and therefore the accuracy of vessel diameter measurements, the video recorder was interfaced with a Dell 486 50-MHz microcomputer. The computer controlled the video recorder frame-advance mechanism so that any individual video frame could be located. Depending on the velocity of red blood cell flow in the selected vessel, every third to eighth video frame from a short 1- to 3-s period of the recording was digitized by a Data Translation DT-2851 frame grabber board (total ~10 frames). Building and microscope vibration caused the video image to move slightly between digitized frames. The computer compensated for this frame-to-frame jitter by relating and shifting successive images to a reference point (e.g., a particularly well-illuminated high-contrast alveolar wall) so that all images became superimposed. Because the superimposition technique stabilized the field, differences in pixel density at the same location over blood vessels between successive frames were nearly certain to be caused by moving red blood cells. The computer determined which pixels differed from frame to frame. These were brightened in proportion to the degree of change to produce a composite image of that period in which changing portions of the image became white and nonchanging portions remained black. In this way the vessel margins were enhanced. At the low flow rates employed, we assumed the plasma layer adjacent to the vessel wall to be of negligible thickness.

Vessel diameter was determined from the enhanced images by using a heuristic approach. A line 3-cm long (corresponding to 100-150 µm on the video image) and one pixel wide was generated by the computer on the video display. The line was placed by eye parallel to and inside one of the vessel margins, which was selected from a region in which the margins were straight and parallel. The operator moved the line orthogonally until it was clearly past the margin of the vessel. The computer was instructed to reposition the line within this range at the location where the summed squared difference in pixel densities on either side of the line was maximal. This process accurately located the line on the vessel margin and was repeated on the opposite vessel wall. Vessel diameter was determined by the computer from the orthogonal distance between the two lines and was measured each time at the same location in each vessel under each experimental condition. After each study, a stage micrometer was videotaped for calibration at the same magnification used during the experimental protocol. Vessel diameters were compared under each experimental condition by using paired two-tailed t-tests.

Flow distribution analysis To determine blood flow distribution within the lobe, different-colored fluorescent polystyrene microspheres (1.5 × 106 microspheres, mean diameter 15.1 µm; Fluospheres Molecular Probes, Eugene, OR) were injected into three of the lobes immediately after steady state was achieved during normoxia and hypoxia. The details of this technique are described elsewhere (7) and so will be described briefly here. Immediately before the 30-s-long injection into the pulmonary artery, the microspheres were sonicaided for 10 min and vigorously vortexed to ensure complete disaggregation. After the experiment, the lobes were flushed with 2% Dextran 70 in 0.9% saline solution until the effluent was clear. The lobes were air dried for 72 h at an inflation pressure of 5 cmH2O and sliced in 1-cm-thick isogravitational planes. Each lung slice was photocopied. The slices were then dissected in an "onion skin" manner from the periphery toward the central portion of the lobe (Fig. 2). These strips of lung were further cut into pieces that weighed ~0.015 g. The location of each piece was drawn on the photocopied image of that slice. The pieces were weighed and numbered, and the distance from the nearest pleural surface was recorded. Each piece was soaked in 1.5 ml of Cellosolve (2-ethoxyethyl acetate, Aldrich Chemical, Milwaukee, WI) for 48 h to extract the fluorescent dye. The fluorescence of each sample in the solvent was measured by fluorimetry. The blood flow per piece was determined by calculating the total blood flow divided by total fluorescence for the whole lobe and multiplying that value by the fluorescence value for each piece. Flow during normoxia and hypoxia was compared and plotted for each piece. Blood flow data from individual pieces were pooled into groups according to their location relative to the nearest pleural surface. These groups were located 0-5.0, 5.1-10.0, ... mm from the nearest pleural surface. The mean percent change in flow from normoxia to hypoxia was calculated for each group. Trends toward redistribution were analyzed by linear regression of the group means as a function of distance from the nearest pleural surface.
Fig. 2. Typical isogravitational slice of lobe showing manner in which pieces were dissected. Note that large vessels (hatched areas) are in central part of lobe.
[View Larger Version of this Image (20K GIF file)]

RESULTS

Blood-gas values were stable during the experiment except for oxygen tensions intentionally changed during hypoxia (Table 1). Hypoxia was associated with a decrease in arteriolar diameter in every single case (Fig. 3). This decrease in diameter occurred whether microvascular pressure was low [7.5 ± 2.7 (SD) mmHg] or high (16.4 ± 2.4 mmHg). There was also a hypoxia-induced decrease in venular diameters in every single case, again occurring at both low and high microvascular pressures. The consistency of these alterations in diameter caused them to be highly significant (Table 2). This reduction in microvascular diameter during hypoxia was reversed by the concomitant administration of inhaled nitric oxide (Table 3, Fig. 4). In each case, microvascular diameter increased with the addition of nitric oxide to the inhaled hypoxic mixture.

Table 1. Results of blood-gas analysis during normoxic and hypoxic conditions

Experimental Condition PO2, Torr PCO2, Torr pH
Normoxia 115.5 ± 3.0* 36.7 ± 0.7  7.412 ± 0.01 
Hypoxia 37.8 ± 2.1  36.4 ± 0.6  7.420 ± 0.01
Values are means ± SE. * Significantly different from hypoxic value, P < 0.05.

Fig. 3. Arteriolar (A) and venular (B) diameter responses to hypoxia under conditions of low [7.5 ± 2.7 (SD) mmHg] or high (16.4 ± 2.4 mmHg) microvascular pressures. Diameter values are means ± SE; n, no. of vessels.
[View Larger Version of this Image (23K GIF file)]

Table 2. Arteriolar and venular diameters under low and high microvascular pressures during normoxia and hypoxia

Microvascular Pressure Vessel Diameter, µm
Normoxia Hypoxia
Arterioles Low 35.1 ± 3.3* 27.9 ± 3.8 
High 46.6 ± 2.3* 31.8 ± 3.3 
Venules Low 39.0 ± 3.8* 30.4 ± 2.9 
High 45.5 ± 3.4* 33.4 ± 3.8
Values are means ± SE. Low pressures averaged 7.5 ± 2.7 (SD) mmHg, and high pressures averaged 16.4 ± 2.4 mmHg. * Hypoxic diameters are all significantly smaller than corresponding normoxic values, P < 0.005.

Table 3. Microvascular responses to hypoxia and hypoxia with the addition of inhaled nitric oxide

Vessel Diameter, µm
Normoxia Hypoxia Hypoxia + inhaled NO
Arterioles 36.9 ± 5.2* 30.0 ± 5.3* 35.1 ± 5.1 
Venules 38.3 ± 4.7* 30.2 ± 3.9* 36.8 ± 5.0
Values are means ± SE. NO, nitric oxide. * Significantly different from value in adjacent column, P < 0.015.

Fig. 4. Microvascular responses to hypoxia and hypoxia plus inhaled nitric oxide. Measurements were made under identical microvascular pressure conditions, and oxygen tensions during hypoxia and hypoxia plus nitric oxide were identical. Diameter values are means ± SE; n, no. of vessels.
[View Larger Version of this Image (16K GIF file)]

In Fig. 5 the relationship between flow during normoxia and flow during hypoxia for a typical lobe is shown. Each data point represents the blood flow in a single piece of the lobe. The normoxic flow and the hypoxic flow for each individual piece corresponded closely. The slope of the regression line in this example was 0.955 with an R2 of 0.95; the results were similar in the two other lobes in which microspheres were injected. In Fig. 6 the percent change in flow from normoxia to hypoxia is plotted against the distance from the nearest pleural surface. The data points are group means from all three lobes. We found no evidence for redistribution of blood flow with hypoxia: the slope of the linear regression plot was not different from zero (P = 0.9, regression slope = 0.04% change in flow/mm from nearest pleural surface, R2 = 0.004).

Fig. 5. Blood flow distribution derived from fluorescent-microsphere distribution. Each data point represents flow in an individual piece (total 362 pieces) during hypoxia and normoxia from a single preparation.
[View Larger Version of this Image (21K GIF file)]

Fig. 6. Pooled data from all 3 preparations in which microspheres were injected. Each data point represents mean percent change in flow (hypoxic flow compared with normoxic flow) plotted as function of mean distance from nearest peripheral edge. There is no evidence of flow redistribution during hypoxia.
[View Larger Version of this Image (14K GIF file)]

DISCUSSION

The diameters of subpleural pulmonary arterioles and venules decreased significantly during hypoxia while microvascular pressure was held constant. The effect was reversed by adding nitric oxide to the hypoxic gas mixture. These data show that hypoxia-induced vasoconstriction occurs in 30- to 70-µm pulmonary microvessels.

Several issues need to be considered in the interpretation of these data. First, the accurate measurement of microvascular diameters in the blood-perfused lung is difficult because there is little contrast between the red blood cells and the background tissue. In previous work from our laboratory, in which a computerized image-enhancement system was utilized, it was shown that our microvascular diameter measurements are both accurate and reproducible (10, 12). Second, we were concerned whether the microvascular pressure was the same during normoxia and hypoxia because a decrease in microvascular distending pressure would cause the vascular diameter to decrease. The distending pressure was held constant by decreasing the pump flow rate and by adjusting the height of the venous reservoir. Because the arteriovenous pressure gradient was always <3 mmHg, the microvascular pressure was constant to backsim 1.5 mmHg during each experimental condition. In the present study, an ~25% decrease in microvascular diameter was observed during hypoxia. Based on previous work on pulmonary microvascular distensibility (12), a reduction in diameter of this magnitude, if it were passive, would require a >20-mmHg decrease in microvascular pressure, a value considerably in excess of the backsim 1.5-mmHg limit of these experimental conditions. The alveolar pressure was held constant and was identical during normoxia and hypoxia. There was no evidence of interstitial edema, because perivascular cuffing would have appeared immediately with the onset of edema and clouded the view of the moving red blood cells, a condition that would cause us to reject the lobe from the study. The combination of constant microvascular pressure and alveolar pressure combined with no evidence of alterations of interstitial conditions suggested that vascular transmural pressures were constant during normoxia and hypoxia. The addition of nitric oxide to the inspired hypoxic gas mixture caused the vessels to dilate to control diameters. This finding demonstrates that the hypoxia-induced vasoconstriction was a reversible and active process. Finally, we were concerned over whether there was an inward redistribution of blood flow during hypoxic vasoconstriction, as has been suggested by Hakim et al. (8, 9). In our preparation there was neither a radial gradient of flow nor a radial redistribution of flow during hypoxia, as demonstrated by the unaltered distribution of flourescently labeled microspheres. In summary, we conclude that hypoxia caused pulmonary microvascular constriction for the following reasons: 1) airway hypoxia caused a downward shift in the pressure-diameter relationship, i.e., at constant intravascular pressures, the microvessels had a >25% reduction in their diameters; 2) the measurement of microvascular diameter was made by using a computer image-enhancing technique of proven accuracy; 3) each vessel served as its own control; 4) there was no redistribution of intralobar flow when the inspired gas was changed from normoxia to hypoxia; and 5) the reduction in diameter during hypoxia was reversed when nitric oxide was added to the inspired gas mixture.

These findings are unexpected because pulmonary microvessels have been considered on morphological grounds to be incapable of vasoconstriction. For example, Fishman (6) emphasized the paucity of contractile elements and stated "... it is difficult to imagine the pulmonary vessels (of 50 µm) as the sites of intense vasoconstriction." He suggested instead that larger precapillary vessels were better constructed for vasoconstriction. Interspecies differences in the structure of the pulmonary circulation, however, are well defined and must be considered when interpreting morphological data from animals (15). In the specific case of the canine pulmonary circulation, there is histological evidence that a small amount of smooth muscle is present in both arterioles and venules. Michel (17) found that normal canine pulmonary arterioles of <50 µm diameter had ~20% of their diameter accounted for by muscular media, whereas venules of the same caliber had ~9% of their diameter accounted for by muscle. In the case of larger canine pulmonary vessels, 51-100 µm in diameter, arterioles had ~12% of their diameter accounted for by muscular media and venules had 7% of their diameter accounted for by muscle. These data show that the contractile elements for vasomotion are present in canine pulmonary arterioles and venules. Thus, even though the media may not be completely circumferential, contraction of the muscular elements would still reduce the luminal diameter.

Although the case for precapillary vasoconstriction, all the way to the smallest arterioles, appears convincing, evidence for a postcapillary site of increased vascular resistance is less clear cut. Audi et al. (3) calculated that the increase in pulmonary vascular resistance occurring in hypoxic isolated canine lobes occurred predominantly within the arterial side of the capillary bed, with the venous side only accounting for ~20% of the increase in total resistance. In another study from Al-Tinawi et al. (1) utilizing X-ray angiography of isolated perfused canine lobes, the caliber of 200- to 1,000-µm canine pulmonary veins decreased by only 9% during hypoxia. Using hemodynamic modeling, Al-Tinawi et al. predicted that this change in caliber accounted for only 4% of the total increase in pulmonary arterial pressure and suggested that, although hypoxic venoconstriction represented a significant increase in local resistance, vasomotion in 200- to 1,000-µm veins did not represent a significant contribution to the overall increase in total pulmonary vascular resistance. In the present study, we observed significant venoconstriction in vessels of 30-70 µm. Constriction of 30- to 70-µm venules may be partly responsible for the difference between the 20% increase in pulmonary vascular resistance accounted for by the change in total venous resistance [Audi et al. (2)] and the relatively modest 4% increase in pulmonary vascular resistance occurring in the 200- to 1,000-µm vein compartment [al-Tinawi et al. (1)]. In addition, Wagner and Latham. (27) found no alteration in the pressure gradient between 2-mm pulmonary veins and the left atrium during hypoxia. These data suggest that hypoxic venoconstriction occurs predominantly in venules <200 µm and most likely tapers to insignificance by the time veins of several millimeters are reached.

It has been well documented that inhaled nitric oxide reverses hypoxic pulmonary vasoconstriction (28, 29). Our data support previous measurements using vascular occlusion techniques that have consistently demonstrated inhaled nitric oxide-induced vasorelaxation of hypoxia-constricted small pulmonary arterioles (21, 23). However, the same investigators have found more variable effects of inhaled nitric oxide on the venous side of the pulmonary circulation. Roos et al. (21) reported that inhaled nitric oxide dilated endothelin-1-constricted venules in isolated rat lungs when perfused with a hemoglobin-free solution. In contrast, Tod et al. (23) did not find nitric oxide-induced vasodilatation of small pulmonary veins in hypoxic isolated blood-perfused lamb lobes. In the present study, we demonstrate that inhaled nitric oxide does cause significant venodilation in hypoxia-constricted blood-perfused canine lobes. It may be that vascular occlusion techniques are unable to adequately resolve the resistance changes occurring in the smallest venules. Furthermore, it is likely that larger vessels within the venous circulation are unresponsive to inhaled nitric oxide in blood-perfused preparations because nitric oxide is bound to hemoglobin before reaching those vessels.

The majority of current evidence suggests that ventilation-perfusion matching is maintained predominantly by constriction of pulmonary arteries that direct blood flow away from hypoxic regions. This concept, born with the classic study of von Euler and Liljestrand (24), has since been confirmed by many investigators. As the region of hypoxic lung becomes smaller, the fraction of blood diverted to better ventilated regions increases, thus making hypoxic vasoconstriction more effective in smaller regions (16). Data concerning the hemodynamic consequences of hypoxia have been utilized in a mathematical hemodynamic model (11) that predicts that vessels <200 µm probably account for the majority of the increase in vascular resistance during hypoxia. Our experiments support that prediction by demonstrating that microvessels in the 30- to 70-µm range are capable of significant hypoxia-induced constriction. One implication of this finding is that ventilation-perfusion regulation could occur well within the acinus. The extent of ventilatory heterogeneity within an acinus remains to be determined; calculations based on the rate of molecular diffusion in the gas phase suggest that acinar gas is homogeneous, at least in the normal lung (19). Enlargement of the acinus in disease, however, could almost certainly lead to ventilatory heterogeneity (22). Under those pathological conditions, intra-acinar ventilation-perfusion regulation could become much more important.

ACKNOWLEDGEMENTS

We thank Drs. R. G. Presson, Jr., C. F. Rothe, H. G. Bohlen, T. C. Lloyd, Jr., B. J. DeWitt and T. M. Wagner for helpful criticism of the manuscript.

FOOTNOTES

   This work was supported by National Heart, Lung, and Blood Institute Grant HL-36033.

Address for reprint requests: W. W. Wagner, Jr., MS 374, 635 Barnhill Dr., Indianapolis, IN 46202-5120.

Received 22 February 1996; accepted in final form 15 November 1996.

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