Pulmonary

vascular

reactivity

in Fischer

rats

LISHAN HE, SHIH-WEN CHANG, AND NORBERT F. VOELKEL Cardiovascular Pulmonary Research Laboratory and Webb- Waring Lung Institute, University of Colorado Health Sciences Center, Denver, Colorado 80262

HE, LISHAN,~HIH-WENCHANG,ANDNORBERT F. VOELKEL. Pulmonary vascular reactivity in Fischer rats. J. Appl. Physiol. 70(4): 1861-1866, 1991.-We previously reported that Fischer (F) rat lungs developed more extensive injury when challenged with oxidants than age-matched Sprague-Dawley (SD) rat lungs. We now describe a reduced pulmonary vascular response to alveolar hypoxia and angiotensin II (ANG II) in F compared with SD rats. The comparative studies were performed with isolated lungs perfused with salt solution or blood, catheter-implanted awake rats, and isolated main pulmonary arterial rings. Isolated lungs from F rats perfused with either blood or salt solution had reduced vasoconstriction in comparison with lungs from SD rats when exposed to alveolar hypoxia or challenged with ANG II. Instrumented awake F rats had a smaller mean increase in total pulmonary vascular resistance (PVR) than SD rats (35 vs. 94 mmHg . min. l-‘, P < 0.05) when challenged with 8% oxygen. The contractile response of isolated pulmonary artery but not thoracic aortic rings to KC1 and ANG II was reduced in F compared with SD rats. In addition, F rats exposed to 4 wk of hypobaric hypoxia developed less pulmonary hypertension and right ventricular hypertrophy (when corrected for the hematocrit) than SD rats. We conclude that the oxidant stress-sensitive inbred F rat strain is characterized by a lung vascular bed that is relatively unresponsive to vasocontricting stimuli. The mechanism underlying this genetic difference in lung vascular control remains to be defined.

chronic

hypobaric

hypoxia;

phorbol

ester

is known for its propensity to develop spontaneous cancers (4), premature aging (3), and susceptibility to develop liver cell necrosis (12, 13) and lung injury (6, 7) when exposed to oxidants. Although it is well appreciated that large species differences in lung vascular control exist, especially in the lung’s response to alveolar hypoxia (15), it is not known whether lung vascular responses are different in various animal strains. We were interested in comparing the lung vascular responses of the Fischer rat with those of the Sprague-Dawley rat and hypothesized that the Fischer rat may develop less acute pulmonary vasoconstriction and less chronic pulmonary hypertension than the Sprague-Dawley rat. We based this postulate on recent observations by Weir and colleagues (18, 19) and Burke and Wolin (2), which suggest that oxidants can act as pulmonary vasodilators. If Fischer rats were characterized by an imbalance of endogenously produced oxidants not adequately “buffered” by antioxidants, then the Fischer rats might be under a high chronic “oxidant, or peroxide tone” and have a relatively vasodilated pulmonary vascular bed. We have previously demonstrated de-

THE FISCHER RAT STRAIN

0161-7567/91

$1.50

Copyright

creased lung ATP levels in Fischer compared with Sprague-Dawley rats (7), a finding consistent with a tissue response to active 0, (6). To investigate potential differences in lung vascular control between these two rat strains, we measured the pressor response to acute alveolar hypoxia or angiotensin II (ANG II) injection in isolated perfused lungs and in chronically instrumented awake rats. We complemented these studies with an assessment of the contractile responses to KCl, ANG II, and phorbol myristate acetate (PMA) of main pulmonary artery rings from Fischer and Sprague-Dawley rats. Finally, rats of both strains were exposed to hypobaric hypoxia for 4 wk, and pulmonary arterial pressure and right heart hypertrophy were assessed.Using this comparative approach, we found differences in lung vascular reactivity between genetically distinct strains of rats that may be related to, or may perhaps be a consequence of, the different susceptibility of the lungs to oxidant-induced injury. METHODS

Isolated perfused lungs. Male pathogen-free SpragueDawley (SD) rats and inbred Fischer 344 (F) rats weighing 200-300 g were obtained from a commercial vendor (Harlan, Indianapolis, IN) and housed in laminar flow hoods in our animal care facility, where they had free access to food and water. The animals were anesthetized with pentobarbital sodium (100 mg/kg ip), and their lungs were removed for extracorporeal perfusion as described (8). Briefly, the lungs were ventilated through a tracheal cannula with a Harvard small animal respirator (model 646) at 50 breaths/min with 8 cmH,O inspiratory pressure and 3 cmH,O positive end-expiratory pressure. Throughout the experiment (unless stated otherwise), the inspired gas consisted of 21% O,-5% CO,-74% N,. A median sternotomy was performed, and after injection of heparin (100 U) into the right ventricle, the pulmonary artery was cannulated. A second cannula was placed in the left ventricle to collect the effluent perfusate from the lungs. The heart, lungs, and mediastinal structures were removed and placed in a constant-temperature humidified chamber. The lungs were perfused at constant flow (0.03 ml g body wt-l min-‘) with either a solution containing 50% rat blood or a physiological salt solution. Vasoconstriction after ANG II and during alveolar hypoxia. We initially used a solution containing 50% blood plus 50% physiological solution containing 3 g albumin/ 100 ml (Sigma Chemical, St. Louis, MO). Five lungs from each strain were perfused. At the end of a 30-min equili-

0 1991 the American

l

Physiological

l

Society

1861

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1862

LUNG

A

20

VASCULAR

REACTIVITY

q SD n=5 q Fischer n=5 1

T *

ANG llO.O!S~g

B I

3%0xygen

-

12 IO 55 E 8 g 6x z 4 2-

17 SD n=7 q Fischer n=6

OO%Oxygen

ANGII O.lpg

FIG. 1. Change in pulmonary arterial pressure (Ppa) in isolated Sprague-Dawley (SD) and Fischer (F) rat lungs perfused with a mixture of 50% blood-50% physiological salt solution after either airway hypoxia (3% 0,) or bolus injection of angiotensin II (ANG II, 0.05 pgl 0.1 ml saline, A) or blood-free physiological salt solution, after either airway hypoxia (0% 0,) or bolus injection of ANG II (0.1 pg10.1 ml saline, B).

bration, 0.05 pg ANG II (Sigma Chemical) in 0.1 ml saline was injected as a bolus into the pulmonary artery. Ten minutes later, the lungs were challenged with airway hypoxia (3% 0,) for 8 min. Then two more pairs of alternating ANG II and hypoxic challenges were performed, with each challenge separated by a lo-min interval. The second pair of responses to ANG II and hypoxia, calculated as the maximal change in mean pulmonary arterial perfusion pressure, was compared between the two strains. To eliminate the effects of blood components on the TABLE

IN

‘I1

l

501+11

Ppa, mmHg Psa, mmhg mmHg mmHg

1-l. min . I-’ min l

l

0.11+0.02 I 28.9-i2.05 125k3.07 I 221t-43 1,364&266

1

.

hypOXlC

.

and anglotenstn 11 cnauenges 1

l

.

TT

8% 0,

Baseline

HR, beats/min CO, l/min

RATS

pulmonary vascular response, physiological salt solution osmotically stabilized with 4% Ficoll (mol wt 70,000; Sigma Chemical) (8) was used in a separate experiment. Seven SD rat lungs and five F rat lungs were perfused. After an equilibration period of 30 min, bolus injections of 0.05 pg ANG II and hypoxic challenges (0% 0, ventilation for 8 min) were alternatively applied at 5-min intervals, and the change in pulmonary arterial pressure was recorded. ANG II (0.1 pg) was injected again, and the hypoxic response was repeated one more time. The magnitude of the largest ANG II- and hypoxia-induced vasoconstriction was compared in the two strains. Studies of instrumented awake rats. Male SD and F rats (260-330 g, n = Ugroup) were anesthetized with intramuscular injection of ketamine hydrochloride (50-100 mg/kg) and xylazine (5 mg/kg). With the use of sterile instruments, the right carotid artery was cannulated with a PE-50 catheter (0.58 mm ID) and ligated distally. A polyvinyl catheter (PVl, 0.28 mm ID) with a shallow bend at its tip was inserted into the right jugular vein and guided into the main pulmonary artery. The location of the catheter was verified by a characteristic pulmonary arterial pressure tracing displayed on an oscilloscope. After the pulmonary artery catheter was in place, a second catheter (PVl) with a straight tip was introduced into the same vein and advanced into the superior vena cava. Finally, a fourth catheter (PE-50) was placed in the left jugular vein. All catheters used were previously sterilized with sporicidin and flushed with heparinized saline. After placement, the catheters were tunneled subcutaneously to the back of the neck; they were protected in a plastic housing sutured to the skin and covered with a rubber cap. More than 90% of catheters prepared in this way remained patent for >72 h. After recovery from anesthesia (24-48 h later), the awake rats were placed in a small rectangular plastic chamber. An inlet on the wall of the chamber allowed ventilation with either normoxic (room air, Denver altitude 1,600 m) or hypoxic (8% 0,) gas. The catheters were connected to P23 Db transducers (Statham, Oxnard, CA) for measurement of heart rate, aortic pressure (via the carotid catheter), and mean pulmonary arterial pressure (via the pulmonary artery catheter). The other two venous catheters provided access for fluid, drug, or dye injection. Cardiac outputs were measured with the dye-dilution method described previously (17). Systemic vascular resistance and total pulmonary resistance were

1. Hemodynamic data of SD and F rats at baseline ana cturlng

SD

PVR, TSR,

FISCHER

F

SD

504-t 16 0.10+0.01

518~~0.4 0.13+0.03

25.8t2.09* 120+8.00 202+31.0* 1,281-t179

1

ANG F

SD

11

_

II Infusion F

517+12 0.21+0.07

51723.0 0.10+0.02

520-t0.6 0.09-to.02

35.9t1.07 125k3.70

28.2k3.7 128k9.00

37.lk3.06 169k4.01

31.6t4.07 158211.0

315i58.0 1,097+199

237k39.0 1,110+223

375+112 1,707t417

1

Values are means t SE for 5 rats/group. HR, heart rate; CO, cardiac output; PVR, pulmonary vascular resistance; TSR, total systemic resistance. Brackets, There were no corresponding significant increments in the Fischer rat strain.

Ppa, pulmonary arterial significant hypoxia-induced

310+49 1,728&312

pressure; Psa, systemic arterial pressure; increments in Ppa or PVR. * P < 0.05.

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LUNG

TABLE

during

VASCULAR

REACTIVITY

2. Blood gas and Hct values of SD and F rats 8% 0, inhalation Baseline SD

PH

p%x)2, 7I-br Paoz, Torr Hct, %

7.45kO.005 30.7+ 1.002 74.4+1.008 48.3+0.009

8% 0, F

7.44kO.007 26.6+ 1.008* 77.71~3.002 45.4&0.007*

Values are means t SE for 5 rats/group. Pao2, arterial Paz; Hct, hematocrit. * Compared

SD

7.60+0.01 22.1kO.05 29.1t0.07 Pa,,*, arterial with SD rat,

F

7.54-io.04 21.3t1.04 33.7k3.01

Pco~; P < 0.05.

calculated by dividing mean aortic pressure or mean pulmonary arterial pressure by the cardiac output. Hypoxic challenges were performed by overflowing the study chamber with 8% 0, for 5 min. The hypoxic pressor response was expressed as the difference between the maximal mean pulmonary arterial pressure during hypoxia and mean pulmonary arterial pressure immediately before hypoxia. Blood samples (0.5 ml each) were drawn from the aortic catheter for measurements of blood gas tensions and pH. Each rat was given the hypoxic challenges with 8% 0, twice, separated by 20 min of normoxia. Then ANG II was infused continuously for 10 min at a dose of 0.0618 pg/min. The second hypoxic challenge and the maximal pulmonary pressure response to ANG II were recorded. Studies of isolated pulmonary artery and thoracic aorta rings. The two main branches of the pulmonary artery and the thoracic aorta were removed from SD and F rats and placed in a physiological salt solution, which was kept at 38°C and bubbled with 5% CO,-95% air. The composition of the salt solution was (in mM) 116 NaCl, 4.7 KCl, 0.83 MgSO,, 1.04 KH,PO,, 1.8 CaCl, . 2 H,O, 5.5 glucose, and 22.6 NaHCO,. The vascular rings were connected to a Grass force transducer and equilibrated for 1 h at a resting tension of 1.5 g for the aortic and 0.5 g for pulmonary arterial rings. The endothelium was considered intact in vascular rings that showed >80% relaxation to 1 PM acetylcholine (Sigma) while being precontracted by 5 X IO-’ M phenylephrine. The first series of experiments compared the dose-response curves to KC1 in the rings from the two strains by cumulatively adding lo-80 mM KC1 to the muscle bath at 5-min intervals. The bath was then flushed twice with fresh salt solution and, after the tension of the rings had returned to baseline, the cumulative dose responses to ANG II were elicited by adding the agonist increments to provide a bath concentration of 10m7,10s6,and 10s5g/ml. In a second set of experiments, the contractile effects of PMA, a protein kinase C activator, were examined in SD and F rat vascular rings. PMA (500 mM) was added to the bath and observed for 90 min. The contractile responses were recorded and compared. Chronic high-altitude exposure. Male SD and F rats weighing 200-238 g were exposed to 16,000-ft simulated high altitude for 4 wk, while the control rats of the two strains were kept at Denver altitude (5,000 ft) for the same period. After the exposure to high altitude, the rats were returned to the laboratory altitude and anesthetized (pentobarbital sodium, 50 mg/kg ip), and a PVl catheter

IN

FISCHER

RATS

1863

was placed via the right jugular vein into the pulmonary artery. After the measurement of pulmonary arterial pressure, the chest was opened and 1 ml of blood was removed by cardiac puncture for hematocrit measurement. The heart was removed, and the right ventricle and left ventricle plus septum were separated and weighed to determine the right ventricle-to-total heart weight ratio (RV/T) as a measure of right ventricular hypertrophy. Statistical analysis. The data are means t SE. When two groups were compared, an unpaired Student’s t test was used; for comparison within one group, a paired Student’s t test was used. For comparison of more than two groups, analysis of variance followed by a Student-Newman-Keuls test was used. Differences were considered significant when P < 0.05. RESULTS

Pulmonary pressor responses to alveolar hypoxia and ANG II in isolated lungs. When isolated lungs were challenged either with airway hypoxia or bolus injection of ANG II, the pressor responses were markedly reduced in the lungs from F rats compared with those obtained in the SD rats under identical conditions, perfused either with blood (Fig. 1A) or with a physiological salt solution (Fig. 1B). Hemodynamic changes to alveolar hypoxia and ANG II in instrumented rats (Table I). There was no difference in baseline hemodynamic data between the two strains of rats. However, during 8% 0, breathing, F rats demonstrated a markedly blunted pulmonary pressor response compared with SD rats (28.2 t 3.7 vs. 35.9 t 1.07 mmHg, P < 0.05) despite a clear increase in cardiac output. The F rats also showed a trend toward a lower pulmonary pressor response due to ANG II infusion (Ppa 5.8 in F vs. 8.2 mmHg in SD rats). Total pulmonary resistance (TPR) increased less in F rats during the hypoxic challenge (TPR 35) than in the SD rats (TPR 94). The magnitude of the hypoxic stimulus was comparable between the two rat strains as assessedby the arterial PO, (Table 2). Vascular rings. Responsesto KCl, ANG II, and PMA. As shown in Fig. 2A, the pulmonary arterial rings from F rats exhibited reduced contractile responses to KC1 and ANG II in comparison with those from SD rats (P < 0.05). When the aortic ring data are compared (Fig. 2B), F rats also had a lower dose-response curve to KC1 than SD rats, but the difference was not as marked as in the pulmonary artery rings. The contractile response to ANG II in the aortic rings was not different between the two strains. PMA, a protein kinase C activator, contracted the pulmonary artery rings from both rat strains to the same degree (Fig. 3). Effect of chronic high-altitude exposure on pulmonary arterial pressure, hematocrit, and heart weight (Fig. 4, A and B). Exposure to 4 wk of chronic hypobaric hypoxia caused pulmonary hypertension, polycythemia, and right ventricular hypertrophy in both rat strains. Although the baseline pulmonary arterial pressure was lower in the anesthetized F rat than in the matched SD rat, the relative increase in pulmonary arterial pressure after alti-

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1864

LUNG

VASCULAR

REACTIVITY

IN

FISCHER

RATS

0

SD rat (n=5) F rat (n=5)

l

0:





10 20

I

40

I

60

I

1

80

100

1

I

1 o-‘0

KCI (mM)

I

10-g

A Angiotensin

1 O-8 II (g/ml)

0 SD rat (n&j)

8-

F rat (n5)

l

4 3 -1 2

T

1 0

0

20

I

40

-

I

60



KCI (mM) FIG.

aorta

2. Tension developed rings (B) after cumulative

I

80

-

1

100

01

lo-

10-g 1o’8

Angiotensin

II (g/ml)

by SD and F rat pulmonary artery rings with intact endothelium (A) and by thoracic addition of KC1 (left) or ANG II (r&ht) to muscle bath fluid (n = Wgroup). *P < 0.05.

tude exposure was comparable for both strains. Likewise, there were comparable increases in both the hematocrit and the relative mass of the right ventricle in both rat strains. Also, when pulmonary arterial pressure and RV/ T were plotted against the hematocrit, it became apparent that F rats during the chronic altitude exposure had developed a degree of right heart hypertrophy and pulmonary hypertension that one would predict for the degree of polycythemia (Fig. 4, A and B). DISCUSSION

Pulmonary vascular reactivity. Vasoconstriction was induced in the isolated perfused lungs from F and SD rats with alveolar hypoxia, which causes pulmonary vasoconstriction by an unknown mechanism, and with ANG II, which occupies specific cell surface receptors and activates phospholipase C and protein kinase C. We

found that F rat lungs developed less vasoconstriction, regardless of the stimulus used. This depression of pulmonary vasoconstriction was observed in lungs perfused either with blood or with physiological salt solution. Because pulmonary vascular reactivity in rats changes with age and with body weight (10,15), we conducted our studies with both age-matched (4-5 mo old, data not shown) and weight-matched groups of animals. Because pulmonary vasoconstriction was blunted and hypoxic vasoconstriction was nearly absent in the F rat lungs under both experimental conditions (i.e., age or weight matched), we conclude that the ability of the pulmonary circulation to respond to vasoconstriction under the experimental conditions of artificial ventilation and pump perfusion at constant flow depended on the strain of the animal and that the inbred F rat was characterized by weak pulmonary pressor responses.

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LUNG

VASCULAR

REACTIVITY

n=6

n=6

S/D FIG.

F rats (PMA)

F

3. Tension developed by pulmonary in response to addition of 500 mM to bath fluid (n = 6).

artery phorbol

rings from myristate

SD and acetate

Hemodynamic measurements in instrumented awake rats. We also compared the response of the pulmonary and systemic circulation in the alive unanesthetized animals. When the instrumented F and SD rats were challenged with a comparable degree of airway hypoxia, the pulmonary arterial pressure rose less in the F than in the SD rat. Because cardiac output increased in F but not SD rats during acute hypoxia, TPR was not affected by hypoxia in the F rat but increased in the SD rats (Table 1). In contrast to the isolated lung preparation, in which the acute pressor response after ANG II was clearly reduced in F compared with SD rat lungs, the pulmonary pressor response during ANG II infusion in the intact rats was not markedly different between the two strains. Importantly, the systemic vascular resistance at baseline and during ANG II infusion was comparable in the two rat strains. The data from aliv ‘e rats and is01ated lungs perfused at controlled flow are thus mutu ally supportive and consistent, insofar as the lung circulation in the F rat strain is characterized by a reduced acute hypoxic pressor response. Because this finding was reminiscent of the acquired blunted pulmonary vasoconstriction of rats acclimatized to chronic hypoxia (16,17) and we postulated that the aberrant behavior of the lung circulation in the F rats was attributable to the contractile properties of the pulmonary vessels, we examined the contractions of pulmonary arteries and thoracic aortas isolated from F and SD rats. Isolated vascular ring studies. Becau.se the length .-tension characteristics of the pulmonary artery rings from both rat strains were comparable (data not shown), we performed a cumulative dose-response study with K+-induced depolarization of the smooth muscles (17). Both maximal contractile response and contractions at each KC1 bath concentration were lower in the F than in the SD rat pulmonary artery rings. Similarly, the receptordependent contractions to ANG II were less in the F than in the SD rats. When we studied the thoracic aorta and compared it with the lung vessels, we found that the con-

IN

FISCHER

1865

RATS

tractile responses to several KC1 concentrations were reduced in the aortas from F compared with SD rats, but that the contractile responses to ANG II were comparable. To explain the reduced pulmonary artery ring responses, we considered that rings from F rats had either less vascular smooth muscle or an impairment of the contractile marchinery. The former appears to be unlikely because PMA, which recently has been shown to contract pulmonary arteries independent of extracellular calcium (l4), caused contractions of comparable magnitude in F and SD pulmonary artery rings (Fig. 3) and because the amount of protein per wet ring weight was comparable. Thus both resistance vessels, tested with hypoxic vasoconstriction in the isolated lung, and conduit pulmonary arteries from F rats, tested with KC1 and ANG II, show reduced reactivity when compared with either the lungs or the conduit arteries isolated from SD rats. At present, we have not yet elucidated the mechaof impaired vascular smooth muscle contractility. Because both KCl- and ANG II-induced contractions were reduced in the pulmonary vascular ring preparations (and also contractions elicited by phenylephrine; data not shown), we speculate that the contractile defect is not due to a specific membrane receptor desensiti zation but rather to some postreceptor event. Because the Ca2’ entry-independent PMA-triggered ring contractions were not reduced in F rings, we speculate that the contractile defect of the F rat lung vessels is caused by an alteration in vascular smooth muscle cell Ca2+handling, perhaps overproduction of a vasodilator that blocks Ca2+ A 40 35

1

cc c-

1

C-

0 SD low altitude A SD high altitude

I.

10

0 F low altitude A F high altitude I

-

5 40

50

60

Hematocrit

70

(%)

B 0.4 0.3

t 2

'6 Oa2

0.1

0.0

: 40

60

Hematocrit (%) FIG. 4. Relationship between mean pulmonary arterial pressure (Ppa, A) and right ventricular weight-to-total heart weight ratio (RW T, B) and hematocrit for SD and F rats after chronic high-altitude exposure (16,000 ft for 4 wk). Control animals (open symbols) were kept at 5,000 ft. Slopes of regression lines are 0.509 and 0.44 1 for Ppa and 0.0052 and 0.0049 for RWT; they are not statistically di fferent.

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I,WG

1866

VASCULAR

REACTIVITY

entry into vascular smooth muscle cells. Further studies are necessary to better define whether Ca2’ influx or intracellular Ca2’ release is affected in the vessels from F rats. Whether a higher degree of “peroxide tone” as a result of a postulated imbalance between oxidants and antioxidants (1, 5, 9, 11) causes the lung vessels to be less responsive to contractile stimuli remains to be seen. Although F rat lungs are more susceptible to oxidant-induced injury (‘i), it is unclear whether the lungs produce on an ongoing basis more vasodilatory metabolites than SD rat lungs. Cyclooxygenase inhibition with meclofenamate did not reverse the blunted vasoreactivity of isolated F rat lungs, indicating that cyclooxygenase-derived vasodilators were not involved. Chronic hypoxia-induced pulmonary hypertension. In addition to documenting in F rat lungs a decreased pressor response to acute hypoxia, we also examined in F rats the degree of chronic hypoxia-induced pulmonary hypertension. F and SD rats had similar degrees of right ventricular hypertrophy and pulmonary hypertension, even when related to the kse in hematocrit. Because the erythropoietic response to hypoxia is obviously intact, and possibly slightly more pronounced, in the F rat, it follows that the F rat does not simply have a generalized hypoxia-sensing problem. In summarv, we have described reduced contractile responses in thi lung circulation of the F rat strain, which is also more prone to develop oxidant-induced lung injury (‘7). We conclude that the reduced pulmonary vascular contractile responses of the F rat, which include blunted hypoxic vasoconstriction, are not related to altered sensing of hypoxia but result from altered pulmonary vascular contractility per se. The authors acknowledge the :ldvice of Dr. Ivan F. McMurtry the preparation

01 the manuscript

by Marcia

Brassor

and Rebecca

and Wo-

linsky. This work was funded by National Heart, Lung. and Blood Institute (NHLBI) Grants HL-MW’i and HL-07171. L. Hc has been supported by a World Health Organization stipend, S.-W. Chang is the recipient. o1’ .UHLBI Clinical Investigator Award HL-01966, and N. F. Voelkel is the recipient of a Career Award of the American Lung Association. Address for reprint requests: X. I!. Voelkel, University of Colorado Health Sciences Center, Box B-133, 4200 East 9th Ave., Denver, CO 80262. Received

1 C, October

1990: acccpf.cc~ in final

form 19 November 1990.

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2.

IN FISCHER

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Pulmonary vascular reactivity in Fischer rats.

We previously reported that Fischer (F) rat lungs developed more extensive injury when challenged with oxidants than age-matched Sprague-Dawley (SD) r...
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