Response of Small Pulmonary Arteries to Unllobar Hypoxia...

Response of Small Pulmonary Arteries toUnllobar Hypoxia and Hypercapnla

By Mikio Kato, M.D., and Norman C. Staub, M.D.

ABSTRACTWe measured the internal diameters of small muscular pulmonary arteries

in the right and left lower lobes of lungs rapidly frozen in the anesthetized,open-thorax cat. In every cat the right lower lobe was ventilated with the testgas and all other lobes were ventilated with O2. In 4 cats, the test gas suppliedto the right lower lobe was also O2 (control experiments); in 6, it was 100%N2 and in 6 it was 90% N2-10% CO2. In the 4 controls, there was no differencebetween the internal diameters of corresponding arteries in the right and leftlower lobes. In the other 12 cats, there was a highly significant decrease in thediameter of arteries in the right lower lobe that correlated well with a largedecrease in blood flow to that lobe, calculated using a shunt equation. Ventila-tion of the right lower lobe with 10% CO2 in air (4 cats) did not affect thediameter of arteries and ligation of the pulmonary artery to the right lowerlobe resulted in only a slight decrease in arterial dimensions in 3 of 4 cats.

These data show that in regional alveolar hypoxia without systemic hypoxiathe muscular pulmonary arteries of the terminal respiratory units in the hy-poxic region actively constrict. The constriction occurs with or without al-veolar hypercapnia.

ADDITIONAL KEY WORDS altitude carbon dioxide lungoxygen pulmonary artery pulmonary circulation respirationlocal regulation of pulmonary circulation pulmonary vasoconstrictionhypoxia hypercapnia pulmonary artery occlusionanesthetized cats

• Most investigators now agree that re-duced partial pressure of oxygen in alveolarair leads to an acute increase in pulmonaryvascular resistance in several species of mam-mal, including man.1-2 The vasoconstrictionoccurs both when decreased oxygen is notassociated with increased carbon dioxideconcentration, as at high altitude,8 and whenthe two occur together, as during hypoventi-lation at sea level.4 The most recent evidenceindicates a positive correlation between thevasoconstrictor response and the presence of

From the Cardiovascular Research Institute andDepartment of Physiology, University of CaliforniaSan Francisco Medical Center, San Francisco, Cal-ifornia.

This work was supported in part by U. S. PublicHealth Service Grants HE-06285 and HE-5251, theCalifornia Tuberculosis and Health Association andNonr Contract 222(55).

Dr. Kato was a Trainee of the National HeartInstitute.

Accepted for publication April 11, 1966.

both alveolar hypoxia and mixed venous blood(tissue) acidosis.5

A constrictor response can be mediated en-tirely within the lung, for it can be inducedin isolated perfused lungs.6'7i 8 In intact ani-mals, when one lung breathes air low in oxy-gen but systemic hypoxia is prevented byhaving the other lung breathe a mixture richin oxygen, the constriction is confined to thehypoxic lung.9'10

As to the location of the change in resis-tance, the major pulmonary vascular resis-tance normally11'12 and during alveolar hy-poxia is in vessels beyond the tip of anycatheter.8'18 The control site must be some-where in the small muscular pulmonary arter-ies,14"18 the capillaries17 or small veins.13' 18~21

All of these vessels are exposed to the gascomposition of the alveoli they supply.22 Inman, cat, and dog, at least, these vessels arenot fed by the bronchial artery,28 but obtaintheir nutrition from luminal blood or from

426 CircuUtioa Ruaircb, Vol. XIX, A*fust 1966

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HYPOXIC PULMONARY VASOCONSTRICTION 427

the surrounding gas. Alveolar gas can readilypenetrate the walls of the vessels,24"28 andchanges in oxygen tension of alveolar gas aremore effective in altering vascular resistancethan are changes in the oxygen tension ofmixed venous blood.8'27> 28

Our working hypothesis was that the per-fusion of each terminal respiratory unit22 ismost readily controlled by the single smallmuscular pulmonary artery that closely accom-panies its airway and is exposed to the alveo-lar gas of the unit. In these experiments wehave applied the method of rapid freezing ofliving lung29 to obtain direct evidence for onemajor site of active pulmonary vasoconstric-tdon during regional intrapulmonary hypoxiawith and without hypercapnia. We measuredthe internal diameters of the small muscularpulmonary arteries at the level of the termin-al or respiratory bronchioles: the results indi-cate that active constriction of these vesselsoccurs and is sufficient to explain the changesin flow distribution observed.

MethodsWe anesthetized cats (2.5-4.8 kg) with sodium

pentobarbital (30 mg/kg) and gave scopola-mine hydrobromide (0.13 mg subcutaneously) todecrease airway secretions. We made a tracheo-tomy and inserted a concentric, dual-lumen can-nula into the trachea (fig. 1). The center cannulaextended into the right lower lobe main bronchusand supplied gas to that lobe; the outer cannula(5 mm i.d.) supplied gas to the rest of the lung.The center cannula was a 12-gauge stainless steeltube (2.8 mm o.d., 2.2 mm i.d.), 24 cm long,slightly bent 4 cm from the distal end, with apolyvinyl sleeve at the tip to help hold it in itsfinal position. We then paralyzed the cats withgallamine triethiodide (20 mg iv), establishedpositive pressure ventilation, split the sternum toopen the thorax, and spread wide the rib cagewhile being careful to stop the escape of blood.We carefully dissected die bronchus and thehilum of the right lower lobe free of the lobarvessels, advanced the center cannula to thehilum and tied it in place, thereby interruptingthe bronchial circulation and innervation of thelobe. During surgery the lungs were covered withgauze sponges wet with warm saline.

The right lower lobe, about 22% of the lung,80

could now be ventilated with a hypoxic gas mix-ture without inducing systemic hypoxia if theremainder of the lung was ventilated with oxygen.

CirctUtwm Risttrcb, Vol. XIX, August 1966

TO K/GHTLOWE* LOBE.

TO RESTOF LUNG

FIGURE 1

Schema of dual concentric cannula system for venti-lating the right lower lobe (RLL) separately from therest of the lung. Note that the azygous lobe (AL) isnot included with RLL. All lobes except RLL wereventilated with 100% Ot.

We controlled the pressure of ventilation ratherthan the volume because of the disparity of sizebetween lung and lobe, and because there is lesschance of changing the internal structure of thelung during freezing if the pressure is constant.Ventilating gases came from large compressed-gascylinders through two-stage reducing valves. In-spiratory and expiratory pressures were regulatedby adjustable water seals. We ventilated bothlung and lobe by an occlusive pump that com-pressed the expiratory pressure lines 8-12 timesper minute—ample time for alveolar pressures toequilibrate with the pressures in the source line.Strain gauges (Statham P23B and PM 131TC)connected to a Grass direct-writing polygraphrecorded airway pressures continuously from theupper end of both cannulas. We adjusted pres-sures in lung and lobe to be as close to oneanother as possible. A Beckman Microcell In-frared CO2 analyzer, also recording continuouslyon the polygraph, measured end-tidal CO2 con-centration in the main lung airway.

After the cannulas were in place, we ventilatedboth lung and lobe with 1001 O2 for 10 minutes,inflated the lungs slowly and deeply (+ 30 cmH2O) to remove all compression atelectasis, care-fully adjusted airway pressures, and watched both


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lower lobes for evidence of injury or impairedventilation or circulation. In several animals wesaw signs of inadequate ventilation (obstructionof cannula) or uneven or darkened surface colora-tion; these we discarded. The time from comple-tion of lobe cannulation to freezing of the lungswas less than 30 minutes.

We placed one polyethylene catheter in afemoral artery to draw samples of arterial bloodand to continuously record pressure via a straingauge (Statham P23AC), and another in themain pulmonary artery through an 18-gaugeneedle trocar through the outflow tract of theright ventricle. We sewed the ventricular catheterin place and, except for transient bleeding andarrhythmia during insertion, noted no persistenteffects. The catheter recorded pulmonary arterypressure continuously via a strain gauge (StathamPR23-6G). connected to the polygraph, and wasused to obtain samples of mixed venous blood.

We took bubble-free samples of arterial andmixed venous blood during the control and ex-perimental periods and immediately measuredPo9, Pco2, and pH on electrodes at 37°C, cor-rected to the animal's deep rectal temperature.The total amount of blood drawn for thesedeterminations was about 15 ml, including thatused to determine total hemoglobin concentrationby the standard cyanmethemoglobin method. Weobtained percent oxyhemoglobin saturation fromthe Po2, using a standard oxyhemoglobin equilib-rium curve for cat blood, 81 and corrected forpH:82

We used standard commercial gas mixtures.After the first 10-minute period, when all of thelung received 100% O2, the right lower lobebreathed 99.5$ O2, 99.8% N2, 90$ N2-10% CO2)or 10% CO2 in air for 5 minutes; the rest of thelung always breathed 99.5% O2. The choice ofgas for each cat was randomized.

After we completed the physiologic measure-ments, we froze the right and left lower lobes atend inspiration by inundating both lungs withliquid propane (—180°C) continuously for 2minutes. We rapidly resected the lobes andstored the pieces in liquid nitrogen. Later wetransferred them to a cryostat (CambridgeRefrigeration Co., Cambridge, Mass.) at — 30°C.We cut two symmetrical blocks from each lobe-one wedge-shaped from the lateral and diaphrag-matic side (including the costophrenic angle) andone rectangular from the upper lateral surface.We immersed the blocks in anhydrous fixative(Carney's solution saturated with mercuric chlor-ide) at — 40°C and fixed them for 4 weeks in adry-ice chest ( - 4 0 ° C ) .

We embedded the blocks in 30% nitrocellulose(Randolph Products Co., Carlstadt, New Jersey)and cut them on a Reichert sliding microtome.

We alternated thick (200 fi) and thin (10 ft)serial sections. The sections were perpendicularto the pleural surfaces in the wedge block andparallel to the single pleural surface in the rectan-gular block. The sections were stained withchromotrope 2R and fast green by Crossman'smethod.33

In the thick sections we located 20 terminaland respiratory bronchioles and their associatedsmall muscular arteries (fig. 2). These samestructures were marked on the thin sections andphotographed at 10 X magnification (controlledby photographed stage micrometer) and the smal-lest internal diameter of the airway and pulmo-nary artery measured on die large projected image.Since in our experience the true cross-section ofthe small arteries is circular, and since the arterieswere sectioned randomly, we accepted the smal-lest diameter as the true diameter. We counteda random sample of vessels and avoided choosingmore than one bronchiole that branched from thesame parent airway." We calculated the averagediameter and standard deviation of each set ofairways and vessels from the control and experi-mental lobes and compared each pair statistically,using the one-tailed t-test. We chose a P valueof < 0.01 as being clearly significant.

FIGURE 2

Fixed, frozen section of cat lung, showing terminalbronchiole (TB) and its associated pulmonary artery(PA) as they appear in our thin sections. Note how theartery and airways are completely surrounded byalveolar ah spaces. Generally these alveolar spaces arepart of the same terminal respiratory unit that thebronchiole and artery are suppyling. Vessels thatappear on sagittal section such as the one seen abovethe artery were not included in measurements becausewe could not be certain they contained a proper di-ameter. The black spot below the airway is a markerwe used in the counting procedure. This picture isfrom a control lung and thus represents normal ap-pearance of bronchiole and oessel.

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Four animals were prepared as described, butwe ligated the main artery to the intubated lobewhile both the control and experimental lobebreathed 99.5% O2. These lobes were frozen, sec-tioned, and examined in the same way as thosein the other experiments.

CALCULATIONS

We used the shunt equation33" to calculate theshuntlike effect during the control period andduring the experimental period when 99.8% N?> or90% N2-10% CO2 ventilated the lobe. We assumedthat the oxygen content of the pulmonary veindraining the hypoxic lobe was equal to that ofmixed venous blood. Subtracting the shunt valueduring the control period from that in the experi-mental period (AQs), we obtained the percentflow through the hypoxic lobe. Assuming thatnormal flow in the cat would be proportional tolung weight,34 we calculated the lobe flow as apercent of normal (22%), using the equation

lobe xiooFor example, if the shunt during the controlperiod was 4% and during the experimental periodwas 15%, then 11% is the flow through the hypoxiclobe (about half of control flow).

This calculation must be a maximal value forlobe flow because,we would expect the blood inthe isolated lobe to have given up some of itsoxygen as it passed through the capillaries. Thus,the actual residual lobe flow in the lobe isless than our calculation (see Appendix).

ResultsOXYGEN (CONTROL)

The major cardiorespiratory data for 4 con-trol animals in which all lobes were venti-lated with 99.5% O2 are given in table 1; mea-surements of the diameters of bronchioles andtheir associated small muscular arteries aregiven in table 2. A scattergram of individualmeasurements of animal no. 4 is shown infigure 3A.

The pressures in the systemic and pulmon-ary arteries decreased slightly during the ex-periment. The PTP values in the control andexperimental lobes were within the tidalrange and were within 0.5 cm H2O of eachother except in cat no. 3 during inspiration.In spite of the manipulation of the lung and

3 0 0

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200 300 400 500 600 700 200 300 4O0 5O0 600 700BRONCHIOLES (1.0,fx)

FIGURE 3

Scattergrams of individual measurements from four experiments. (A) control; (B) hypoxia; (C)hypoxia with hypercapnia; (D) hypercapnia. The lines are the best fit by least squares ofpulmonary artery diameter as a function of bronchiole diameter.

GrcUtio* Rtiurcb, Vol. XIX, Axguit 1966


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the open thorax, the calculated shunt was low(4-535 of cardiac output).

The color hue and intensity of the rightand of the left lower lobes were indistinguish-able. In 3 animals there was no differencebetween the size of the bronchioles in theexperimental lobe (e) and in the control lobe(c), although on the average this dimensionwas slightly reduced in the experimental lobe(average e/c = 0.95). The pulmonary arterydiameters showed no significant difference be-tween lobe and lung. In two animals, thepulmonary arteries in the experimental lobewere larger than in the control lobe (e/c =1.07). The scatter of dimensions as in figure3A shows that there was a fair correlation be-tween the size of the bronchiole and itsassociated artery. The artery is about half thediameter of the airway.

HYP0XIA

The major cardiorespiratory data for 6animals in which the experimental lobe wasventilated with nitrogen are given in table 1and measurements of bronchioles and theirassociated small muscular arteries are givenin table 2. A scattergram of individual mea-surements of animal 6 is shown in figure 3B.

The systemic and pulmonary artery pres-sures usually showed a slight downward drift,as in the controls. There is no indication ofpulmonary hypertension developing when justone lobe became hypoxic. The PTP of lobeand lung were within the tidal range andclosely matched except in animal no. 5 duringdeflation. Control period shunt flows were3-5%. The increase in shunt flow during lobarhypoxia ranged from 6 to 14$, giving calcu-lated lobe flows of 27-64$ of normal.

We saw the right lower lobe change colorover several breaths after switching to nitro-gen ventilation. The lobe ultimately becamevery purplish. It did not appear congested(as judged by color intensity). On frozen sec-tion the hypoxic lobe's vessels all containeddeoxygenated blood as judged by hue, where-as the hyperoxic lobe's large arteries containedvenous blood but the veins and small arteriescontained bright red blood.24 We traced the


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large arteries and veins in some of the lobesbut did not find any evidence of occlusiveconstriction.

In 3 animals the bronchiole diameters inthe hypoxic lobe were significantly smallerthan in the control side, but the group aver-age showed only a slight difference (e/c =0.96). The pulmonary artery measurements allshowed reduced internal diameters in thehypoxic lobe. These differences are significantin 5 and borderline in 1. The group averageshowed a highly significant decrease in sizein the hypoxic lobe (e/c = 0.68). The scatter

of sizes in figure 3B suggests that nearly allthe vessels of the type measured are affected.

HYPOXIA AND HYPEJtCAPNIA

The major cardiorespiratory data for 6 ani-mals in which the experimental lobe was ven-tilated with 90? nitrogen and 10% carbon diox-ide are given in table 1 and measurements ofbronchioles and their associated small muscu-lar pulmonary arteries are given in table 2.A scattergram of individual measurements ofanimal no. 11 is shown in figure 3C.

The systemic and pulmonary artery pres-sures did not show the downward trend seen

TABLE 2

Internal Diameters of Terminal Bronchiole and Related Pulmonary Artery Ratios ofExperimental Lobe to Control Lobe

Catno.

i234

Mean

56789

10Mean

111213141516

Mean

17181920

Mean

21222324

Mean

Bronchiolecont.

437 ± 100533 ± 138480 ± 79418 ± 86467

470 ± 81467 ±62444 ±53342±55479 ±38471 ± 123446

362 ±54644 ±80339 ±62664 ± 142583 ±58529 ± 91514

461 ±84479 ± 62529 ± 107543 ±77503

462 ±88595 ±105511 ±63686±88564

a (M)ezpt.

435 ±68525 ±95400 ±98404 ±101441

404 ±74474 ±58399 ±58358 ±59431 ±51474 ± 115423

351 ±70582 ±79407 ± 53616 ±95557 ±90444 ±61493

482 ±77486 ±51532 ±77552 ±785i3

279 ± 97474 ± 126352 ±95672 ± 116444

e/c

1.000.980.830.970.95

0.861.010.901.050.901.010.96

1.080.901.200.930.960.840.99

1.051.011.011.021.02

0.600.800.690.980.77

Signtf.P

> 0 1> 0.1<0.01> 0.1

<0.01> 0.1<0.01> 0.1<0.01> 0.1

90%>0.05>0.01<0.01>0.05> 0.1<0.01

Arteries (H)cont.

189 ± 71202 ±62219 ± 49251 ±18215

99.8% N,180 ±37155 ±36154 ±19142 ±44200 ±44227 ±81176

N, + 10% COt

190 ±42184 ±36160 ±46207 ±48168 ±43148 ±33176

10% CO, in Air>0.1> 0.1> 0.1> 0.1

137 ± 41196 ±42200 ±42217 ± 53188

expt.

186 ± 42238±54256 ±68237 ±69229

134 ±6090±2893 ±39

111 ±45148 ±40142 ±42120

85±34117 ±3899±35

144 ±48118 ±31108 ±32112

131 ± 43198 ±40174 ±69253 ±86189

Pulmonary Artery Ligated<0.01<0.01<0.01> 0.1

217 ±65236 ±61217 ± 46222 ±48223

250 ±48211 ±49192 ±60209 ±46216

• / c

0.991.181.170.941.07

0.740.580.600.780.740.630.68

0.450.680.560.700.700.730.63

0.961.010.871.171.00

1.150.890.880.94037

SlgnifP

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<0.01<0.01<0.01>0.01<0.01<0.01

<0.01<0.01<0.01<0.01<0.01<0.01

>0.1> 0.1>0.05>0.05

>0.01>0.05>0.05> 0.1

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in the controls and in the hypoxia-alone series.Arterial pH was reduced especially in theseanimals with the greatest fall in Pao2 indi-cating the least effective flow shift. See Ap-pendix for pH and P02 of lobar ruin blood.The PTP of the experimental lobe and the con-trol lung were closely matched except in ani-mal no. 15 (inflation) and no. 16. The pres-sures were within the tidal range although inanimal no. 15 inflation pressure was higherthan usual. Control period shunt flow was 3-4%.The change in shunt flow during lobar hypoxiaand hypercapnia ranged from 1-13% givingcalculated lobe flows of 5-55% of normal.

The gross appearance of the lobe and lungswas the same as with hypoxia alone. Wetraced out the large arteries and veins in someof the lobes. There was no sign of occlusiveconstriction.

In 1 animal the bronchiole diameters in thehypoxic-hypercapneic lobe were significantlysmaller than on the control side and in 1animal were significantly larger. The groupaverage showed no significant difference(e/c = 0.96). The pulmonary artery measure-ments all showed reduced internal diam-eters in the experimental lobe. These differ-ences are highly significant in every animal.The group e/c = 0.63. The scatter of sizesin figure 3C again suggests that nearly all ofthe vessels sampled were affected.

HYPERCAPNIA

The major cardiorespiratory data for 4 ani-mals receiving 10% CO2 in air are shown intable 1 and measurements of bronchioles andtheir associated small muscular pulmonary ar-teries are shown in table 2. A scattergram ofindividual measurements in animal no. 18 isshown in figure 3D.

Systemic and pulmonary artery pressuresdid not show a downward trend. Arterial pHwas reduced. The PTP were within the tidalrange and closely matched. Control periodshunt flow was 3-4%. We did not attempt tocalculate lobar flow during 10% CO2 ventila-tion since the lobe was ventilated with air.

The gross appearance of the lobe and lungswas the same as in the control series. The

Rutrcb, Vol. XIX, Amgusi 1966

added CO2 did not visibly affect lung colorhue or intensity.

There were no measured differences inbronchiole internal diameters in the hyper-capneic lobe compared to the control lung.The group e/c = 1.02. The pulmonary arterymeasurements did not show any significantchanges in the experimental lobe although 1showed a borderline decrease and one a bor-derline increase. The group e/c = 1.00. Thescatter of sizes in figure 3D shows the lack ofresponse in all vessels measured.

PULMONARY ARTERY LIGATION

Measurements of bronchioles and their as-sociated small muscular arteries are shown intable 2. Cardiorespiratory data are not listedbut were similar to the control group. Oneimportant difference was a marked decreasein expired CO2 from the lobe to levels be-low 0.5%.

The lobe became slightly to moderately paleduring the first minute after the artery wasligated. The diameters of the bronchioles weresignificantly decreased in the lobe as com-pared to the control lung in 3 of 4 animals.The group e/c = 0.77. The pulmonary arterydiameters of the experimental lobe were in-creased in one and decreased in three, but notsignificantly. The group average showed nosignificant change (e/c = 0.97).

Discussion

The method had four major problems:(1) the sensitivity of the sample size to dis-tinguish changes in artery diameter, (2) theselection of pulmonary arteries of compar-able type, (3) the randomness of the samples,and (4) the influence of the trauma of pre-paring the animal.

1. Sensitivity. Given the standard deviationof our samples (range 7-35%; average 25%),we can, with samples of 20 each, detect dif-ferences of 20% (on the average) betweenmeans at the 1% level of statistical significance.

2. Selection of Arteries. The problem ofselecting arteries of comparable type wassolved by choosing those vessels accompany-ing terminal or respiratory bronchioles. Thesebronchioles are easy to define and to see in


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thick sections of inflated lung and can betraced from alveolar ducts to respiratorybronchioles to terminal bronchioles. In thelower lobes of the cat lung, respiratory bron-chioles are very short and differ from ter-minal bronchioles only by having a fewsmall alveoli. The last three branching ordersof purely conducting airways are usuallyconsidered together as terminal bronchioles.88

Our choice was nearly always the final order.In our study, we preferred terminal bron-chioles to respiratory bronchioles, so themajority of airways in any sample are final-order terminal bronchioles. The method ofselecting pulmonary vessels by fixed land-marks has been discussed by others.88 Unfor-tunately, it applies only to the pulmonary ar-terial system and for that reason we did notmeasure the pulmonary veins. The arteries wechose are an example of a type, namely,those vessels termed muscular pulmonary ar-teries that are at the terminal respiratory unitlevel surrounded by the alveolar gas of theunit they supply and without vasa vasorumfrom the bronchial artery.

3. Randomness of Selection. We chose twodifferent zones from each lobe and sectionedthe specimens in two different planes to in-sure that the samples would be representative.All bronchioles selected were within 0.5 cmof the pleural surface, most were within 0.3cm. This bias in selection was made necessaryby the rate of freezing29 but was offset bythe fact that a large fraction of the cat lung iswithin 0.5 cm of the surface and we are com-paring differences within this region. Thecriteria for selecting the 20 airways and ves-sels were such that in the total sample [20sections X 0.02 cm thick per section X 1 cm2

area (approximately)] of 0.5 cm8 almost alldifferent bronchioles (1 each from a familyof branching terminal bronchioles) had to beincluded. Thus, biased selection was not aproblem.

4. Trauma. The four control experiments(fig. 4) show that the operative procedures,including the intubation of the experimentallobe, did not significantly affect the dimen-sions of the arteries.

EFFECTS OF PULMONARY ARTERY LIGATION

We conclude that completely obstructingthe main pulmonary artery to a lobe does notsignificantly alter the dimensions of the smallarteries (fig. 4, ligation). In 3 animals, vascu-lar internal diameter seemed to decrease, butat the 1% level of significance for each experi-ment and the group as a whole there wasno effect. The slight effect attributable to apassive decrease in the transmural pressure ofthese vessels is probably due to their beingtied directly into the connective tissue of theterminal respiratory units, and therefore arecontrolled principally by lung volume whenthere is little or no active constrictor tone. Inaddition, the vessels are open to pulmonaryvenous pressure. In several of the experiments

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ie

Summary bar graph of all experiments by groups as inDiscussion. Open bar, control lobe; shaded bar, ex-perimental lobe. Top of bar represents average ofpulmonary artery diameters and bracketed lines are ±1 standard deviation.

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in which we induced hypoxia and hypercap-nia, we examined the larger vessels accom-panying the cartilagenous bronchi of thefrozen lobe. In no instance did we see com-plete obstruction nor did we find the vessels tobe more constricted than those in the con-trol lobe. This evidence, although subjective,agrees with evidence others have obtainedthrough catheterization that the pressure doesnot decrease in the large pulmonary vesselseither normally or in hypoxia.8' n~13 Our find-ings do not necessarily conflict with the pul-monary volume changes during hypoxia re-ported by Sackner and DuBois.87 The wholeanimal was hypoxic in their experiments, soadditional central reflex effects may have comeinto play; also, changes of volume are notnecessarily synonymous with changes of re-sistance. On the basis of our results with pul-monary artery occlusion, we can state with ahigh degree of certainty that any changesfound in the small arteries are the result oflocal active constriction.

EFFECTS OF CO, ALONE

The results of hypercapnia (10? CO2)alone (fig. 4) show that this level of tissueacidosis had no demonstrable effect on thesmall arteries when alveolar Po2 was rela-tively high. The literature is contradictory onthe effects of increased alveolar CO2 on pul-monary vascular resistance. Some report in-creases in resistance,6'7 but most have failedto note such effects.10'38 There is indirectevidence89 that breathing increased CO2 leadsto increased pulmonary capillary blood vol-ume, suggesting that any effect that did occurwould be in the pulmonary veins. Since wedid not measure the veins our results cannotidentify them as a possible site of action. Insummary, over a short time (10 min) moder-ate alveolar hypercapnia to a lobe of the lungdoes not measurably affect the small muscu-lar pulmonary arteries.

EFFECTS OF HYPOXIA

Hypoxia alone (figure 4, 100? N2) such asoccurs at high altitude and hypoxia with hy-percapnia (figure 4, N2-CO2) such as occursin hypoventilation both cause highly signifi-

CircMUtion Rvttcb, Vol. XIX, AmgMil 1966

cant active constriction of the small muscularpulmonary arteries. Admittedly, the levels ofhypoxia we used were extreme ones, but otherworkers8 have shown that graded hypoxialeads to graded pulmonary vascular resistancechanges. Because our sampling method wouldnot readily show constrictor responses lessthan 20%, we felt it necessary to choose theextreme hypoxic condition. We seemed tohave overdone a good thing, however, sincethe hypoxic response alone was so markedthat the addition of CO2 did not show astatistically greater constrictor effect, althoughthere is a trend in that direction. Enson andco-workers5 have shown a good positive inter-action between acidosis and hypoxia. Thisinteraction has also been found in the new-bom.40 Our results are compatible with En-son's although they cannot be taken as con-firming it. If we extrapolate their data to thecondition of extreme alveolar hypoxia theeffect of added acidosis of moderate degreewould be masked. Since hypoxia alone didnot constrict the arteries in our experimentswe think it is most useful to place the primarycontrol of the constrictor response on oxy-gen lack as modified by local tissue hydrogenion concentration.

CORRELATION OF STRUCTURE AND FUNCTION

An important question is whether thechanges in the caliber of muscular pulmonaryarteries are sufficient to explain the observedchanges in blood flow to the lobe. In view ofour rather crude estimate of lobe flow fromthe shunt equation we cannot pursue thisargument too far, but figure 5 does reveal acorrelation between lobe flow expressed as apercent of the control and the fourth powerof the average diameter of the arteries in theexperimental lobe expressed as a fraction ofthe fourth power of that in the control lobe

(PAeVPXc4). The standard correlation coeffi-cient = +0.59, rank correlation coefficient =+ 0.64 (p = 0.02). This application of Poi-seuille's equation to pulsatile flow in the pul-monary vascular bed may seem farfetchedbut, since other variables are nearly constant,the change in vascular diameter probably


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436 KATO, STAUB

70

6 0

5 0

LOBEFLOW( % OFCONTROL)

3 0

20

10

O.I 0.2 0.3 0.4

PA<

FICUJtE 5

Lofce /Jou> during hypoxia with or without hypercapniaas a function of the ratio of the experimental lobeaverage pulmonary artery diameter to the control lungpulmonary artery diameter raised to the fourth poweras in Poiseuille's equation. The solid line is the leastsquares best fit of flow on ratio. It has the same slopebut a positive ^-intercept compared to the theoreticalline calculated for 22% of the lung involved. Part ofthe difference is due to our over estimation of lobe flow(see Appendix).

fits the fourth power rule reasonably well.41

In figure 5 we have plotted the theoreticalline of lobe flow from the vessel diameterratios and the fact that only 22% of the lungvessels are in the hypoxic lobe.

Theoretical calculations and the correlationin figure 5 permit us to make two points.First, the smaller the volume of lung involvedby hypoxic vasoconstriction the less is theconstriction necessary to divert blood awayfrom that zone (assuming constant totalflow). Thus, in localized regional hypoven-tilation the fact that the lung has so manyparallel circuits means that the slightest con-striction of the afferent artery to the regionwould divert flow to other areas. For example,if 5% of the lung became hypoventilated sothat the resistance vessels in that portion

constricted by 10% (FAV/FAV = 0.66) thenflow through that region would be reducedby 33% with only 1% increase in driving pres-sure. On the other hand, if resistance vesselsin half of the lung were constricted by 10%,flow through that portion would be reducedby only 20% and driving pressure would in-crease by 20%, and if the entire lung werehypoxic, flow would not be reduced at all al-though driving pressure would be increased.

The second point to be made from figure 5is that within the limits of our determinationof flow we can successfully account for nearlyall of the theoretical flow change by con-striction of the small muscular pulmonaryarteries, of which those at the terminal bron-chiole level serve as the example. Actually,our points fall above but parallel to thetheoretical maximum shift in flow partly be-cause we consistently underestimated the flowreduction (see Appendix). We infer from thedata that nearly all of the change in resistanceis in the small muscular arteries. This agreeswith histologic evidence obtained from lungsof people born and living at high altitude42

and newborn infants with chronic hypoxemiaassociated with hyaline membrane disease,pneumonia, or hypoventilation.48 We furtherinfer that normally, when alveolar pressure isless than pulmonary artery pressure, the majorsite of pulmonary vascular resistance is inthese same vessels.

The variable degree of bronchoconstrictionfound in some of the experiments does notappear to have had any effect on the pul-monary artery dimensions. Reduced alveolarPco2 would explain the marked bronchocon-striction in 3 of 4 of the animals with pul-monary artery ligation and in 3 of 6 animalsventilated with nitrogen.44 By keeping the res-piratory rate low (5 sec or more per breadi)we believe we have avoided any effects ofincreased airway resistance. We carefully ob-served the lung and lobe and discarded all ex-periments in which the intubated lobe didnot expand or move as well as the controllobe. Since we measured only pressure, thereis the possibility that significant changes inlung volume could occur if lobe compliance

CircuUtion Rts—rcb, Vol. XIX, August 1966


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changes. However, in an earlier study inwhich we used constant volume inflation wefound the same dimensional changes in thesmall muscular pulmonary arteries duringhypoxia.45

The results of this study show active con-striction of small muscular pulmonary arteries,but do not rule out changes in other portionsof the vascular bed. Strictly speaking, ourresults apply only to regional hypoxia and notto whole lung hypoxia in which other fac-tors (reflexes, heart failure) may play im-portant roles. However, it is difficult to imag-ine why essentially different mechanismswould be invoked for the primary vasocon-strictor effect.

AppendixThe equation for anatomical shunt in the

lung during 100$ O2 breathing uses the O2

content of mixed venous blood (C?) for theoxygen content of the shunted blood on theassumption that no exchange of oxygen occursin the shunted blood during its transit fromthe venous to arterial side of the circulation.In the present experiments it is apparent thatthe assumption is false. Blood reaching thepulmonary capillary bed of the hypoxic lobewill give up some oxygen to the alveolar gasbecause in this situation the capillary bloodPo2 exceeds that of alveolar gas. The amountgiven up cannot be predicted because ofnumerous contributing factors such as therate of oxygen liberation, the capillary-alveolarPo2 difference, the time required for the redcells to travel through the capillary bed, thedegree of pH shift, and the rate of Po2 changein alveolar gas. Whatever the factors may be,however, the estimate of hypoxic lobe flow bythe equation

% lobe flow = 100

will always be an overestimate if C; is usedinstead of CPV (the O2 content of the venousblood leaving the hypoxic lobe).

To get some idea of how much the over-estimate might be, we studied 5 anesthetizedcats prepared as described in the main experi-ment except that we intubated the left lower

CircmUtum Rtsircb, Vol. XIX, A*gmji 1966


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438 KATO, STAUB

lobe instead of the right and placed a smallpolyethylene catheter through the left atrialwall and advanced it about 1 cm into thepulmonary vein draining the lobe. The reasonwe changed to the left lower lobe was tofacilitate placement of the catheter in thepulmonary vein. After 5 minutes of constantventilation with each gas mixture we obtainedbubble-free blood samples from the pulmo-nary artery, lobar vein, and femoral artery.The samples were drawn and measured with-in one minute for pH, Po2, and Pco2. An ad-ditional sample was taken for determinationof total hemoglobin concentration. Each ex-periment consisted of controls during oxygenbreathing before and after pure hypoxia and10% CO2 in nitrogen. Oxyhemoglobin satura-

tion was corrected for pH as described inmethods section of the main paper.

Table 3 lists the raw data we obtained ineach experiment and the corrected saturationas calculated. In every experiment the Po2

and saturation of blood from the pulmonaryvein was much less than in the mixed venousblood, indicating that oxygen had been un-loaded during a single trip through the pulmo-nary capillaries. The effect was greatest whensaturation of mixed venous blood was highest(as in cat B) and least when the saturationwas lowest (as in cat C). The effect occursregardless of whether Pco2 in increasing ordecreasing.

Table 4 lists the calculated shuntlike effectsfor each gas mixture and the apparent change

TABLE 4

Lobar Blood Flow Calculated Using Mixed Venous Os Content (C^) and LobarVein O, Content (CPV)

Cat

A

Lobeventilaion

AQi Lobar flow(% of control)

D

E

N2

N2

N2

o2

co2

2

2

2

2

co2

2

2

co2

2

2

2

2

co2

2

2

2

2

2

c?C P V

C-C P V

CfC P V

c5C P V

c?C P V

C-C P V

C-C P V

c?CPV

2.19.07.11.96.55.81.7

5.19.87.73.8

4.511.010.64.5

10.09.24.2

4.013.411.83.6

20.419.43.7

2.29.6

9.1

7.05.1

4.74.0

5.43.3

6.56.1

5.64.8

9.68.0

16.815.8

6.25.7

3223

2118

2415

3028

2522

4436

7772

2826

CircmUsiom Rutmrcb, Vol. XIX, August 1966


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in lobar blood flow. In every instance thelobar flow is less if pulmonary vein oxygencontent is used in the shunt equation. Theamount of correction varies from 2% to 9% ofcontrol flow. These results have the effect oflowering the points in figure 5, thereby bring-ing the data regression line closer to the theo-retical line and increasing the likelihood thatthese vessels are the main resistance vesselsor that all resistance vessels behave in thesame manner as the measured small muscularpulmonary arteries.

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CircuUtton Rttarcb, Vol. XIX, A.g.il 1966

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MIKIO KATO and NORMAN C. STAUBResponse of Small Pulmonary Arteries to Unilobar Hypoxia and Hypercapnia

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