644

Resting and Exercise Renal Blood Flows in ImmatureOvine Aortic Coarctation

Impact of Gradient Relief

James E. Lock, Thomas J. Kulik, Thomas P. Green, Theresa Niemi, and Stanley EinzigFrom the Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota

SUMMARY. The primary purpose of this study was to determine whether a neonatally inducedthoracic aortic coarctation reduces renal blood flow dunng physiological stress (treadmill exercise),and whether relief of the gradient returned renal blood flow during exercise to normal. Twoancillary questions were also addressed: does a coarctahon alter the responses of enteric and othervisceral vascular beds to treadmill exercise? Eight newborn lambs that underwent sham thoracot-omy with placement of left atrial lines served as controls; in seven Iambs we also created arecently described form of dilatable juxtaductal coarctation. This preparation is unique in that,like human coarctation, the obstruction does not get worse as the animal grows. Rest and exercisevascular pressures and regional blood flows were detemined 2-2V2 months after surgery. Coarc-tations were relieved with balloon dilation angioplasty catheters, inserted percutaneously. Post-dilation rest and exercise hemodynamic studies were performed, at the same level of exercise, 24hours after dilation. Renal blood flow did not change with exercise in the control animals. Inlambs with coarctation, renal blood flow fell (—22%, P < 0.01) during exercise. Unexpectedly, anexercise-induced fall in renal blood flow (—22%, P < 0.001) persisted even after effective relief ofthe coarctation (descending aortic blood pressure fell 25% with exercise predilarion, but remainedunchanged with exercise postdilation). Blood flow to the terminal ileum and cecum followed aqualitatively similar pattern to that of renal blood flow in control, predilation, and postdilationlambs, and this pattern was distinct from that of other enteric and visceral organ flows. Theseresults demonstrate an expected abnormality in the regulation of exercise renal blood flow inlambs with coarctation of the aorta; however, the persistence of this abnormality after effectivegradient relief does not support the previously advanced theory that postcoarctarion hypertensionis largely nonrenal in origin. The apparent similarity between ileocecal and renal blood flowcontrol under these circumstances may provide a clue to the known predilection of the terminalileum to suffer ischemic injury. (Circ Res 53: 644-654, 1983)

EARLIER in this century, the hyptertension abovean aortic coarctation was attributed to abnormalaortic wall compliances (Blumgart et al., 1931; Binget al., 1948). Subsequently, however, renal auto-transplantation experiments indicated an importantrole of the kidney in producing this hypertension(Scott and Bahnson, 1951), presumably on the basisof impaired renal blood flow (RBF) (Parker et al.,1982). Despite this, previous attempts to documenta coarctation-associated decrease in renal perfusionhave either been unsuccessful (Harris et al., 1950;Fallo et al., 1978), or have required the unphysiol-ogical stresses of marked sodium restriction and/orgeneral anesthesia (Bagby et al., 1975; Alpert et al.,1979). Thus, the mechanism by which a coarctationproduces hypertension remains unresolved.

More recently, the advent of successful surgicalcorrection for coarctation has uncovered a secondabnormality of blood pressure control in that lesion:paradoxical postcoarctation hypertension, as re-cently reviewed by Nanton and Olley (1976). Thishypertension frequently occurs not only acutely (i.e.,in the first week after repair), but also may evolve

into chronic hypertension. Recent studies into thegenesis of acute postcoarctation hypertension, per-formed largely in humans, have implicated nonrenalcauses, such as the 'silent' residual obstruction seenlate postoperatively (Freed et al., 1979), catechol-amine excess (Rocchini et al., 1976), and a resettingof the carotid sinus baroreceptor (Sehested et al.,1982). Animal studies into postcoarctation hyperten-sion have been limited (Igler et al., 1981): surgicallycreated 'coarctations' are difficult lesions to correctat reoperation and previously have required a majorthoracic operation. Thus, the possibility that a per-sistent abnormality in renal perfusion may contrib-ute to the acute form of postcoarctation hyperten-sion has not been explored.

We have recently described an experimental formof aortic coarctation in newborn lambs which isunique from all other such preparations in that theaortic gradient remains stable with animal growth(Lock et al., 1982). In this preparation, the coarcta-tion can be successfully relieved without a thoracot-omy by a balloon-tipped dilating catheter. We haveused this preparation to address three questions:

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Lock et a/./Exercise Blood Flows in Coarctation 645

WedgeResected

Non-ConstrlctiveAbsorbable

SutureFIGURE 1. Coarctation surgery. The resected wedge is intended toconstrict the aorta by 50%. As. Ao. = ascending aorta; DM. AO. =descending aorta; PDA = patent ductus arteriosus.

How does a neonatally induced, nonprogressive aor-tic coarctation influence renal and visceral bloodflows at rest? Does a modest physiologic stress (i.e.,submaximal treadmill exercise) produce abnormali-ties in blood flow distribution in such animals? Doesreduction of the aortic gradient restore resting andexercise blood flow patterns to normal in the im-mediate postcorrection period?

Methods

Creation and Correction of Aortic CoarctationThis dilatable form of aortic coarctation, and the pro-

tocol used for gradient relief, have been described in detail

previously (Lock et al., 1982). Briefly, 3-21-day-old lambsunderwent a left thoracotomy, the proximal descendingaorta was dissected free for a distance of 2-3 cm, and thenonpatent ductus arteriosus was ligated and divided. Aposterior wedge of aortic wall, comprising 50% of theaortic diameter, was resected posteriorly and repaired withrunning 5-0 polypropylene suture. The narrowed segmentwas then wrapped with 2-0 catgut suture (Fig. 1). In eachlamb, we strove for an intraoperative gradient of 40—60mm Hg, larger gradients being generally fatal in the im-mediate postoperative period. An 8F heparin-filled um-bilical artery line was inserted into the left atrium via theappendage and secured. The thorax was dosed, and theleft atrial (LA) line was buried subcutaneously betweenthe scapulae.

After 2-3 months, predilation rest and exercise cardiacoutputs, organ blood flows, and intravascular pressureswere determined (see below). The same day, the lambswere anesthetized with ketamine (10 mg/kg), the rightfemoral artery was cannulated percutaneously, and thegradient across the coarctation site was determined bymeasuring the pressure on either side of the obstruction.In addition, the diameter of the aortic narrowing wasmeasured directly from a lateral aortogram, using thecatheter diameter to correct for magnification. Balloondilation angioplasty was then performed with a polyeth-ylene dilation catheter (Medi-tech, Inc. or Cook, Inc.)introduced percutaneously from the femoral artery. Thediameter of the balloon, when inflated with saline, waschosen to be between 2V2 and 3 times the angiographicallydetermined diameter of the coarctation. A second aorto-gram and gradient determined the degree to which dila-tion had succeeded (Fig. 2). We then allowed the animalto recover overnight before determining postdilation rest

FIGURE 2. Lateral aortogram before (PRE) and 15 minutes after (POST) balloon dilation angioplasty. Before dilation, large collateral vessels whichoriginate from the ascending aorta enter the dilated descending aorta.

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646

and exercise outputs, organ flows, and intravascular pres-sures (see below).

So that the effects of exercise on organ flow distribu-tions and intravascular pressures could be determined ina group of lambs which had never been exposed to aorticcoarctation, sham thoracotomy was performed from theleft chest when the lambs were between 3 and 21-daysold. The proximal descending aorta was dissected, thenonpatent ductus arteriosus was ligated and divided, anda side-biting clamp was applied to the aorta for a total of30 minutes in a fashion identical to that described above.However, the aorta was neither incised nor sutured. After30 minutes of partial aortic occlusion, the clamp wasremoved, a left atria] line was placed, and secured asdescribed above, and the chest was closed. These lambsthen underwent training, rest and exercise studies, anddissection identical to that undergone by lambs in whicha coarctation had been made. Finally, the absence of anyaortic gradient was confirmed in each sham-operated lambby direct pressure measurements.

Rest and Exercise Intravascular Pressures, CardiacOutputs, and Organ Flows

Prior to dilation, all lambs were trained to run on ananimal exercise treadmill; in each case, the maximumspeed that each lamb could reliably maintain for 7-10minutes was recorded. On the day of study, lambs wereanesthetized with ketamine (10 mg/kg, iv), the left atrialline was retrieved from its subcutaneous pouch, and cath-eters were placed in the ascending aorta and pulmonaryartery from a cutdown over the right carotid artery andjugular vein, respectively. The position of all three cathe-ters was confirmed fluoroscopically with contrast injec-tions. In one lamb, the left atrial line had become dislodgedduring the 2Vi months between thoracotomy and study;in that animal, a second soft arterial line was advancedretrogradely across the aortic and mitral valves and posi-tioned in the left atrium. At least 75 minutes were allowedbetween the last dose of ketamine and the first hemody-namic study, ensuring a return to baseline hemodynamicstatus (Lock et al., 1980).

Intravascular pressures were measured with fluid-filledcatheters, zeroed to midchest, connected to Stathamp23Db transducers, and recorded on an E for M DR 12multi-channel recorder. Resting pressures were measuredwith the lamb standing quietly on the treadmill; exercisepressures were determined after 3 and 8 minutes of exer-cise (see below). Mean pressures were obtained electri-cally.

Cardiac outputs and organ flows were determined withradiolabeled microspheres, by a protocol previously de-scribed (Einzig et al., 1980). Briefly, after sonication for 15minutes in an ultrasonic bath, an injection vial was filledto capacity with isotonic saline, and the '15 ' /xm-radiola-beled (46Sc, MICe, '"Sr, and 95Ni) microspheres (MinnesotaMining and Manufacturing) were flushed for 10-15 sec-onds with 10 ml of saline into the left atrium at rest andduring exercise; the number of beads actually injectedranged from 0.1 to 5.7 X 106. Blood was withdrawn fromthe ascending aorta at a continuous rate (7.5 ml/min) fora total of 2'/2 minutes to ensure complete microspherecollection; the radioactivity of that sample was used todetermine tissue flow and cardiac output via the referencesample technique (Buckberg et al., 1971; Heymann et al.,1977). After the last microsphere injection, the lambs werekilled by sedative overdose, and the "carcass dissected toallow determination of organ flows.

Circulation Research/Vo/. 52, No. 5, November 1983

Tissue samples (1-3 g) were obtained from the spleen(n = 1), liver (n = 1), and head and tail of the pancreas (n= 2). After removal of the renal capsule, medulla, andupper and lower poles, four samples were obtained fromthe right and left renal cortices. The total weight of thefour full-thickness renal cortical samples was 11.23 ±1.3 g. Full-thickness samples were also obtained from fourdifferent regions of the small and large intestine: the first10-15 cm (2.17 ± 0.67 g) of the duodenum) the terminal10-15 cm (2.47 ± 0.71 g) of the ileum, the first 8-12 cm(2.26 ± 0.69 g) of the cecum, and 8-12 cm (1.91 ±0.60 g) of the middle portion of the large intestine. Allrenal cortical samples contained at least 356 spheres (av-erage 5027 ± 5865 spheres). The mean number of micro-spheres in the intestinal samples was 730 ± 876/samplefor the duodenum, 582 ± 512/sample for the ileum, 860± 814/sample for the cecum, and 394 ± 416/sample forthe mid large intestine. Reference blood and tissue sampleswere counted for 10 minutes in a Packard Autogammascintillation spectrometer at window settings selected tocorrespond to the peak energies of the different nuclides.All counts were corrected for background and cross-overactivity. Blood flow to each sample was calculated bysolving the equation Ai/Fi = Ar/Fr, where Ai = tissuesample count rate, Ar = reference sample count rate, Fi =tissue sample flow rate (ml/min) and Fr = referencesample flow rate (ml/min). Tissue blood flow was dividedby wet weight to express flow as ml/min per g of tissue.Computations were performed on a Hewlett-Packard9831A computer (Einzig et al., 1980).

Treadmill exercise was performed on a Reliance animaltreadmill, at a level grade, employing speeds of 2-3 milesper hour. After resting pressures and injection of micro-spheres for measuring resting flows had been determined,the treadmill speed was rapidly advanced to the speedwhich the animal was known to tolerate (see above), andthe time of initiating exercise was noted. After 3 minutesof exercise, pressures and heart rates were recorded, theaortic and LA lines were detached from the transducers,and microspheres were injected between 4 and 4'A min-utes of exercise. At the end of aortic sample withdrawal,the lines were flushed, and while the lamb was stillexercising, repeat pressures were measured, in each casebetween 7 and 8V2 minutes after exercise was instituted.The exercise protocol performed after coarctation reliefwas identical to that performed prior to gradient relief.Exercise intravascular pressures were taken as the valuesobtained at 3 minutes of exercise; in each lamb, for eachvariable, there was no significant change in any pressureor heart rate between 3 and 8 minutes of exercise.

Since we expected RBF during exercise to return tonormal after gradient relief, and since accurate determi-nation of the resting and exercise gradients across thecoarctation site would require dissection of an artery inthe hindlimb (a procedure which might compromise theability of the lamb to exercise), no attempt was made todetermine exercise coarctation gradients in these lambs.However, when analysis of the data (see below) indicatedan unexpected fall in RBF with exercise even after thecoarctation had been relieved, the presence of an undi-minished exercise-induced coarctation gradient became adistinct possibility. Accordingly, in six other lambs, alimited dissection was carried out over the posterior tibialartery to obtain simultaneous pressures in the ascendingand descending aorta during exercise before and afterdilation. This was achieved in four of the six lambs;however, artifacts induced by running made identificationof the systolic pressure difficult. In each, the postdilation

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TABLE 1Summary of Angioplasty Results and Exercise Loads

Sham-operated lambs

Coarctation predilation

Coarctation postdilation( n - 7 )

Age (days)

71.8 ±8.9

86.3 ± 9.3

87.3 ± 9.3

Weight

16 4 ±

16.2 ±

(kg)

5.5

2.4

Coarctationgradient (mm Hg)

0

37.2 ± 16.1

6.6 ± 6.0'

Coarctationdiameter (mm)

4.8 ± 1.3

8.5 ± 1.7*

Exercisespeed (mph)

2.8 ± 0.3

2.3 ± 0.6

2.3 ± 0.6

Exerciseduration (min)

8.0 ±0.4

8.0 ± 0.6

7.8 ± 0.9

*P = 0.05.

infra-coarctation blood pressure was not measured in thesame leg that was cannulated for passage of the dilationcatheter, to avoid the possibility of femoral artery stenosisinduced by the dilation procedure itself.

Data AnalysisSince the primary purpose of these experiments was to

determine the impacts of both exercise and coarctationrelief on RBF, the statistical significance of changes in RBFand intravascular pressures were tested with the Student'spaired r-test. To determine the impact of either exercise orgradient relief on individual organ flows, the paired (-testwas modified, using the Bonferroni method. To determinethe significance of changes in overall visceral organ bloodflow, caused either by exercise, the presence of a coarcta-tion, or the relief of a coarctation, an analysis of variancewas employed (Wallenstein et al., 1980). All data areexpressed as the mean ± SD.

Results

Creation and Correction of Aortic CoarctationEight lambs underwent a sham thoracotomy; each

survived, none had any measurable aortic gradientat the time of study, and each underwent a full restand exercise protocol. In three of these lambs, lateralaortography did not demonstrate any aortic distor-tion, due to the dissection and clamp application,which might have produced an exercise gradient.

A total of 13 lambs underwent both coarctationcreation and LA line placement in the newbornperiod; one expired of pneumonia prior to any study.One lamb died unexpectedly during dissection ofthe carotid artery prior to the predilation exercise

study, one lamb suffered a ruptured aortic wall atthe time of dilation and exsanguinated, and onelamb suffered a ruptured femoral artery, secondaryto dilation catheter placement, and eventually diedfrom intra-abdominal blood loss. One lamb hadneurological impairment after the predilation exer-cise study, and could not exercise effectively afterdilation. Finally, the LA line became dislodged be-tween the first and second exercise study in onelamb, with the result that all radioactivity injectedpostdilation was ultimately found in the left pleuralspace.

The hemodynamic and angjographic results ofcoarctation creation and subsequent dilation in theseven remaining lambs are listed in Table 1. Themean systolic gradient, measured during ketamineanesthesia just before dilation, was 37 mm Hg, witha coarctation diameter of 4.8 mm. Although balloondilation angioplasty did not restore the aortic anat-omy to normal in any lamb (Fig. 2), it did cause asubstantial increase in the diameter (77%) and adecrease in the systolic gradient (82%) across thenarrowed site (Table 1).

Rest and Exercise Pressures and Cardiac OutputsThe exercise loads and duration of exercise for

each group of lambs are listed in Table 1; thesevariables were similar for each group. The changesin heart rate, intravascular pressures, and cardiacoutputs at rest and during exercise are shown inTable 2. In the sham-operated lambs, there was a57% increase in heart rate, and a similar (60%)

TABLE 2Rest and Exercise Values of Blood Chemistry and Pressures

Sham-operatedlambs

Coarctationpredilation

Coarctationpostdilation

• P < 0.05.fP<0.01.

RestExercise

RestExercise

RestExercise

pH

7.52±0.017.50±0.06

7.57±0.127.57±0.03

7.56±0.02

Pco,

30.2±4.623.3±5.1

31.0±4.925.3±3.9

25.8±7.124.-4±4:2-

Po,

76.4±11.182.5±11.5

82.6±8.386.2±7.3

89.4±9.4

Hematocrit(%)

30.6±4.232.5±5.0

31.5±1.131.5±2.2

26.7±2.427JS±2.7

Ao(mm Hg)

83.8±7.285.4±7.1

116.7±14.9

86.9±11.4108.0*±15.1

PA(mm Hg)

18.1±3.719.2±3.7

22.6±4.929.6±9.8

18.0±3.821.4±6.8

LA(mm Hg)

3.6±2.94.2±3.9

4.6±4.86.0±5.2

6.1±5.18.6±5'.8

Heart rate(beats/min)

148.3±36.7232.5±41.9f

178.6±30.8234.6±34.0t

166.7±35.9

Cardiac output(ml/min per

kg)

274.3:t92.0438.5±105.6f

299.7±54.7440.9±78.4f

244.3±44.4402-.0±89;9t

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648

140

enIE3 120

<D

a.

o 100

CDC

T3C<DO

80

60

SYSTOLICPRESSURES

O Control

D Coarct, prediction

A Coarct, postdilation

DIASTOLICPRESSURES

• Control

• Coarct, pradllatlon

A Coarct, postdllatlon

I

Rest ExerciseFIGURE 3. Exercise-induced changes m systolic and diastohc ascend-ing aortic blood pressures in control, predilation, and postdilationanimals.

increase in cardiac output with exercise. Althoughsystolic aortic blood pressure rose (96-115 mm Hg)and diastolic blood pressure fell with exercise (73-60 mm Hg), there were no significant changes, in-duced by exercise, in mean aortic, left atrial, orpulmonary arterial blood pressures.

The rise in heart rate (35%) and cardiac output(47%) during exercise in the lambs with aortic coarc-tations was not significantly different from those ofcontrol lambs (57 and 60%, respectively). Again,

Circulation Research/Vol. 53, No. 5, November 1983

although systolic blood pressure rose (from 126 to140 mm Hg) and diastolic blood pressure fell (98-93 mm Hg) with exercise, there were no significantchanges in mean aortic, left atrial, and pulmonaryarterial blood pressure induced by exercise in thelambs with coarctation. Thus, other than the factthat baseline blood pressures in the ascending aortaare higher in lambs with a coarctation, the generalhemodynamic response to treadmill exercise inlambs with a significant, long-standing coarctationis minimally different from that of control lambs.

The exercise-induced rise in heart rate (41%) andcardiac outputs (65%) in the coarcted lambs, 1 dayafter gradient relief, is similar to that of both controllambs and their own predilation values. Baselineaortic blood pressures were returned to normal lev-els (mean ascending aortic pressure = 87 mm Hg)after dilation. However, there was a substantial andunexpected increase in systolic (100-127 mm Hg),diastolic (77-89 mm Hg), and mean aortic bloodpressures (87-108 mm Hg) induced by exercise inthese postdilation lambs (Fig 3). Not only was theexercise-induced rise in aortic blood pressure signif-icant (P < 0.001), it was also significantly greaterpostdilation than predilation (P < 0.001), in thesesame lambs, and was significantly greater than thechange observed in sham-operated lambs (P < 0.01,unpaired Ntest). There were no changes in left atrialor pulmonary arterial blood pressures, induced byexercise in postdilation lambs. Thus, 24 hours aftergradient relief, lambs that have had a long-standingaortic coarctation have normal resting hemody-namics. However, exercise produces an abnormalrise in aortic blood pressure in these lambs, in theface of normal changes in heart rate, cardiac output,and left atrial pressures.

Rest and Exercise Blood Flow Distributions

Renal Blood Flows

In the sham-operated lambs, RBF was well-pre-served during exercise. There was less than a 5%fall in combined RBF (Table 3). Although resting

Sham-operatedlambs

Coarctation pre-dilation

(« = 7)Coarctation

postdilation

RestExercise

RestExercise

RestExercise

TABLE 3Visceral Rest and Exercise Blood Flow Distributions

Renalbloodflow

8.88±2.328.42±3.42

8.54±1.736.69±1.25f

6.68±1.375.21±1.12f

Terminal

flow

0.81±0.300.84±0.26

1.39±1.010.95±0.61*

0.93±0.270.65±0.23f

Cecalbloodflow

1.45±0.441.42±0.64

1.67±0.641.29±0.64*

1.57±0.751.18±0.53

Hepaticbloodflow

0.25±0.270.12±0.13

0.08±0.040.06±0.04

0.08±0.110.07±0.07

Pancreaticbloodflow

1.29±0.340.82±0.18

2.03±0.801.14±0.46*

2.01±0.961.48±0.71

Splenicbloodflow

1.37±1.231.00±0.79

3.14±2.040.47±0.32

1.73±0.600.95±0.66

Colonicbloodflow

0.47±0.220.40±0.19

1.07±0.530.74±0.34

0.84±0.490.56±0.41

Duodenalbloodflow

1.25±0.480.90±0.39t

1.36±0.330.98±0.27f

1.18±0.341.06±0.35

All flows are expressed in ml/min per g.•P<0.05.tP<0.01.

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RBF was normal in the coarcted, predilation lambs(8.9 vs. 8.5 ml/g per min), exercise produced asignificant, 22% (P < 0.01) fall in RBF. Thus, thephysiological stress of treadmill exercise unmasksan abnormality of RBF in aortic coarctation notpresent at rest.

The response of RBF to gradient relief by a balloondilation catheter was entirely unexpected; restingRBF was slightly lower postdilation than it had beenpredilation. In addition, RBF fell even further withexercise postdilation, from 6.7 to 5.2 ml/min per g(P< 0.001).

Other Visceral Blood Flows

Hepatic, splenic, pancreatic, duodenal, terminalileal, cecal, and sigmoid colonic blood flows werealso determined in all three groups at rest and onexercise (Table 3). In general, blood flow to visceralorgans other than terminal ileum and cecum be-haved as one might have anticipated; there was afall in organ blood flow with exercise in the sham-operated lambs of variable statistical significance,and a similar or larger fall was observed in thecoarcted lambs. After dilation, the resting bloodflows remained largely unchanged. Further, themagnitude of the exercise-induced decrease in bloodflow in postdilation lambs was generally smallerthan that observed prior to dilation. These general-izations apply to the liver, spleen, duodenum, andpancreas.

In contrast, blood flow to the terminal ileum andcecum behaved in a different fashion. Flow was wellpreserved to these organs during exercise in thesham lambs (changes of +4% and —2%, respec-tively), but blood flows to the terminal ileum andcecum fell substantially with exercise in the coarctedlambs (-32 and -23%). Finally, dilation had noapparent beneficial effect on exercise-induced fallsin organ blood flow to either the terminal ileum orthe cecum. In each of these respects, terminal ilealand cecal blood flow responses mimicked the renalresponses to both exercise and gradient relief. Theresponse of colonic blood flow to either exercise or

649

gradient relief is intermediate; blood flow is perhapsless well preserved during exercise (—18%), but thereis little beneficial effect of balloon dilation on theexercise-induced decrease in flow. These changesare summarized in Table 4.

The percentage differences in the responses ofrenal, terminal ileal, and cecal blood flow on theone hand and the rest of the viscera on the otherare illustrated in Figure 4. On the x axis, we haveplotted the percent fall in blood flow, induced byexercise, in the sham-operated lambs. On the y axisare plotted the influences of gradient relief on ex-ercise-induced blood flow decreases (expressed asthe fall in blood flow, predilation minus the fall inblood flow, postdilation, divided by the fall in bloodflow, predilation).

Miscellaneous Studies

When preliminary inspection of the data indicatedthat there was a fall in renal blood flow after gra-dient relief, that this exercise-induced fall in RBFmight persist even after coarctation dilation, andthat aortic blood pressure might rise more withexercise after dilation than before, several furtherstudies were incorporated into the protocol to at-tempt to shed light on these issues. Thus, adrenalblood flow was found not to change with exercisein six sham-operated lambs (5.28 vs. 5.99 ml/minper g); in six coarctation, predilation lambs (3.88 vs.3.72), and in only three coarctation, postdilationlambs (4.86 vs. 7.20). Similarly, there were no ap-parent changes in aortic wall blood flow, measuredin five sham-operated lambs and in four coarctation,pre- and postdilation lambs (Table 5), that wereinduced either by exercise or by gradient relief.Finally, we measured ascending and descendingaortic blood pressures in four lambs at rest and withexercise. Exercise caused large artifacts in the de-scending aortic pressure tracing, making systolic anddiastolic pressures difficult to identify; thus, onlymean pressures are reported. Although exerciseclearly increased the mean gradient across a coarc-tation site, both predilation (from 49 mm Hg at rest

Sham-operatedlambs

Coarctation predi-lation

Coarctation postdi-lation(n = 7)

Renalbloodflow

- 5 %

-22%

-22%

Visceral

Terminalilealbloodflow

+4%

-32%

-30%

Rest and

Cecalbloodflow

- 2 %

-23%

-25%

TABLE 4Exercise Blood Flow Distributions

Percentage changes caused by exercise

Hepaticbloodflow

-52%

-25%

-12%

Pancreaticbloodflow

-36%

-44%

-26%

Splenicbloodflow

-27%

-85%

-45%

Colonicbloodflow

-15%

-31%

-33%

Duodenalbloodflow

-28%

-28%

-10%

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650 Circulation Research/Vol. 53, No. 5, November 1983

Pancreas

DuodenumA

Spleen

Liver

•

Colon Kidneys<i O

A Q P R E - A Q P O S T

OPRE

- 60%

- 40%

- 20%

TerminalO lleum

-40% -20%A

Cecum

Exercise-Induced Changes in OrganBlood Flow, Control Lambs

10%

- -20%

FIGURE 4. The influence on organ blood flows of exercise and gradient relief for seven different visceral organs. On the x-axis is plotted thepercent change in blood flow occurring during exercise in normal (sham) operated lambs; on the y-axis is plotted the impact of gradient relief onexercise flaws (expressed as the percent change in blood flow, predilation, minus the change in blood flow, postdilation, divided by the percentchange in blood flow, predilation, Q^, — Q ^ , / — Qpn).

to 73 mm Hg on exercise) and postdilation (from 10mm Hg at rest to 32 mm Hg on exercise), thegradient increased predilation due to a fall in de-scending aortic blood pressure (from 78 to 59 mmHg), whereas, in postdilation lambs, it was due to arise in ascending aortic blood pressure (from 94 to117 mm Hg). Of interest, the descending aorticblood pressure in postdilation lambs remained notonly constant with exercise, but as high as or higherthan descending aortic blood pressure in the resting,precoarctation lambs (see Table 4). Thus, the fall inaortic pressure with exercise (—25%) in these predi-lation lambs was similar to the fall in RBF predilation(—22%) previously described. Since aortic pressuredid not fall with exercise postdilation, the exercise-induced fall in RBF postdilation would appear to bedue to renal vasoconstriction. A similar argumentapplies to blood flow changes in the terminal ileumand cecum.

DiscussionThe primary purpose of the experimental studies

described above was to provide a direct test of anold, widely held, but as yet unproved hypothesis,

that decreased RBF contributes to the genesis ofcoarctation-associated hypertension. Thus, rest andexercise RBF were measured in lambs with andwithout a thoracic aortic coarctation. The advent ofan experimental form of aortic coarctation, dilatablewith a balloon-tipped catheter (Lock et al., 1982),obviated the need for a thoracotomy for gradientrelief, and allowed us to address a second question:does gradient relief acruely restore resting and ex-ercise RBF to normal values?

Since radiolabeled microspheres were used to as-sess RBF, we were also able to address severalancillary questions: e.g., are all visceral organsequally susceptible to stress-induced ischemia in acoarcted animal? Of interest, clinical studies haveidentified a post-coarctectomy syndrome of ischemicbowel disease associated with signs of mesentericarteritis. Virtually all previous reports of this syn-drome (Sealy, 1953; Lober and Lillehei, 1954; Ringand Lewis, 1950) have demonstrated a marked pre-dilection for bowel ischemia to occur in the terminalileum and cecum. Furthermore, clinical experiencewith a newborn form of ischemic bowel disease hasalso noted a strong tendency for the terminal ileum

TABLE 5Ascending and Descending Aortic Blood Pressures in FOOT Lambs

Mean ascending aor-tic pressure

Mean descendingaortic pressure

Rest

127.0 ±

78.0 ±

Predilation

Exercise

13.5 131.2 ±20.1

13.9 58.8 ± 13.8

94

84

Rest

.2±

.2±

Postdilation

Exercise

4.3 117.5 ±12.8

7.0 85.2 ± 15.9

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Lock et al. /Exercise Blood Flows in Coarctation 651

and cecum to suffer ischemic damage (Touloukianet al., 1967; Stevenson et al., 1969; Briski et al.,1982). Is there is a discernible physiological basis forthis known predisposition of the terminal ileum tosuffer ischemic damage?

Response to Exercise in Normal LambsSince the flow distribution responses to exercise

in immature animals have not previously been re-ported, we performed sham thoracotomies with leftatrial line insertion in eight lambs and subsequentlydetermined their exercise responses. Broadly speak-ing, these results in juvenile lambs are quite similarto previously published results from adult animals(Van Citters and Franklin, 1969; Vatner et al., 1971;Pannier and Leusen, 1977). Aortic systolic pressurerises while there are minimal changes in mean aortic,left atrial, or pulmonary artery pressures. Althoughthere was considerable scatter in the blood flows tovarious visceral organs, blood flow to most of theviscera (including the liver, pancreas, and spleen)tends to fall with isotonic exercise, RBF was un-changed, and the fall in overall enteric blood flow(—10%) was insignificant. These results are indistin-guishable from those previously reported for adultdogs, and do not shed further light on the previouslynoted apparent discrepancy between canine andhuman RBF responses to exercise (Rowell, 1974).

Unlike previous workers, we measured regional,rather than total, gut blood flow at both rest andexercise. Within the gut, exercise-induced changeswere not uniform; blood flow to the terminal ileumand cecum was best preserved with exercise,whereas flow to the duodenum and sigmoid fell.

Response to Exercise in Coarcted LambsThe surgically induced coarctations produced a

substantial (41%) increase in mean resting aorticblood pressures. Despite this, the resting blood flowsand their responses to exercise in coarcted lambswere surprisingly normal. In fact, exercise-inducedchanges in heart rate, cardiac output, and intravas-cular pressures, were minimally different from thosein normal lambs.

The major hemodynamic abnormality we ob-served in the coarcted lambs was a signficant, 22%decrease in RBF with exercise, which occurred in theface of normal resting RBF's. There was also anonsignificant tendency for blood flow to most vis-ceral organs to fall more with exercise in the face ofa coarctation. This was especially true for the ter-minal ileum and cecum; i.e., although organ flowwas completely preserved in those organs duringexerise in control lambs (see above), it fell 32 and23%, respectively, in the face of a coarctation. Thus,it would appear that, in the presence of a neonatallyproduced aortic coarctation, regional flow duringexercise is nonsignificantly decreased for most vis-ceral organs, but is significantly decreased in thekidneys, terminal ileum, and cecum.

Response to Exercise in Lambs after "Correction"of Aortic Coarctations

Although most of the results described to thispoint might have been anticipated, the response ofthe postdilation lambs to exercise was surprising ina number of respects. Firstly, although mean aorticpressure rose less than 5% with exercise in the firsttwo groups of lambs, exercise produced a substantial(25%) increase in mean aortic pressure in the post-dilation group. This abnormality could not be attrib-uted to concomitant 'abnormal* changes in cardiacoutput or left atrial pressure with exercise. Analysisof the aortic pressures indicated that, although theexercise rise in systolic aortic pressure was similarfor sham, predilation, and postdilation lambs (20,12, and 26%, respectively), diastolic blood pressuresfell significantly in both sham (17%) and predilation(6%), but actually rose 16% (P < 0.02) in the post-dilation lambs (Fig. 3).

The behavior of the blood flows to the visceralorgans after gradient relief was also somewhat un-expected. Although gradient relief tended to bluntthe fall in organ blood with exercise for most visceralorgans (including the liver, spleen, duodenum, andpancreas), the exercise-induced fall in blood flow tothe kidneys, termianl ileum, and cecum was entirelyundiminished by coarctation relief. Thus, the threevisceral organs whose flow was best preserved dur-ing exercise in control animals are precisely the samethree organs whose exercise flow is least improvedby relief of an aortic coarctation (Fig. 4).

Four of the physiological observations detailedabove warrant further discussion. (1) Neonatallyinduced aortic coarctation causes no measurable dis-turbances at rest, but induces a fall in renal bloodflow during treadmill exercise. (2) Relief of an aorticcoarctation is associated with fall in renal bloodflow, measured 24 hours after dilation, and a per-sistence of the exercise-induced fall in RBF. (3) Ex-ercise produces an unexplained rise in mean anddiastolic aortic blood pressures after, but not before,release of an aortic obstruction. (4) The regulationof blood flow to the terminal ileum and cecumduring exercise and before and after coarctationrelief is different from that of other visceral organs,but is indistinguishable from that of renal vessels.

Exercise-Induced Falls in RBF in CoarctationSince the pioneering work of Scott and Bahnson

(1951), most physiologists have assigned an impor-tant role to relative renal ischemia in the genesis ofcoarctation-associated hypertension. Despite that,multiple attempts to document decreased renalblood flow with aortic coarctations under baselineconditions have been unsuccessful (Harris et al.,1950; Fallo et al., 1978). More recently, severalgroups have adduced indirect evidence from plasmarerun levels obtained under conditions of nonphy-siological stress, that renal blood flow can be im-paired by an aortic coarctation (Bagby et al., 1975;

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652

Alpert et al., 1979). In that light, therefore, ourobservation of exercise-induced reductions in RBFin lambs with an aortic coarctation provides, for thefirst time, direct confirmation of a widely held hy-pothesis.

Paradoxical Behavior of Exercise RBF afterCoarctation Relief

The finding that relief of a coarctation gradienthas no beneficial effect on the exercise-induced fallin RBF in the postcoarctation lambs was entirelyunexpected. 'Protection' of the renal bed from ahigh, postcoarctectomy driving pressure seems un-likely, as gradient relief lowered ascending pressure,rather than raising descending aortic pressure. Al-though previous workers have shown that bloodpressure may remain high after coarctectomy on thebasis of a 'resetting' of the carotid sinus baroreceptor(Sealy et al., 1953; Igler et al, 1981), hypertensionon that basis should be mediated by sympathetics(Rocchini et al., 1976), and thus should show nospecial selectivity for renal vascular vasoconstric-tion. A third possibility is that the dilation did notsuccessfully relieve the obstruction. However, suchwas not the case; predilation exercise reduced meandescending aortic pressure (—28%) to a degree sim-ilar to the fall in RBF (-22%); postdilation, meandescending aortic pressure actually rose slightly withexercise (+1%) despite a fall in RBF of 22%, indicat-ing exercise-induced renal vasoconsfriction. Perhapscoarctation relief adds a new low-resistance circuitin parallel to the high resistance circuits of the upperbody, and thus may act to "steal' flow from abnor-mally resistive cerebral and cardiac vasculature. Tominimize this steal, the body may selectively con-strict vessels to less "essential' viscreal organs, thusprotecting CNS and myocardial flow (see Table 6).Such constriction would clearly be needed moreduring exercise.

Circulation Research/Vo/. 53, No. 5, November 1983

Exercise-Induced Hypertension PostcoarctotomyUpper extremity blood pressure is known to in-

crease substantially with exercise in children whohave undergone coarctation resection (James andKaplan, 1974; Hohn et al., 1975), Freed et al. (1979)have attributed this to residual obstruction. Residualobstruction would not appear to explain the abnor-mality in our lambs: The rise in mean ascendingaortic pressure with exercise before coarctotomy wassignificantly less than that observed after coarc-totomy, the gradient across the dilated site is alsogreater in exercising lambs predilation, and the risein ascending aortic pressure is due chiefly to in-creased diastolic blood pressures on exercise. Sinceexercise-induced hyptertension after gradient reliefcannot be attributed to abnormal changes in cardiacoutput, left arrial pressure, or heart rate, it wouldappear that the hypertension after coarctotomy isdue to diminished exercise-induced systemic vaso-dilarion in these lambs.

Regulation of Terminal Deal and Cecal BloodFlow

The predilection of the gut on either side of theileocecal value to suffer ischemic damage is wellknown to the surgeon, neonatologist, and cardiolo-gist (Sealy, 1953; Lober and Lillehei, 1954; Ring andLewis, 1956; Touloukian et al., 1967; Stevenson etal., 1969; Briski et al., 1982). To date, there havebeen no studies directed at identifying the cause ofthis peculiar distribution of ischemic lesions, al-though ill-defined anatomic considerations havebeen invoked in the past (Ring and Lewis, 1956).Our data do not support an anatomic reason forterminal ileal and cecal ischemia. Indeed, in normallambs, we observed the opposite; blood flows to theterminal ileum and cecum are better preserved dur-ing exercise than are flows to any other visceralorgan. However, whereas an aortic coarctation did

Leftventricular

bloodflow

TABLE 6Miscellaneous Flows*

Rightventricular

bloodflow

Totalbrainbloodflow

Bicepsfemorisbloodflow

Tricepsmusclebloodflow

Massetermusclebloodflow

Pulmonarytrapping

(%)

Sham-operatedlambs(n = 8)

Coarctation pre-dilation

RestExercise

RestExercise

1.92 ±0.743.16 ±0.91

2.58 ± 0.623.46 ± 0.65

1.37 ± 0.572.96 ± 0.84

1.74 ±0.283.00 ± 0.56

0.85 ± 0.200.93 ± 0.28

0.91 ±0.180.99 ±0.14

0.15 ±0.090.64 ± 0 44

0.21 ±0.130.99 ± 0.54

0.10 ±0.080 74 ± 0.29

0.11 ± 0.030.78 ± 0.31

0.06 ± 0.030.06 ± 0.03

0.15 ± 0.120.08 ± 0.05

6.45 ± 1.865.50 ± 1.79

5.33 ± 3.205.01 ± 1.05

Coarctationpostdilation

RestExercise

2.01 ± 0.364.52 ± 2.16

1.43 ± 0.404.11 ±2.12

1.00 ±0.150.94 ±0.15

0.12 ± 0.040.65 ± 0.31

0.09 ± 0.020.94 ± 0.49

0.09 ± 0.040.07 ± 0.03

4.43 ± 3.384.24 ± 2.24

* Studied at rest and on exercise (2.6 miles/hr) prediction, and 24 hours postdilation. All flows are expressed in ml/min per g oftissue. No attempt was made to assess the statistical significance of any flow changes in this table.

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not decrease resting ileocecal flow, it did produce anexercise-induced fall in ileocecal blood flow. Ofconsiderable interest, however, the terminal ileumand cecum resembled the kidneys in their responseto gradient relief. Terminal ileal flow fell after coarc-totomy, and exercise-induced ischemia to both or-gans persisted undiminished after gradient relief.

These results, instead of implicating an anatomichindrance to flow, suggest something else. The kid-neys and the ileocecal region of the gut may sharesome neurohumoral vasoconstrictor mechanismwhich becomes very important in the face of a long-standing, neonatally produced aortic coarctation.Again, this study provides no data which mightallow us to identify such a mechanism.

Methodologic Advantages and PitfallsThere are several aspects of the methodology used

in this study which not only enhance its value, butalso limit the conclusions that can be drawn. Unlikeall previous reports of constrictive hemodynamiclesions in growing animals, this form of coarctationclosely mimics human disease, in that the gradientremains constant with animal growth (Lock et al.,1982). Since the obstruction can be relieved withoutthoracotomy, the lambs can be studied, with exer-cise, very shortly after gradient relief and withoutthe confounding effects of a major operative proce-dure. Finally, since an extensive mediastinal dissec-tion through old scar tissue is not required to relievethe obstruction, the possibility of damage to sym-pathetic nerves can be avoided.

In addition, there are some weaknesses whichwarrant discussion. Since multiple organs were sam-pled, accuracy of the flow determinations mighthave been hampered by small microsphere numbersin each sample; however, all renal and nearly allintestinal samples contained at least 400 micro-spheres. Since 24 hours elapsed between the firstand last bead injections, we considered it possiblethat microspheres were released from the capillaries;however, there were no differences in systemicshunting of microspheres as approximated by pul-monary counts in the pre- and postdilation injec-tions, and the resting renal blood flows were similarin sham and predilation lambs.

What is most important is the fact that—becauseof the design of the study—the cause of the persist-ent fall in RBF postcoarctotomy cannot be estab-lished. There are several reasons for this. Descend-ing aortic blood pressure during exercise was notmeasured in all lambs, so that actual renal vascularresistance could not be calculated. Although itwould appear (at first glance) that this measurementwould be easy to obtain, such is not, in fact, thecase. Percutaneous entry of at least one femoralartery was necessary for dilation; in these pulselesslambs, entry proved difficult, and frequently bothfemoral arteries were used. Thus, the use of a chron-ically implanted femoral artery line (which may ormay not allow exercise in these lambs) as previously

653

described (Weismann and Clarke, 1981) would nothave been feasible in many lambs. Passage of acatheter from a neck vessel across the coarctationsite to measure descending aortic blood pressureswould have required removal of the catheter at thetime of dilation; repassage of the catheter throughthe coarctation after a recent dilation would haveplaced the lambs at risk from transvascular rupture(Lock et al., 1982). Although we used a limited tibialdissection to gain information about the descendingaortic pressure, it proved impossible to pass thecatheter to a central aortic position, resulting inconsiderable motion artifact during exercise. Finally,since previous workers have suggested that nonrenalfactors cause postcoarctation hypertension, we didnot expect to find persistence of a renal abnormalityafter coarctation relief. As a result, no studies wereperformed to determine the duration or possiblemediators of the decreased RBF.

In summary, these studies have provided directexperimental support for the long-standing hypoth-esis that physiological renal 'ischemia' contributesto the genesis of coarctation-associated hypertensionin immature animals. At the same time, it has raiseda larger number of questions: Why does the exercise-induced decrease in RBF persist after coarctationrelief? How long does it last? Why do systemicvessels fail to vasodilate with exercise after coarcta-tion relief? Why does the apparent control of ileoce-cal blood flow seem to resemble that of the kidneysrather than that of other visceral organs? The an-swers to such questions may ultimately bear on thetherapy of such diverse childhood diseases as po-stcoarctation hypertension and neonatal necrotizingenterocolitis.

Supported by Grant HL 28241 from the National Institutes ofHealth.

Dr. Lock is supported by an Established Investigator Award fromthe American Heart Association.

Address for reprints: Dr. James E Lock, Division of PediatncCardiology, Box 94, Mayo Memorial Building, University of Minne-sota Hospitals, Minneapolis, Minnesota 55455.

Received January 31, 1983; accepted for publication August 25,1983.

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INDEX TERMS: Coarctation • Renal blood flow • Exercise

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J E Lock, T J Kulik, T P Green, T Niemi and S Einziggradient relief.

Resting and exercise renal blood flows in immature ovine aortic coarctation. Impact of

Print ISSN: 0009-7330. Online ISSN: 1524-4571 Copyright © 1983 American Heart Association, Inc. All rights reserved.is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation Research

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