separation of responses of arteries and veins to...

Separation of Responses of Arteries andVeins to Sympathetic Stimulation

By Ben G. Zimmerman, Ph.D.

• The sympathetic innervation of the vascu-lar tree consists of postganglionic fibers de-rived from the sympathetic ganglion cells inthe cervical, thoracic, and lumbar regions ofthe sympathetic trunks. In most vascular bedsthe blood vessels receive their innervationfrom postganglionic nerves which accompanythe main arterial vessels supplying the bed.Information is sparse, however, regarding thederivation of the sympathetic innervation ofthe individual vessels, i. e., the arteries, ar-terioles, and veins, making up the vasculartree. Kuntz1 sums up current knowledge re-garding innervation of the peripheral vascu-lature with the statement "The peripheral ves-sels are supplied by sympathetic fibers thatjoin them through the somatic nerves that liein closest proximity to them." One wouldsurmise from this that arteries and veinscould be innervated by anatomically separatenerve trunks; however, physiological evidenceconfirming this is needed.

The perfused hind paw of the dog pro-vided a convenient means of investigating theinnervation of the segments of this particularvascular bed. The paw consists mainly ofskin and bone and is practically devoid ofmuscle; therefore, the vasomotor responseelicited in this bed is ascribed to cutaneousvessels which can be thought of as respondingin a quantitatively similar manner. Applicationof the technique of Haddy and Gilbert- todetermine resistance changes of the individualvascular segments arranged in series, i. e., thearteries, small vessels, and veins is consideredjustifiable since the total segments making up

From the Department of Pharmacology, Univer-sity of Minnesota, Minneapolis, Minnesota.

Supported by Crant HE-08570 from the U. S.Public Health Service and a grant from the MinnesotaHeart Association.

Accepted for publication October 12, 1965.

Circulation Research, Vol. Will, April 1966

the vascular network in this bed even thougharranged in parallel do respond homo-geneously.

MethodsFifteen mongrel dogs weighing from 9 to 20.9

kg were employed in these experiments. The ani-mals were anesthetized with 30 mg/kg of sodiumpentobarbital injected intravenously. Supplemen-tal doses of 3 to 6 mg/kg were administeredroutinely about every hour after the initial dosein order to maintain a deep level of anesthesia.Decamethonium, 0.25 mg/kg, was administeredthrough a cannulated femoral vein and the animalswere placed on artificial respiration. Neuromus-cular blockade was employed and maintained inorder to prevent motor nerve stimulation duringthe subsequent sectioning and in some cases elec-trical stimulation of the tibial nerve, and also toprevent voluntary respiratory movements whilethe animal was on the respirator. Heparin sodiumwas injected intravenously in a dose of 5 mg/kgto prevent clotting.

The procedure used to perfuse the hind pawand to record segmental vascular blood pres-sures shown in figure 1 is a modification of thatof Haddy and Gilbert,2 and has been describedin detail elsewhere.8 This consisted of exposingthe abdominal aorta through a retroperitonealincision in the left flank, and the right femoral,left cranial tibial, and left saphenous (plantarbranch) arteries and a left superficial dorsalmetatarsal vein through skin incisions. Greatcare was taken when separating the saphenousartery from the surrounding tibial nerve, so asnot to damage the nerve fibers.

Pressures were recorded retrogradely fromthe small artery (1 mm O.D.) and vein (0.75 mmO.D.) by passing a narrow bore polyethylenecatheter (0.6 to 1.0 mm O.D.) as far into thevessel as possible, making sure that the tip of thecatheter was not occluded and that a true lateralpressure was recorded. Valid small artery pressurewas recorded since the saphenous artery formsmany anastomoses with the cranial tibial artery ata site distal to the cannulations.4

A constant blood flow to the paw was de-livered through the cranial tibial artery with aSigmamotor pump which was supplied with theanimal's own blood from a catheter passed into

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430 ZIMMERMAN

Sympathetic chain

Electrode

Oeep Fibulor Nerve

Cranial TibialArtery

tsion pressure

Large vein pressure

Small artery pressure

Small vein pressure

FIGURE 1

Diagram of autoperfused hind paw of dog.

the aorta through the right femoral artery. A tiewas made on the aorta around the catheter inorder to prevent any collateral blood flow to thepaw. All regions of the paw were effectivelyperfused through the cranial tibial artery becauseof the anastomoses in the paw. The paw waseffectively isolated from the remainder of theleg, since the cranial tibial and saphenous ar-teries were found to be the main blood supply tothe paw and they were tied off. Also, in experi-ments in which a tight ligature was passedaround the paw (with care not to include nervesor veins in the tie), no difference in the vaso-constrictor response to nerve stimulation wasnoted as compared to experiments in which noligature was used.

Flow averaged 27 ml/min and this produceda perfusion pressure (large artery pressure) offrom 60 to 105 mm Hg in the paw. Perfusionpressure was measured from a T-tube connectedto the cannula in the cranial tibial artery. Inseveral experiments a large vein pressure wasrecorded from the lateral saphenous vein, how-ever, since this pressure did not change signifi-cantly during nerve stimulation, its measurementwas omitted from most experiments.

The left lumbar sympathetic chain was isolatedthrough the incision made to expose the aorta,and after the perfusion was begun, sympatheticdenervation was performed by crushing the chainproximal to the L5 ganglion. A Harvard electrodewith its clamp removed, was placed under thenerve distal to L5 and held in place with asmall clamp to insure contact of the n'erve withthe electrode. Stimulation was done by meansof a Tektronix pulse wave generator through an

isolation transformer. In five experiments pulsesof 4 volts, 1 msec duration, and 2 to 10 cyclesper second (cycles/sec), were employed, and inthe remainder of the experiments 8 to 10 voltswhich provided a stimulus of supramaximal in-tensity, were used. The duration of the stimula-tion period ranged from 30 seconds to 3 minutes,but usually a duration of one minute was em-ployed. In four experiments the tibial nerve wasstimulated in order to compare this response tostimulation of the lumbar sympathetic trunk.

The control period in the sympathetic stimula-tion experiments consisted of obtaining responsesto stimulation usually at a low frequency (2cycles/sec) and at a high frequency (10 cycles/sec). In four experiments norepinephrine, 0.5 to2 /xg, was injected intra-arterially to compare theresponse to direct action of norepinephrine withthat of nerve stimulation. The tibial nerve wasthen tied and cut, and the response to nervestimulation was repeated. In most experiments thedeep fibular nerve was then sectioned and oneor both responses to nerve stimulation were re-peated. Bretylium tosylate (10 mg/kg) or /3TM10* (10 mg/kg) were given intravenously inseveral experiments to block the remaining re-sponse to sympathetic stimulation. Procaine hy-drochloride in 5% solution was injected into thesubcutaneous tissue all around the paw in theregion below the site where the tibial nervewas exposed, in two experiments. Transectionof the subcutaneous tissue completely around thepaw and sectioning of the remaining nerve fiberswas done in two experiments to abolish theremaining response to stimulation.

The vascular resistance changes occurring inthe paw as the result of sympathetic stimulationwere calculated as

A pressure in mm Hgflow in ml/min

by means of the following equations:

1. Change in total resistance =

peak change from control of perfusion pressureflow

2. Change in arterial resistance =

peak change in perfusion pressure—peak change in small artery pressure

flow3. Change in small vessel resistance =

peak change in small artery pressure—simultaneous change in small vein pressure

flow

•Obtained from Smith Kline and French Labora-tories.

Circulation Research, Vol. XVIII, April 1966



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RESPONSES OF ARTERIES AND VEINS 431

4. Change in venous resistance =

peak change in small vein pressureflow

The main interest in these experiments washow the peak vasoconstrictor effect in the vascu-lar segments was influenced by nerve section,and for this reason the vascular resistances werecalculated from the changes of peak pressures.Because the peaks of pressure changes in the smallveins were often delayed compared to perfusionand small artery pressures, the small vessel resis-tance was calculated from peak small arterypressure minus small vein pressure at that time.Because of this and because the peak venousresistance change occurred at a later time, the sumof the arterial, small vessel, and venous resistancechanges approximates, but does not necessarilyequal, the total resistance change.

CONTROL NERVESECTION

PROCAME

PRESSURES

SYSTEWC »ki i MI m moJ

PERFUSKM

SMALLVEM

LARGEVEIN

A. *. *. -

A — •

mo*M 8(22T

CONTROL AFTER NERVESECTION

PRESSURESIn rnm HQ

200

SYSTEMIC

400

PERFUSION 200

O

J.

SMALLARTERY

SMALLVEM

800

100

0J

40

20

0J

L/L

S 2cptImin

FIGURE 2

Pressure changes in perfused paw elicited by sympa-thetic stimulation at 2 cycles per second (cps) in arepresentative experiment (exp. no. 92). Lumbar sym-pathetic trunk was stimulated for one minute in thecontrol period as indicated by time marks. Stimula-tion was repeated at the same parameters after tibialnerve section (second panel) and after deep fibularnerve section (third panel).

FIGURE 3

Pressure changes in perfused paw elicited by sympa-thetic stimulation in exp. no. 113. Measurement ofsmall artery pressure was deleted and large vein pres-sure was recorded in this experiment. In the controlperiod the lumbar sympathetic trunk was stimulatedat 10 cycles per second (cps) for one minute andnorepinephrine (0.5 iig) was injected intra-arterially.Sympathetic stimulation was repeated after the tibialand deep fibular nerves were sectioned. Procainehydrochloride was injected into the tissue around theentire paw immediately below the site of nerve sec-tion and the stimulation and intra-arterial injectionof norepinephrine were repeated.

Results

Stimulation of the lumbar sympathetic nerveelicited a marked vasoconstrictor response inthe paw. This was characterized by increasesin perfusion, small artery, and small veinpressures (fig. 2), but not in large vein pres-sure (fig. 3). The total resistance changewas produced by increments in arterial,small vessel, and venous resistance (table 1).A low frequency of stimulation (2 cycles/sec)caused a similar degree of small vessel con-striction as the high frequency stimulation(10 cycles/sec), but arterial and venous con-strictions were greater at 10 than 2 cycles/sec. This pattern and degree of constrictionof the vascular segments of the paw produced

Circulation Ruttrcb, Vof. XV111, April 1966



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432 ZIMMERMAN

TABLE 1

Changes in Segmental Resistances in Control Period and After Nerve Section

Control resistance change* Resistance change* after nerve sectionExp.no.

929394

103116t

Total

7.274.004.175.405.87

Arterial

2.871.830.672.204.56

Smallvessel Venous

Stimulation at 23.801.303.432.200.35

0.961.230.470.400.96

Total

cycles/sec1.171.071.100.201.09

Arterial

-0.330.130.13

-0.280.13

Smallvessel

0.37-0.27

0.470.280.00

Venous

1.131.200.530.240.96

MeanSD

5.341.34

2.431.44

2.221.44

0.800.36

0.920.41

-0 .040.24

0.170.30

0.810.41

Stimulation at 10 cycles/sec8890919394

103111*113

5.945.126.007.236.007.606.868.79

2.814.621.604.571.502.72

2.120.443.800.634.102.72

1.000.740.602.031.531.002.171.46

1.001.030.832.001.331.002.141.88

-0.060.380.070.130.00

-0.08

-0 .03-0 .35-0.20-0.57

0.000.08

1.091.001.032.431.331.042.142.08

MeanSD

6.691.17

2.971.37

2.301.55

1.320.58

1.400.51

0.070.17

—0.180.24

1.520.60

*imm Hg/ml per min.tStimulation: 5 cycles/sec in this experiment.tStimulation: 20 cycles/sec in this experiment.

by sympathetic stimulation is similar to thatreported earlier.3

After sectioning the nerve trunks accom-panying the main arterial supply of the paw,the tibial and deep fibular nerves, stimulationof the lumbar sympathetic nerve produced anelevation in total resistance which was ac-counted for almost entirely by increased resis-tance of the paw veins. In table 1 and alsoin figure 2, it can easily be seen that the in-crements in arterial and small vessel resistancebefore nerve section were essentially elimi-nated while the increment in venous pressurewas unchanged or increased. The mean re-duction in the small vessel resistance incre-ment was -92.8% at 2 cycles/sec and -99.5%at 10 cycles/sec. It appears that the slightresidual small vessel constriction which occur-red at 2 cycles/sec was masked when stimu-lation was carried out at 10 cycles/sec. Thismay result from greater passive distension ofthe small vessels brought about by the largerincrease in small vein pressure at the highfrequency. The mean reduction in the arterial

resistance increment after nerve section was-94.1% at 2 cycles/sec and -97.4% at 10cycles/sec.

Venous resistance was increased at 2cycles/sec after nerve section by amountssimilar to those in the control period; however,at 10 cycles/sec the venous resistance in-crease tended to be greater after nerve section.In most experiments the peak changes in smallvein pressures tended to occur later than thepeak increases in small artery and perfusionpressures, which usually occurred synchron-ously. A transient impounding of blood in thelarger arteries of the paw caused by the veryhigh resistance of the smaller arteries at thehigher frequency, and therefore a transientfall in venous blood flow, may add to the lagin the pressure rise in the veins. Since thepump delivers a constant flow, in a short timethe flow in the veins must return to control.In some cases it is possible that the peakrise in venous pressure was not reached inthe minute of stimulation before nerve sec-tion. However, after nerve section, when no

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such impounding of blood occurs due to ab-sence of arterial constriction, venous pressurerises faster and a higher peak is thus attainedat the end of one minute. Such a result isfound in figures 2 and 3; it should be notedalso that after nerve section, the increasesin perfusion, small artery, and venous pres-sures occur synchronously, which would beexpected if the increase in venous resistanceaccounts for the increase in small artery andperfusion pressure.

The venous constrictor response after nervesection was blocked completely or reducedmarkedly after administration of the adrener-gic neuronal blocking agents, bretylium and/3TM 10 (table 2). This indicates that stimula-tion of sympathetic nerves was responsible forthe rise in small vein pressure. Sectioning thenerves accompanying the veins on the an-terior surface of the paw in two experimentsreduced ( - 3 5 and -23%), but did notabolish, the venous constrictor response re-maining after arterial nerve section. However,transection of all tissue around the paw,except the large veins, eliminated essentiallythe remaining venous response to sympathetic-nerve stimulation (table 2). Similarly, infiltra-tion of procaine into this same region alsoblocked the remaining response to sympatheticnerve stimulation (table 2).

Responses to intra-arterially administerednorepinephrine were neither altered signifi-cantly by nerve section in four of these experi-ments, nor was the response to norepinephrine

reduced by the infiltration of procaine (fig.3). The latter result indicates that blockadeof venous constriction by procaine was not dueto a direct depressant effect on the venoussmooth muscle, but was due to nerve blockade.

Stimulation of the peripheral end of thecut tibial nerve elicited the segmental vascularresistance changes shown in table 3. A largeincrease in total resistance was producedwhich consisted predominantly of an increasein arterial resistance and to a lesser extentin small vessel resistance. In two of the fourexperiments no change in venous resistancewas obtained and in two experiments onlya small increase was elicited; these changesin venous resistance were far less than thosebrought about by lumbar sympathetic nervestimulation.

DiscussionThis investigation has provided evidence for

the partial segmentalization of the sympatheticinnervation of the blood vessels in the dog'spaw. The sympathetic postganglionic fibersincluded in the somatic nerve bundles accom-panying the main arterial vessels in the pawdistribute mainly to specific sections of thevascular tree. The evidence that the innerva-tions of the arteries and small vessels arederived from these arterial nerves is providedby the finding that their responses to lumbarsympathetic stimulation are nearly abolishedby sectioning the tibial and deep fibularnerves. The veins, on the other hand, receive

TABLE 2

Effect of Adrenergic Neuronal Blockade, Local Infiltration of Procaine, and Subcutaneous TissueTransection on Venous Resistance Change Produced by Sympathetic Stimulation After NerveSection

Exp.no.

Change in venous resistance*

Agent

BretyliumBretyliumBretylium/3TM 10ProcaineProcaineTransectionTransection

Before blockadeor transection

1.001.031.330.682.080.963.030.96

After blockadeor transection

0.150.070.400.000.160.000.000.13

909194103113116L62172

*Amm Hg/ml per min.

Circulation Research, Vol. XVIII, April 1966



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434 ZIMMERMAN

TABLE 3

Changes in Segmental Resistances Elicited by Tibial Nerve Stimulation

Exp.no.

169170171172

Total

7.505.887.607.61

Resistance

ArterialA mm Hg/m5.254.126.406.52

changesSmallvessel

1 per min2.251.761.921.09

Venous

0.000.000.360.20

P

volts20203030

arameters of stimulicycles/sec

20101010

itionmsec

1111

most of their sympathetic supply from nervesseparate from those which accompany thearteries, because the venous response remainedafter arterial nerve section and only a smallvenous constrictor effect was obtained on sub-sequent tibial nerve stimulation. A small pro-portion of the fibers innervating vessels in-cluded in the segment defined as the smallvessels segment, accompanies the nerves whichsupply the veins, since at low frequency ofstimulation a small degree (about 7% of con-trol) of small vessel constriction persistedafter arterial nerve section.

It has not been determined in the presentstudy whether all veins, or only veins of acertain size making up the venous segment,or only localized sites5 in the veins areresponsible for the increase in venous resis-tance elicited by nerve stimulation. The evi-dence does indicate, however, that the in-crease in small vein pressure is brought aboutby constriction somewhere along the venoussegment beginning at the collateral vesselsfrom which the small vein pressure is derived(veins of about 0.1 to 0.5 mm O.D.) andending at the large vein (about 3 to 4 mmO.D.) which is at the level of nerve section.Constriction of larger veins upstream to thissite does not contribute significantly to thevenous response for the following reasons.Transection of the subcutaneous tissue, at thelevel at which the tibial nerve was cut,abolished for the most part the venous re-sponse to sympathetic nerve stimulation. Ifsympathetic fibers, leaving the tibial or deepfibular nerves at a higher level, innervatedlarge veins which constricted during sympa-thetic stimulation and were responsible for theincreased venous resistance we would have ex-pected such an effect to occur after transec-

tion of the tissue at the level of the cut tibialnerve. Similarly, infiltration of procaine atthis same site also abolished or greatly re-duced the venous response after nerve section.Finally, opening to the atmosphere a T-tubewhich had been interposed in the large veindraining the paw, had no effect on the venousresponse during sympathetic stimulation, in-dicating that constriction of large veins up-stream to the site of arterial nerve sectiondid not contribute significantly to the venousresponse in these experiments. The nervefibers that innervate the veins contributingmainly to the response run with the somaticnerves accompanying the veins themselvesand through the subcutaneous tissue in theabsence of somatic nerves. This conclusionwas reached because sectioning the somaticnerves accompanying the veins reduced thevenous response to some extent but did notabolish it in two experiments and becausetransection of the remaining small nervesvisible in the subcutaneous tissue abolishedthe response in two other experiments. Appar-ently relatively few fibers innervating the veinsalso accompany the tibial nerve because intwo of four animals tibial nerve stimulationdid cause slight venous constriction. Thenerve distribution to the arterial side of thevascular bed does not appear to be as diffuseas that to the venous side, since arterial andsmall vessel constriction can be largely eli-minated by cutting two nerve bundles, thetibial and deep fibular nerves. It appearsthat the majority of the sympathetic fiberssupplying the arteries and small vessels runin the tibial nerve, because a large incrementin arterial and total resistance was obtainedupon stimulation of this trunk. However, somefibers accompany the deep fibular nerve as

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well, because section of this nerve is necessaryto eliminate the arterial and small vessel con-striction during sympathetic stimulation.

It can be argued that if maximal constric-tion of the veins occurs at a lower frequencyof stimulation0 than that required for thearteries and small vessels, it would be possibleto eliminate most of the arterial and smallvessel constriction elicited by sympatheticstimulation by only a partial denervation andnot affect the venous response as much. Inthis study it was found that the arterial andsmall vessel responses were abolished orgreatly reduced, and the venous response wasleft intact, by stimulation at 2 cycles/sec aswell as at 10 cycles/sec even though thevenous response was not maximal at 2cycles/sec. Furthermore, in previous work7 nodifference was found in the frequency re-sponse curves for the arteries and veins ofthe dog's paw, whereas maximal constrictionof the small vessels did seem to occur atlower frequencies of stimulation. These resultswould rule out the possibility that the separa-tion of the arterial and venous responses byarterial nerve section is dependent on fre-quency of stimulation.

Besides providing physiological evidence forthe separate innervation of arteries and veinsin the paw, this study has verified furtherthe validity of the procedure for the measure-ment of segmental vascular resistances in thecutaneous vessels in the paw.2 Calculationsof segmental resistances assume that the vas-cular bed is a continuous system and, whenflow is constant, that resistance changes inveins, small vessels, and arteries will be re-flected back and raise pressure in that portionof the vascular bed proximal to the site ofconstriction. Under the conditions of theseexperiments, the resistance increase in theveins produced by sympathetic nerve stimula-tion after arterial nerve section was reflectedback into the small vessels and arteries,raising their respective pressures and account-ing for the increase in calculated total resis-tance. The apparent complete closure of thesmall veins and the lack of communicationwith the circulation in the proximal vessels


in the paw during sympathetic nerve stimula-tion obtained by Davis and Hamilton5 maybe attributed to a difference in techniques.In their preparation blood flow was not main-tained constant. When changes of segmentalvascular resistances during sympathetic stim-ulation are to be determined, as in the pre-sent study, it appears essential to maintainconstant blood flow.

SummaryLumbar sympathetic nerve stimulation pro-

duced an increase in arterial, small vesseland venous segmental resistances in the per-fused hind paw of the dog. Repeating thestimulation, after having sectioned the soma-tic nerve bundles accompanying the mainarterial supply of the paw, brought about anincrease only in venous resistance which wasequal to or greater than that obtained in thecontrol period. This venous constrictor re-sponse was reduced greatly by the intravenousadministration of adrenergic neuronal block-ing drugs, by local infiltration of procainearound the paw, or by transection of the sub-cutaneous tissue around the paw and thenerves accompanying the veins. These resultsindicated that sympathetic postganglionicfibers supplying the arteries and small vesselswere derived from nerve bundles accompany-ing the arteries (tibial and deep fibularnerves). The fibers supplying the veins aredistributed more diffusely in that they arefound in somatic nerve bundles accompany-ing the veins themselves, in the tibial nerve,and in the subcutaneous tissue of the paw.

References1. KUNTZ, A.: The Autonomic Nervous System.

Philadelphia, Lea and Febiger, 1953.2. HADDY, F. J., AND GILBERT, R. P.: The relation

of a venous-arteriolar reflex to transmuralpressure and resistance in small and largesystemic vessels. Circulation Res. 4: 25, 1956.

3. ZIMMERMAN, B. C , AND GOMEZ, J.: Increasedresponse to sympathetic stimulation in thecutaneous vasculature in presence of angioten-sin. Intern. J. Neurophamiacol. -1: 185, 1965.

4. MILLER, M. E.: Anatomy of the Dog. Phil-adelphia, W. B. Saunders Company, 1964.

5. DAVIS, D. L., AND HAMILTON, W. F.: Small



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vessel responses of the dog paw. Am. J. Physi- ance and capacitance blood vessels in theol. 196: 1316, 1959. cat. Acta Physiol. Scand. 50; suppl. 176: 1,

6. RICE, A. J., AND LONG, J. P.: An unusual veno- 1960.constriction produced by acetylcholine. Phar- 8. ZIMMERMAN, B. G.: Influence of sympatheticmacologist 7: 138, 1965. stimulation on segmental vascular resistance

7. MELLANDER, S.: Comparative studies on the before and after adrenergic neuronal block-adrenergic neurohormonal control of resist- ade. Arch. Intern. Pharmacodyn. In press.




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Ben G. ZimmermanSeparation of Responses of Arteries and Veins to Sympathetic Stimulation

Print ISSN: 0009-7330. Online ISSN: 1524-4571 Copyright © 1966 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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