Relation Between Blood Flow and Contraction Force in Active Skeletal Muscle By Leo Hirvonen, M.D., and Ralph R. Sonnenschein, M.D., Ph.D. • Observation of the effects on contractile ability of skeletal muscle as affected by in- duced alterations in its total blood flow might yield insight into the role of vasomotor in- nervations, whether constrictor or dilator, in the regulation of blood flow, and hence of performance, of active muscle. Additionally, it might prove possible to infer the actions of vasomotor nerves and pharmacological agents on the partition of total blood flow within the active muscle between the "nu- tritional" flow, i.e., that component of total flow involved in the exchange of nutrients with the tissue, and "non-nutritional" flow. Such observations constitute the present re- port. Methods The experiments were performed on cats weigh- ing 1.9 to 3.5 Kg., anesthetized, after initial etherization, with intravenous chlornlose (50 mg. per Kg. body weight) augmented with urethane JIS required. After eannulation of the trachea, one hind limb was shaved and skinned completely. The subsequent procedure varied according to which of the following preparations was used. In the first, the "isolated" preparations, blood flow was measured in active muscles only, while in the others, the "combined" preparations, flow to the entire musculature of the leg was followed. "ISOLATED" GASTROCNEMIUS-SOLEUS PREPARATION (FIGURE 1) All attachments of the thigh muscles to the tibia were lighted and sectioned. The tibialis group of muscles was ligated at each end and removed in toto. All branches of the femoral artery ex- cept for the direct supply of the gastrocnemius- soleus muscles were ligated. A ligature was placed around the ankle to occlude circulation of the paw. The tibial nerve was exposed for the place- ment of stimulating electrodes. After hepariniza- tion of the animal (Upjohn, 500 to 700 U.S.P. units per Kg.), the femoral artery was cannu- From the Department of Physiology, University of California School of Medicine, Los Angeles, California. Supported by Grant H-5157 from the National In- stitutes of Health. Keceived for publication September 20, 1961. lated and arterial flow was redirected to it from the opposite femoral artery. Flow in this closed system was measured with a drop counter, as described by Lindgren, 1 and recorded in terms of intervals between successive drops or pairs of drops. In this method, the arterial flow is divert- ed through a, cannula system to a plastic chamber. In the latter, blood falls as uniform drops of 0.18 ml. from an orifice at the top through a layer of low density, low viscosity, liquid silicone where it interrupts a light beam which activates a photo-cell circuit. The blood is returned through a cannula to the distal arterial segment. No contamination of the blood ordinarily occurs with the immiscible silicone, and the system offers little resistance to flow. Measurement is limited to the maximum rate which allows separate drops to form, approximately 30 ml. per minute. The systemic arterial pressure was recorded in the femoral artery while the local perfusion pres- sure was recorded from the cannula distal to the drop chamber, both pressures being monitoi'ed with Statham P23A transducers. A screw clamp on the cannula proximal to the drop chamber served for the control of the perfusion pressure. Intra- arterial infusions were made through a side arm of the distal cannula using an infusion pump (Harvard Apparatus Co.). The leg was held rigidly in place by pins screwed into the femur and tibia. A thread was led from the ealeaneus to a tension transducer (Grass Instrument Co., FT10). A bipolar platinum stimulating electrode was placed on the tibial nerve. The leg was then recovered with its skin. Temperatures in the esophagus and in the muscle were measured by indwelling thermocouples and maintained at rela- tively constant levels by an electric heating pad under the animal and by an adjustable heat lamp directed at the leg. The tibial nerve was stimulated twice every sec- ond by a Tectronix type 161 pulse generator gated by a Grass Model S4 stimulator so as to give with each stimulation a train lasting 60 msec, of mono- phasic square wave impulses each of 0.02-msec. duration, spaced at intervals of 5 msec. The amplitude of the pulses was adjusted in order to give maximal response as detected by the force transducer, which generally required 0.5 to 1.0 volts. The duration of the individual impulses, 0.02 msec, was short enough so that autonomic fibers should not have been excited. The stimulus 94 Circulation Research, Volume X, January 196S by guest on May 21, 2018 http://circres.ahajournals.org/ Downloaded from
Transcript
Relation Between Blood Flow and ContractionForce in Active Skeletal Muscle
By Leo Hirvonen, M.D., and Ralph R. Sonnenschein, M.D., Ph.D.
• Observation of the effects on contractileability of skeletal muscle as affected by in-duced alterations in its total blood flow mightyield insight into the role of vasomotor in-nervations, whether constrictor or dilator, inthe regulation of blood flow, and hence ofperformance, of active muscle. Additionally,it might prove possible to infer the actionsof vasomotor nerves and pharmacologicalagents on the partition of total blood flowwithin the active muscle between the "nu-tritional" flow, i.e., that component of totalflow involved in the exchange of nutrientswith the tissue, and "non-nutritional" flow.Such observations constitute the present re-port.
MethodsThe experiments were performed on cats weigh-
ing 1.9 to 3.5 Kg., anesthetized, after initialetherization, with intravenous chlornlose (50 mg.per Kg. body weight) augmented with urethaneJIS required. After eannulation of the trachea,one hind limb was shaved and skinned completely.The subsequent procedure varied according towhich of the following preparations was used.In the first, the "isolated" preparations, bloodflow was measured in active muscles only, while inthe others, the "combined" preparations, flow tothe entire musculature of the leg was followed.
All attachments of the thigh muscles to thetibia were lighted and sectioned. The tibialis groupof muscles was ligated at each end and removedin toto. All branches of the femoral artery ex-cept for the direct supply of the gastrocnemius-soleus muscles were ligated. A ligature was placedaround the ankle to occlude circulation of thepaw. The tibial nerve was exposed for the place-ment of stimulating electrodes. After hepariniza-tion of the animal (Upjohn, 500 to 700 U.S.P.units per Kg.), the femoral artery was cannu-
From the Department of Physiology, University ofCalifornia School of Medicine, Los Angeles, California.
Supported by Grant H-5157 from the National In-stitutes of Health.
Keceived for publication September 20, 1961.
lated and arterial flow was redirected to it fromthe opposite femoral artery. Flow in this closedsystem was measured with a drop counter, asdescribed by Lindgren,1 and recorded in terms ofintervals between successive drops or pairs ofdrops. In this method, the arterial flow is divert-ed through a, cannula system to a plastic chamber.In the latter, blood falls as uniform drops of0.18 ml. from an orifice at the top through alayer of low density, low viscosity, liquid siliconewhere it interrupts a light beam which activatesa photo-cell circuit. The blood is returnedthrough a cannula to the distal arterial segment.No contamination of the blood ordinarily occurswith the immiscible silicone, and the system offerslittle resistance to flow. Measurement is limitedto the maximum rate which allows separate dropsto form, approximately 30 ml. per minute.
The systemic arterial pressure was recorded inthe femoral artery while the local perfusion pres-sure was recorded from the cannula distal to thedrop chamber, both pressures being monitoi'ed withStatham P23A transducers. A screw clamp on thecannula proximal to the drop chamber servedfor the control of the perfusion pressure. Intra-arterial infusions were made through a side armof the distal cannula using an infusion pump(Harvard Apparatus Co.). The leg was heldrigidly in place by pins screwed into the femurand tibia. A thread was led from the ealeaneusto a tension transducer (Grass Instrument Co.,FT10). A bipolar platinum stimulating electrodewas placed on the tibial nerve. The leg was thenrecovered with its skin. Temperatures in theesophagus and in the muscle were measured byindwelling thermocouples and maintained at rela-tively constant levels by an electric heating padunder the animal and by an adjustable heat lampdirected at the leg.
The tibial nerve was stimulated twice every sec-ond by a Tectronix type 161 pulse generator gatedby a Grass Model S4 stimulator so as to give witheach stimulation a train lasting 60 msec, of mono-phasic square wave impulses each of 0.02-msec.duration, spaced at intervals of 5 msec. Theamplitude of the pulses was adjusted in order togive maximal response as detected by the forcetransducer, which generally required 0.5 to 1.0volts. The duration of the individual impulses,0.02 msec, was short enough so that autonomicfibers should not have been excited. The stimulus
Comparison of Effects of Sympathetic Stimulation (S), Clamping (C), Norepinephrine(N), and Epinephrine (E) on "Isolated" Gastrocnemius Preparation
Type ofresponse*
s<c
s>c
No. ofanimals
0
7
0
7
Type ofresponse
N<CN = CN>C
No. ofanimals
1
6
0
7
Type ofresponse
E<C
E>C
No. ofanimals
130
Type ofresponse
N<EN = EN >E
No. ofanimals
030
3
*S < C means Hint for equivalent reductions in flow the reduction in muscle force isloss during sympathetic stimulation than during clamping.
which produced maximal muscle response did notinduce overt autonomic or somatic reflexes.
When indicated, the ipsilateral sympatheticchain was exposed at the level of L3 to Lo andprepared for stimulation with a bipolar platinumelectrode. After the appropriate level for pro-ducing1 vasoconstriction in the leg was determinedby stimulation, the sympathetic trunk was cutcent nil to the electrode. The sympathetic chainwas stimulated hy means of a Grass Model S5stimulator with 2-msec. monophasic square waveimpulses at 10 to lo c.p.s.; the intensity was ad-justed in each case to give the desired change inflow. With few exceptions, this stimulation wasnot accompanied by general cardiovascularchanges.
For hypothalamic stimulation of the vasodilatorcenter, the head was fixed in a stereota.xic instru-ment, the scalp reflected, and a section of skullremoved to allow insertion of u stainless steel elec-trode, 0.4 mm. wide, insulated except at the tip.Monopolar stimulation was effected by 50 to 70c.p.s. monophnsic square wave pulses of 2-msec.duration at 1.5 to 3 volts, delivered by n GrassModel S5 stimulator. The hypothalamus was ex-plored in the area bounded by the standard stereo-taxic coordinates AP +13 to +11, lateral 1 to 3,and vertical 0 to —4 mm., until maximal dilatoreffect was obtained. This general area correspondedwith that previously described.2 The criterion foracceptability of a dilator response was that, dur-ing hypothalamic stimulation, the sympatheticchain being intact and the muscle at rest, an in-crease in arterial flow should occur with essentiallyno change in arterial pressure. When possible thecholinergic nature of the hypothalamic dilator ef-fect was tested by the intravenous administrationof atropine sulphate (U.S.P.) at 0.5 to 1.5 nig.per Kg. body weight.
Synthetic Z-norepinephriru! (Levophed Bitar-trate, Winthrop-Stearns, Inc.) and synthetic Z-epi-nephrine (Winthrop-Stearns) were dissolved in0.9 per cent NaCl in concentrations of 1.0 or 10.0jxg. of base per ml. During'intra-arterial infusions
Circulation Research, Volume X, January 1962
of these agents, the maxmum volume rate was 0.5ml. per min.
Recordings of pressures, flow, and muscle forcewere made with Offner type 133 amplifiers andDynograph.
"COMBINED" PREPARATIONS
Quadriceps as the Active Muscle
With the exception of the following details, thepreparation and methods were as above. Flow wasmeasured in the external iliac artery of one leg.Collateral circulation was controlled by ligationof all appropriate arteries. Adequacy of the con-trol of collateral circulation was tested, -when pos-sible, at the end of each experiment by intra-aorticinjection of 5 to 10 ml. of India ink during occlu-sion of the iliac artery of the test leg. In the courseof some experiments, the existence of functionalcollaterals was ruled out by the absence of muscleresponse during total clamping of the perfusionsystem.
The patellar tendon and fascial connections ofthe quadriceps to the tibia were cut. A thread wasled, from a hole drilled in the patella, to theforce transducer and the distal end of the femurwas held rigidly in place by an inserted pin.The femoral nerve as it passed from within theiliopsoas muscle was prepared for stimulation andits branch to the sartorius muscle was cut.Gastrocnemius-soleus as the ActiveMuscle
Measurement of flow and control of collateralcirculation were as with the quadriceps prepara-tion; fixation of the leg, measurement of muscleforce and stimulation of the tibial nerve were asin the "isolated" gastrocnemius preparation.
ResultsCHARACTERISTICS OF THE MUSCLERESPONSE AND THE ACCOMPANYINGACTIVE HYPEREMIA
When stimulation of the tibial nerve wasbegun, the force of the gastroenemius-soleusreached a high level which then declined with-
Diagram of "isolated" gastrocnemms-soleus prep-aration of the cat.
in several minutes to a relatively constantsteady state of about 1.0 to 1.5 Kg. Thismuscle response corresponded with a steadyrate of flow usually three to six times theresting rate. This steady state of muscleresponse and flow often might continue dur-ing one-half hour of continued stimulation.After a variable period of time, in spite ofconstant arterial pressure, the preparationdeteriorated; the resting flow might be lowerthan previousl}' and the degree of active hy-peremia especially was reduced; the muscleresponse in turn declined commonly toaround 400 6m., considerably less than it hadbeen in the earlier stead3r-state condition. Inview of these changes, comparisons were madeonly of procedures which were performedwithin a short time of each other, whereinitial flow and muscle force were essentiallythe same. As contrasted with the "isolated"gastrocnemius preparation, the usual levelof resting flow in the "combined" prepara-tions was higher, while the increase in flowduring activity was proportionately lower.This would be expected in view of the factthat the flow to all the muscles of the legwas being measured and only a portion of themusculature was active. The usually observedmuscle force was initially in the order of0.5 to 1.0 Kg. for the quadriceps. Otherwise,the course of change in flow and muscle forcewith time was similar to that described forthe "isolated" gastrocnemius preparation.
7-a , CAT, SIKfl. CHL0R4L0SE-URETMANE
FIGURE 2
Effects of sympathetic chain stimulation, arterialcannula clamping, and norepinephrine infusion in"isolated" gastrocnemius preparation (illustratedgraphically in fig. 3A). Decreased flow indicatedby increased amplitude of recording.
EFFECTS OF RESTRICTION OF FLOWBY VARIOUS MEANS
Reduction in Perfusion Pressure byCannula Clamping; SympatheticVasoconstrictor Stimulation; Infra-ArterialNorepinephrine and Epinephrine
"Isolated" gastrocnemius preparation. Anexample of the observed responses with sym-pathetic trunk stimulation, cannula clamping,aud intra-arterial norepinephrine infusion isseen in figure 2. That the effects produced inthis series of experiments are local ones isindicated by the constancy of the systemicarterial pressure. The moderate rise seen inperfusion (cannula) pressure during bothsympathetic stimulation and norepinephrineinfusion is a manifestation of the increase inthe resistance in the peripheral A'essels.
From a steady initial state of blood flowand muscle force, the perfusion pressure wasreduced to a constant level until flow andforce reached a new steady state, where-upon the perfusion pressure was furtherreduced a number of times to new levels,each time only after the corresponding steadystate had been reached. Finally, the clampwas released and flow and muscle force wereallowed to recover. Similarly, sympatheticstimulation was regulated to keep blood flowat successively lower levels until new steadystates of muscle force were reached. In thesame manner, continuous infusion of norepi-nephrine or epinephrine was adjusted step-wise over the range from 0.014 to 3.4 /xg. per
Comparison of Effects of Sympathetic Stimulation(S), Clamping (C), and Norepinephrine (N) in"Combined" Preparations
«"• GASTROCNEMIUS1500 r-
Number of animals Number of animalsType of Quadri- Gastroc- Type of Quadri- Gastroc-reaponse ceps nemius response ceps nemius
s<cssc*s=c
s>c
N<C
N=C
N>C
0 10 03 ]2 03 3
15
*T\vo types of response in snme ;iniin;il.
minute; norepinephrine generally had astronger effect than epinephrine on a weightbasis. The marked diminution in flow andin muscle force produced by sympatheticstimulation or by infusion of norepinephrineor epinephrine was consistently observed.
With one exception, the effects of all pro-cedures on the relationship between muscleforce and flow were essentially identical(table 1 and fig. 3). In general, the rela-tionship between flow and muscle force overthe major part of the range was approxi-mately linear. The first decrement in flowwas often associated with a less than propor-tional decrease in muscle force. This gen-erally occurred only in the early part of theexperiment when both the resting flow andthe flow during activity were at a relativelyhigh level.
"Combined" preparations. Comparison ofthe effect of sympathetic stimulation andclamping on the relationship between flowand muscle force in the quadriceps prepara-tion revealed that, with one exception, thetwo procedures either had equal effects (table2, fig. 4A and D) or that the sympatheticstimulation reduced flow more than it didcontraction force (table 2, fig. 4B). Kesultsin table 2 indicate that norepinephrine hadeither the same effect as clamping or reducedcontraction more than flow; examples areseen in figure 4B, C and D. In no case Avasthe depressant effect of norepinephrine onmuscle force less than that of clamping. Thecomparisons among the effects of the various
16 ml/mm 0
» » CLAMPING
a • SYMP. STIMUL
• - — - • NOREPINEPHRINE
• • EPINEPHRINE
15 mt/min 0
BLOOD FLOW
FIGURE 3
Examples of blood floio (abscissae)-muscle force(ordinaies) relationships in "isolated" gastroc-nemius preparations during reduction of floiv bycannula clamping, sympathetic stimulation, andintra-arterial norepinephrine and epinephrine in-fusions. In each case, points farthest to the rightrepresent values of flow and force prior to startof procedure. Symbols, "S=C=N," etc., are de-fined in table 1.
procedures in each animal were made by ob-serving the plotted results. When the rela-tionships were close as in figure 4A and D,these were noted as showing equal effects ofthe procedures. When obvious differencessuch as in figure 4B and C existed, then theeffects of sympathetic stimulation or of nor-epinephrine were noted as "less than" or"greater than" clamping according towhether the muscle response for a given flowwas greater or less than that during clamp-ing, through most of the range of the in-duced diminution of flow. The distributionsof responses obtained in the gastrocnemiuspreparation were similar to those of thequadriceps (table 2) and indicate no impor-tant differences between these two muscles.
Examples of blood flow-muscle force relationshipsin "combined" quadriceps preparations duringflow reduction by various procedures. For ex-planations, see legend of figure 3.
in the active "isolated" gastroenemius pro-duced essentially identical linear reductionsin muscle force. Dilator action of epineph-rine in small doses as seen in resting muscle(t'.f. Lundholm3) did not appear in the ac-tive muscle.
In the "combined" preparations, the situ-ation was different, in that there were bothcontracting and resting components of themuscle mass whose blood flow was beingmeasured. The differences in effects on theflow-force relationships induced by sympa-thetic chain stimulation and by norepineph-rine infusion, as contrasted with their simi-larity in the "isolated" preparation, may beascribed to quantitative differences in actionsof these agencies on the vessels of contractingand of resting muscles.4'r> The mechanismsunderlying such differences remain to beelucidated. The actions of both sympatheticstimulation and norepinephrine, or epineph-rine, cannot be explained on the basis of theOrbeli effect (c.f. Biilbring and Burn0), sincein the "isolated" gastrocnemius no evidencefor augmentation of muscle force was ob-served.
CAROTID PRESSOR REFLEX
In considering the effects of artificial stimu-lation of the sympathetic chain, as describedabove, it appeared desirable to make a com-parison with the more physiological stimula-tion induced by bilateral occlusion of thecarotid arteries. Fourteen experiments, allyielding similar results, were performed asillustrated in figures 5 and 6. In the firstphase of the experiment, both carotid arterieswere occluded for about two minutes, whileperfusion pressure was maintained constantby adjustment of the clamp on the arterialcannula; systemic arterial pressure rose byan average of 30 mm. Hg (range 20 to 55mm. Hg). In the second phase, lasting one totwo minutes, the cannula clamp was releasedand the perfusion pressure allowed to in-crease while occlusion of the carotids wasmaintained.
"With the muscle at rest, flow decreasedduring the first phase by an average of 20 percent; in the second phase, with increased per-fusion pressure, flow increased by an averageof 25 per cent above the preclainping value.When the muscle was active, only 5 to 10 percent decrease in flow occurred in the firstphase; in the second phase, the average in-crease in flow was about 15 per cent.
In the first phase, muscle force was un-changed or decreased a few per cent. In thesecond phase, muscle force increased so thatit was equal to, or slightly above, its initiallevel.
It is apparent that a small vasoconstrictorinfluence occurs in active as well as restingmuscle during evocation of the carotid sinusreflex; this is considerably less than can beinduced b.y sympathetic chain stimulation, asalso shown by Mercker and Schoedel." If theperfusion pressure is allowed to increase free-ly, an increase in flow with associated en-hancement of muscle force may occur, aspreviously noted by Eein4 and Felix.s
EFFECTS OF STIMULATION OF THESYMPATHETIC VASODILATOR SYSTEM
Little has been known of the functionalsignificance of the sympathetic vasodilatorsystem, whose basic characteristics have been
investigated and reviewed by Uvniis9'10 andhis collaborators. The observations of Hymanet al.11 and Rosell and Uvnas1- suggest that,in resting muscle, the dilators act to increase'' non-nutritional'' blood flow. These findingsraise the question of the action of the dilatorsystem in active muscle both on blood flowand on performance of the muscle. The fol-lowing experiments were performed with thisquestion in mind.
"Isolated" Gastrocnemius Preparation
Ten experiments out of 23 trials met thecriterion for acceptability of the vasodilatorresponse. In these, hypothalamic stimula-tion, with the muscle at rest, was associatedwith, at most, .10 mm. Hg increase in meanarterial pressure, in most cases with no in-crease or a slight decrease. The flow in theresting muscle, 1.(5 to 6.2 ml./min., was in-creased by an average of 80 per cent (range:38 to 186 per cent). In four additional ex-periments, included for comparison, hypo-thalamic stimulation consistently produced apressure rise of 15 to 55 mm. Hg with anassociated increase in flow of 67 to 245 percent.
When the muscle was active, with its flowat a correspondingly higher level (9 to 22ml./min.), hypothalamic stimulation, whenunaccompanied by rise in arterial pressure,produced little or no increase in flow and noincrease in muscle force (figs. 7 and 8). Inthose experiments where the predominant ef-fect of the hypothalamic stimulation Avas arise in pressure, either from the beginningor after repeated stimulations (fig. 8), anincrease in flow and an increase in muscleresponse might occur. A single case (fig. 9)showed unusual results in that a large in-crease in muscle force occurred associatedwith a dilator effect. It is noteworthy thatin this experiment the initial muscle forceand associated flow were considerably lessthan usual.
"Combined" Quadriceps Preparation
This series includes eight experiments.Hypothalamic stimulation increased the flowby 97 (46 to 250) per cent. When the quad-
300 -
ARTERIAL 2 0 0 -PRESSURE
mm Hg 10 0 —tt 1
ON OFFCAROTIDS CLAMPED
tt tON OFF
CAR. CLAMPED
t tON OFF
CANNULA PARTIALLY
CLAMPED
CANN. PART. CL.
CANNULA
PRESSURE
mm Hg
BLOODFLOWml/min.
MUSCLEFORCE
Kg
5 - 2 4 - 6 1 , CAT, 4, SKg CMLORALOSE - URETHANE
FIGURE 5
Carotid clamping experiment in "combined" gas-trocnemius preparation with muscle at rest andactive. Cannula pressure maintained constantduring the first phase of the experiments. Noteslight increase in muscle force during secondphase.
riceps muscle was active, the flow was abouttwice as high as at rest, and hypothalamicstimulation produced on an average 25 (4 to36) per cent increase in the flow of the legmusculature. The corrresponding changes inmuscle force were no greater than ± 6 percent. In the later stages of two experiments,as the levels of the flow and muscle forcedecreased, the vasodilation was associatedwith a relatively greater enhancement ofmuscle force. The same effect occurred intwo other experiments where an increasedpressor response also appeared. In two cases,a small but definite decrease (3 to 12 percent) in muscle force was repeatedly ob-served coincident with 10 to 30 per cent in-crease in flow.
In four experiments, flow was restricted bya reduction in perfusion pressure of 25 to 40mm. Hg; this was associated with a reductionof muscle force and blood flow. The effectof vasodilator stimulation was unchanged bythis procedure. In one experiment of thisseries and one of the gastrocnemius series,hypothalamic dilator stimulation was started
Summary of individual carotid clumping experi-ments. Arterial and cannula pressures shownschematically as mean values.
about 40 seconds prior to the onset of muscleactivation and continued for the first 50 to80 seconds of the muscle response; the muscleresponse was allowed to continue for anotherminute. No difference was seen in the pat-tern of initial fatigue as compared with acti-vation of the muscle in the absence of dilatorstimulation.
As a rule, dilator stimulation in the "iso-lated" preparation had little or no effect ontotal arterial flow or force of contraction ina briskly responding active muscle, with ves-sels already maximally dilated by local fac-tors, presumably metabolic. A different situa-tion obtained in those cases where the vesselsdid not respond as well to the action oflocal factors. When this occurred, as in someof the cited experiments, activation of thedilator system did induce further local dila-tion with improvement in flow and muscle
Hypothalumic dilator stimulation during and afteractivation of gastrocnemius. Slight increase andsecondary decrease in floiv associated with nochange in muscle force.
performance. The greater observed increasein flow in the "combined" preparations dur-ing dilator stimulation was likely due to in-crease in flow in the inactive muscles. Suchan increase in flow in the inactive musclesmight have brought about the occasionallyobserved reduction in muscle force, throughshunting a significant amount of flow awayfrom the active muscles.
DiscussionBefore any interpretation of the results
can be made, the characteristics of one as-pect, in particular, of the experimental pro-cedure must be considered. It was necessarythat the peripheral nerve being stimulatedto activate the muscle be left intact so thatcentrally initiated vasomotor activity couldbe conducted to the vasculature of the muscle.As a result of this, the possibility existed thatstimulation of the peripheral nerve mighthave effects other than the desired one of ac-tivating the muscle. One obvious possibilitywas that afferent fibers might be stimulatedand might bring about reflexes which couldcomplicate the picture. Two observations
1 6 - 6 1 , CAT, 9 , Z . 7 K q CHLORALOSE - URETMANE
FIGURE 8
Hypothalamic stimulation before and during ac-tivation of gastrocnemdus. Early in experiment(panels 1 and 2), response was similar to that infigure 7. Later (panels 3 and 4), stimulationevoked pressor response associated with increasedflow and muscle force.
suggest that this factor played no importantrole. First, the intensity of stimulation ofthe peripheral nerve required to producemaximal muscle response was below thethreshold for producing overt cardiovascularor skeletal muscle reflexes. Secondly, previ-ous observations by Sonnensehein13 indicatedthat the vascular response in muscle, stimu-lated in the same manner as in the presentexperiments, was essentially unaltered whenthe peripheral nerve was decentralized. It isalso unlikely that the mode of somatic nervestimulation, especially with respect to theshock duration, interfered with conductionalong autonomic fibers in the nerve, or initi-ated activity in these fibers. The presentstudy indicates that conduction of centrallyinitiated vasoconstrictor impulses, eitherthrough stimulation of the sympathetic chainor through reflex activation, was apparentlyunaffected by stimulation of the peripheralnerve in the manner used. Damage of peri-vascular nerves during cannulation is of littleimportance, according to Rein;4 the observa-tion in our experiments of potent vasomotoreffects on sympathetic chain and hypothala-mic stimulation supports this contention.Thus, while no absolute answer can be given,it appears unlikely that any of these unde-sirable effects of stimulation of the peripheralnerve occurred.
Circulation Research, Volume X, January 19et
200-,
1 IOO He£
o -J
200 - i
xeE
1 0 0 -
0 - 1
CANNULA PRESSURE
CLAMP
BLOOD FLOW
MUSCLE FORCE
4 0 0
HYPOTHAL. STIMUL.t _ f
I 1 1 2 min.3-23-61, CAT, ?,3.0 Kg.CHLORALOSE-URETHANE
FIGURE 9
Increased flow and force in gastrocnemius duringhypothalamic stimulation. During second trial,increase in perfusion pressure ivas prevented bypartial clamping of cannula. Note levels of flowand muscle force as compared with figures 7 and8.
A major question toward which interpreta-tion of the present results may be directedis that of distribution of blood flow withinskeletal muscle with respect to the "nutri-tional" and "non-nutritional" components offlow. The question arises because of variouslines of evidence that such a distribution oc-curs in resting muscle and that it may bealtered by various procedures. For example,changes in oxygen consumption of restingmuscle during stimulation of vasoconstric-tor14 and vasodilator12 innervations havebeen ascribed to a shunting of blood into areasof low metabolic rate or through arterio-
venous auastamoses which are not functionalin nutritional exchange with the muscle tis-sue itself. Similar inferences from clearancestudies have been drawn11'15"17 for certaineffects of vasomotor innervation and epi-nephrine injection. Through use of micro-particle injections18"-0 and anatomical pro-cedures,-1' — evidence for the presence ofanastamoses in muscle has been obtained;these vessels could conduct the "mm-nutri-tional ' ' flow.
Essentially no information of similar na-ture has been available on the distribution ofblood flow in actively contracting muscle. Thepresent results may be interpreted to this endif the assumption is made that the ability ofa muscle to perform its work, as measured byits maximum contraction force, is an indexof its nutritional flow. Such an operationaldefinition of nutritional flow seems valid, forthe work performed by the muscle understeady-state conditions (with the qualifica-tions noted below) ought to reflect the ex-change of nutrients and metabolites betweenthe blood and the tissue. "Non-nutritional"flow is thus that component of total flowwhich, when changed, has no effect uponmuscle performance. This concept of nutri-tional flow does not presuppose any particu-lar anatomical arrangement of vessels. Ofcourse, reduction in muscle force may alsofollow from effects of neuromuscular trans-mission or upon the muscle itself and theseeffects must be controlled. Further, the mus-cle will have a maximum utilization of nu-trients, beyond which further supply will beineffective in enhancing its performance; thiswas apparently the case often early in anexperiment when it was possible to restrictthe blood flow to a certain extent with littleor no change in muscle force before theusual linear flow-force relationship becameevident.
With the above qualifications it can be in-ferred that, in general, neither those pro-cedures in which total flow was restricted norhypothalamic vasodilator stimulation pro-duced a change in the distribution of flow inthe active muscle. The fact of the linearitv
in the flow-force relationship is the essentialsupport for this conclusion; the discrepanciesseen in the "combined" preparations havebeen otherwise explained above.
The results on the sympathetic vasodilatorsystem are of special interest with respect toits physiological function. The fact that inbriskly contracting skeletal muscle, with ahigh level of active hypereinia, vasodilatoractivation produced no change in total bloodflow or in muscle force suggests that, in theintact animal, this system plays no role inthe maintenance of flow or performance inskeletal muscle in good condition. This A'iewis compatible with the concept of Abrahamset al.-3 that the dilator system, acting inconcert with other cardiovascular mecha-nisms, plays a role in the adjustment and dis-tribution of the cardiac output during thedefence reaction prior to the onset of, ratherthan during, muscular activity. Tn fatiguedmuscle, the system may, however, have anenhancing effect on flow and performance, ifone may extrapolate from our experimentalobservations on the "deteriorated" prepara-tions where the degree of active hypereiniaand muscle force had declined to a low leveland where hypothalamic stimulation in-creased both blood flow and force.
It then appears that a fundamental dif-ference exists in the responses of the vaseula-ture of resting and active skeletal muscle.While a change in the balance between "nu-tritional" and "non-nutritional" flow occursunder various influences when the muscle isat rest, this is not the case when the muscleis actively contracting. One might postulatetwo sets of vessels, one more intimately in-volved than the other in nutritional exchangewith the muscle fibers. With the muscle atrest, a differential action of vasomotor inner-vation may be effective in altering the ratioof resistances in the two sets of vessels, andhence of flow through them. When the mus-cle is actively contracting, however, the po-tent dilating action of metabolic productsmay negate any action of vasomotor inner-vation on local vessels and hence prevent areapportionment of flow among the two sets
of vessels. Change in total flow, as withsympathetic constrictor action, may still oc-cur, however. This may be explained by mak-ing the additional postulate of a second locusof vasomotor effect on resistance vessels up-stream from the two differentiated sets ofvessels. This scheme is only one of severalpossibilities which could explain the observeddifferences. These observations make clearthe danger inherent in carrying over totissues in full functional activity concepts ofvascular behavior derived from the study ofthese tissues at rest.
SummaryThe relationships between blood flow and
contraction force in intermittently contract-ing cat skeletal muscle during alterations offlow by various procedures were studied.
When flow only to the active gastrocnemius-soleus was measured, mechanical reduction inperfusion pressure, sympathetic chain stimu-lation and intra-arterial norepinephrine andepinephriue infusion were found to have es-sentially identical effects in producing reduc-tion in muscle force proportionate to that inblood flow. When flow in the whole leg mus-culature was measured while either the gas-trocneinius-soleus or the quadriceps was ac-tive, varying results were obtained with theseprocedures which could be ascribed to differ-ences in response of vessels in active andresting muscles. During the carotid sinusreflex some vasoconstrictor activity occurredin active muscle. On the assumption thatthe maximal muscle force is an index of thenutritional component of the flow, it may beinferred that, in general, those procedures inwhich total flow was restricted produced noalteration in distribution of nutritional andnon-nutritional flow within the active muscle.
Blood flow and muscle force were generallyunaffected by concomitant stimulation in thehypothalamus of the sympathetic vasodilatorsystem. An increase in flow and force oc-casionally was observed when these were atlow levels, or when a rise in arterial pressureoccurred. The sympathetic vasodilator sys-tem produces no alteration in distibution of
Circulation Research, Volu7ne^$t.January 1962
flow and would seem to play no role in themaintenance of blood flow and performanceof normal active muscle.
A fundamental difference appears to existin the responses of the vasculature of restingand active skeletal muscle; this difference isrelated to the interplay of specialized effectsof the vasomotor innervations and the actionof vasodilator metabolites.
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