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1963;32;671PediatricsChester Hyman

"THE CIRCULATION OF BLOOD THROUGH SKELETAL MUSCLE"

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THE CIRCULATION OF BLOOD THROUGHSKELETAL MUSCLE*

Chester Hyman, Ph.D.

University of Southern California School of Medicine, Department of Physiology,Los Angeles, California

671

M OVEMENT, that most grossly apparentmanifestation of life, results from

skeletal muscle contraction. Energy for con-

traction is ultimately obtained from the ex-

ternal environment so that fuels for trans-

formation in the muscle cell must be

brought from the gut or liver by the cir-

culation. Continuing activity clearly de-

pends on adequate tissue perfusion which

maintains constant the environment of the

cell12 and assures each tissue its necessary

nutrients. In skeletal muscle, the vast range

of potential activity would require either

a constant blood flow adequate for the

maximum demand, or, a rapidly and accu-

rately adjusting circulation to meet the

immediate needs of the tissue. Since the

principle of parsimony rules most biologi-

cal systems, instead of the prodigal maxi-

mum blood flow to resting muscle to pro-

vide for the occasional burst of activity,

the variable blood flow system is the more

logical and the actual solution. However,

at times the maximum needs of active

muscle may exceed the blood supply to

incur a blood flow debt which must be

repaid after the contraction. These general

concepts are supported by numberless

casual observations and many careful sci-

entific studies performed over the past cen-

turies.3 Specific information of the mecha-

nisms regulating the circulation in skeletal

muscle has accumulated during the past

half century4 and several new concepts

have been proposed in the past two dec-

ades.567 What follows is a summary and

personal evaluation of our present knowl-

edge of these mechanisms.

Traditionally, a description of the mor-

phologic stage prefaces the examination of

The literature compilation as well as the original

by a grant from N.I.H., U. S. Public Health Service.

any physiologic mechanism; in this case,

we must examine the arrangement of tubes

which carry the blood through skeletal

muscle. The approach of the larger blood

vessels to muscle and the problem of multi-

ple versus unique arterial supply have been

discussed in Abramsons recent book.8

Gross geometric deformations and disloca-

tions in a tissue might embarrass the blood

supply were it dependent on a single ar-

terial input; however, the several collateral

pathways to muscle assure a continuous

circulation. At the next stage, the arteries

of skeletal muscle form inter-communicat-

ing arcades at successive divisions, further

minimizing the chance of even localized

ischemia. Arterioles originate from the

arcuates and lead in amongst the muscle

bundles where they give off capillaries

which parallel the muscle fibers.9 Thus

several alternative arterial routes assure

distribution of blood to the most remote

capillary. Arrangements for draining blood

from muscle are, happily, similar to those

for supply, since occlusion of a unique

venous pathway could embarrass the cir-

culation almost as easily as arterial occlu-

sion.

Exchange of solutes between blood and

tissue, i.e. the maintenance of the com-

position of the tissue fluid, is the function

of the capillaries alone. Only the blood

flowing in these vessels can serve to nourish

the tissues and may be considered the effec-tive blood flow. This could never exceed,

but might be less than the total blood flow,

since there may be alternative pathways

for movement of blood through muscle.

The exchange of solutes between blood

and tissue fluid in the muscle could be ad-

work reported from our laboratories was supported

PEDIATRICS, October, Part II, 1963

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672 BLOOD SUPPLY FOR SKELETAL MUSCLE

justed by altering the number of patent

capillaries or by modulating flow through

the individual vessel. To a large extent,

the latter is determined by action of the

smooth muscle pre-capillary sphincter, ap-

parently independently activated and

nicely attuned to local tissue needs.b0 Ob-

servations of capillaries in the rats meso-

appendix indicate a stable blood flow over

a moderate range of pressure gradient.11

Some of our own datal2 suggest that the

blood flow through a patent capillary of

skeletal muscle is all-or-none, and effective

blood flow is in fact increased by perfusion

of more capillaries. In contrast, total blood

flow may be modified by: (1) the adjust-

ment of the hemodynamic resistance in the

arterioles; (2) the pressure level on the

venous side determined by factors like the

location of the tissue relative to the heart,

or occlusion of the venous outflow; or (3)

the intramuscular pressure.

Several recent morphologic studieshi,14,lS

suggest a bypass or shunt pathway from the

arteries to the veins in muscle which does

not contribute to the effective circulation.

Although Barlowl6 cannot find typical a-v

shunts in muscle, this does not necessarily

refute the concept of a functional by-

pass for which there is much indirect

physiological support.18

Effective blood flow through muscle

capillaries and its relation to total blood

flow is adjusted by the activity of smooth

muscle cells in the walls of the several

blood vessels. The motley group of ade-

quate stimuli which can influence tone of

vascular smooth muscle may be sorted into

four arbitrary categories: (1) nervous path-

ways; (2) circulating humoral agents; (3)

locally produced chemical agents; and (4)

physical factors.19

Nervous Pathways

Much of the vascular smooth muscle is

richly innervated20 principally from the

autonomic nervous system, but with some

minor contributions from the somatic sys-

tem. Activity of autonomic adrenergic

fibers has been shown to constrict the re-

sistance vessels of the skeletal muscles.23

Although not directly established for

muscle, recent evidence2 suggests similar

adrenergic constrictor innervation of the

small arteries in skin.

Intensive work beginning in 1948 has

established the existence of autonomic

cholinergic fibers whose activity increase

total blood flow through skeletal muscle

in both animal preparations and in

human skeletal muscle.2 In man, severe

emotional stress increases blood flow in the

forearm by vasodilatation in muscle by

activation of cholinergic fibers. Recent evi-

dence suggests that the increased flow is

shunted through muscle;26 but there is no

evidence that either the so-called capacity

vessels27 or the pre-capillary sphincters28

are relaxed. The physiologic significance

of this vasodilation is uncertain27 and de-

tailed information concerning the periph-

eral distribution of the fibers is not yet

available.

Hilton29 demonstrated a wave of vaso-

dilatation which moves centripetally along

the arterioles and arteries when a muscle

is thrown into activity, even in totally de-

nervated preparations. He suggests that

this vasodilatation might travel via a

nerve net or intra-mural nervous system

or by conduction in smooth muscle itself.

Hormones

Several of the circulating humoral agents

can profoundly alter the circulation in

muscle. The catachol amines have been

most carefully studied and their peripheral

vascular effects in man have been sum-

marized by Whelan and de Ia Lande.3#{176}

Intravenously administered adrenaline in-

creases blood flow through muscular seg-

ments of the limbs such as the forearm and

calf3l probably by dilatation of the muscle

vessels.32 Intra-arterial infusion causes

transient vasodilatation often followed by

a fall in flow. The different response to the

two routes of infusion resulted in a search

for an adrenaline induced vasodilator in-

termediate.3 However, the recent observa-

tion that intra-arterial adrenaline is a vaso-

dilator when given in the presence of an

adrenergic blocking agent such as chior-



SUPPLEMENT 673

promazine : and the increase in muscleblood flow which is found even with doses

of adrenaline which reduce total forearm

blood flow3236 make it clear that adrenaline

will dilate muscle vessels when given by

either route. The difference in the responses

to the two routes appears, in fact, to be

quantitative only and probably reflects the

diluting effect of changes in blood flow on

the intra-arterially infused solution.37

Adrenaline probably dilates muscle vessels

by a direct action on the receptors of

the smooth muscle of the arterio1es8 al-

though both release of histamine and of

lactic acid4#{176}have been suggested. Evidence

to date is against the histamine theory4l

and de Ia Lande and Whelan42 were unable

to demonstrate a vasodilating effect of

lactic acid or lactate on human limb vessels.

However, the local glycogenolytic action of

adrenaline on skeletal muscle in man and

animals also increases pyruvate and de-

presses phosphate and potassium outputs

from muscle. Some of these other prod-

ucts of adrenaline induced metabolic ac-

tivity may still play a part in the vaso-

dilator action.

The dilating effect of adrenaline is less

marked or absent in limbs to which the

sympathetic nerves have been cut.44 How-

ever, this change is not seen in the early

stages after sympathectomy or after nerve

block and might be explained by a change

in sensitivity of the a receptors to the con-

strictor component of adrenalines action.

It may be that an exaggerated constriction

of the skin vessels masks the muscle dilata-

tion.

Effect of adrenaline on the partition of

blood flow between the effective and shunt

circulation has not been worked out, but

Mellander23 has shown that physiologic

doses of the amine profoundly dilate the

pre-capillary resistance vessels and only

slightly alter the capacitance vessels.

Glover et al.4#{176}report that both adrenaline

and noradrenalin given intra-arterially con-

strict veins in human forearms. Noradren-

alin given intra-arterially causes a direct,

sustained vasoconstriction: intravenous ad-

ministration produces vasodilatation, but

only in tissues with an intact autonomic

supp1y.3 According to Mellander2 nor-

adrenalin constricts resistance vessels less

than capacitance vessels in a pure muscle

preparation, but probably all vascular

smooth muscle responds to noradrenalin

by constriction.

The pituitary hormones, synthetic oxy-

tocin and vasopressin, both influence blood

flow through the human forearm. Kitchin47

showed that vasopressin diminishes the cir-

culation through skeletal muscle; in earlier

unpublished studies he suggested that nu-

tritional circulation is curtailed by this

hormone. In contrast, oxytocin increases

blood flow in muscle under normal circum-

stances;48 a mixture of 20 parts of oxytocin

to 1 part of vasopressin achieves a neutral

balance. Details of the sites of action of

these agents are still lacking.

Thyroid hormone increases blood flow

through muscle95#{176} and apparently these

increases are only partly related to the

altered tissue metabolism.h1 Bauer et al.,52

showed that clearance of 1131, Na24, and K42

from local injection sites in muscle of

myxedematous patients was much slower

than in normals, and that clearances could

be increased significantly by treatment with

thyroid hormone. A more recent study53

showed that specific thyroid analogues in

doses which increased total forearm blood

flow by 70% increased clearance by 140%.

These data support the argument that thy-

roid hormone increases blood flow through

the effective circulation.

Secretions of the other duciless glands

have not been studied in sufficient detail

to allow even such a vague evaluation of

their effect on blood vessels in skeletal

muscle. Although insulin, or the associated

hypoglycemia, increases blood flow through

the forearm of normal and adrenalecto-

mized human subjects,4 the dilatation is

probably limited to cutaneous tissue.55 Pre-

liminary studies#{176} indicate that the sex

steroids probably do not effect blood flow

through human skeletal muscle. The effects

of the adrenocortical steroids are similarly

equivocal. Clearance of J131 or Na24 from

skeletal muscle is somewhat decreased in




adrenalectomized animals; the change is

reversed by DOCA.57 Evidence for humoral

effects on muscle circulation is obviously

still incomplete and well-established only

for the catachol amines and possibly for

pitressin.

Chemical Agents

Assorted chemical agents constitute the

third category of stimuli to vascular smooth

muscle. Changes in metabolic activity of

tissue can profoundly modify local blood

flow, but no specific vasoactive substance

has as yet been identified. Various agents

have been proposed as the specffic tissue

vasodilator but on the basis of available

evidence, it may be safer to refer to them

as metabolites.8 Some potent vasodilator

apparently adjusts total blood flow, and

effective blood flow, to the activity of the

muscle, independently of central control:

neither sympathetic nervous supply,3 nor

humoral agents influence the nicety of

these adjustments. The great blood flow

increase in muscle is induced by activity,28

as seen in post-exercise and in post-occlu-

sion hyperemia, is accompanied by relaxa-

tion of smooth muscle in all the radio-

graphically demonstrable vessels,60 how-

ever the spread of dilatation may result

from conduction in the continuous smooth

muscle coat of the arterial tree.29 Certain

other simple, non-humoral chemical sub-

stances can alter muscle blood flow. For

example, bradykinin, a by-product of

glandular secretion, increases total and

effective blood flow in muscle,61 with evi-

dence for decreased tone of the smooth

muscle in both the arterioles and in the

pre-capillary sphincters. Since this sub-

stance is probably not produced in muscle,

it is unlikely that bradykinin has a role in

adjusting blood flow in this tissue.

Physical Factors

The final category of adequate stimuli

for smooth muscle is that of physical

changes. Bayliss62 showed that when

stretched, vascular smooth muscle re-

sponded by active constriction; when

placed under lessened tension it responded

by relaxation. This myogenic response,

has recently been confirmed in careful

animal experiments by Folkow.63 Although

vascular smooth muscle tone can be modi-

fied by stretch, how this stimulus adjusts

blood flow under physiologic circumstances

has not been established. Only the major

pre-capillary resistance vessels show this

response;64 it cannot be demonstrated in

capacity vessels

Local temperature changes can modify

the total blood flow through muscular limb

segments, independent of systemic or gen-

eral effects.66 We recently reported that

local heating of exposed muscle prepara-

tions increased tissue clearance of J131 by

a percentage greater than the local metab-

olism,67 suggesting a direct thermal relaxa-

tion of the pre-capillary sphincter. Severe

cooling causes contraction of the walls of

the veins,68 and of arteries, arterioles and

capillaries.66.67

Other physical modalities like ultra-

sound, diathermy, etc. have been studied

for their effects on blood flow through

muscle. There is good evidence that a local

increase in temperature is in fact respon-

sible for the measured increase in blood

flow. Ultra-sound apparently increases

blood flow, but not more than would be

predicted from its thermal effect.69 Perhaps

local electrical stimulation induces a

greater hyperemia than anticipated on the

basis of the induced temperature increase.70

The entire area of the physical modalities

and their influence on blood flow in the

extremities is still open for detailed in-

vestigation.

EXERCISE

Changes in the level of activity of the

muscle initiate important immediate and

long-range adjustments of blood flow.

Blood flow in muscle tends to increase dur-

ing activity, but because of the geometric

changes in the contracting muscle, tissue

pressure and local resistance tend to in-

crease, blunting the dilatation. The maxi-

mum increase in blood flow can be demon-

strated during the immediate post-contrac-

tion hyperemia7l when the dilator tendency



SUPPLEMENT 675

is unopposed. Barcroft and Millen72 found

increased local flow during sustained con-

traction of calf muscle up to 0.3 of its

maximum force; at contraction strengths

above this, measured blood flow was less

than control. Other indirect lines of evi-

dence imply that blood flow becomes sub-

normal only when sustained contractions

exceed 60% of the maximum73 or as in

more recent experiments74 elevated blood

flows were found in the active muscles of

forearm during sustained contraction to 70%

maximum. Barcroft and Dornhorst75 using

a combination of plethysmographic and

occlusive techniques found greater than

resting blood flow in the human forearm

during intermittent rhythmic contraction

but the maximum level was still achieved

in the immediate post-contraction period.

All of these data suggest a balance between

(chemical?) factors tending to dilate the

blood vessels during contraction and an

opposing (physical?) factor which tends to

diminish blood flow.

Even at relatively low levels of rhythmic

exercise there is always some post-contrac-

tion hyperemia suggesting that dilator in-

fluences persist beyond the period of overt

activity.7677

Plethysmographic measurement of total

blood flow through a muscular segment of

a limb in man or arterial or venous flow

measurements in animal experiments give

no clue about possible redistribution of the

circulation within the tissue. Since Krogh78

demonstrated an increase in the number of

patent capillaries in active muscle, many

attempts have been made to estimate the

magnitude of and changes in the effective

or nutritional circulation. Ketys tissue

clearance technique provided one of the

first practical estimates of the effective

flow. Such clearance data#{176}and other evi-

81 suggests that effective flow may

be modified independently of total blood

flow. The quantitative relationship between

the effective blood flow and the tissue need,

as in the exact repayment of prior de-

ficiency,10 contrasts with the repayment of

total blood flow debt which ranges from50 to 200%.s2 Local application of heat,67 or

arterial infusion of certain drugsol can force

clearance, i.e. blood flow through vessels

which permit exchange, to levels which ap-

parenfly exceed the tissue need. The steady

state relationship is most dramatically dem-

onstrated by an exactly compensatory

period of sub-normal clearance following

withdrawal of the forcing stimulus. These

findings at least imply a depletion of some

local dilating substance during the period

of augmented clearance, and its repletion to

control level. Clearance of Na24 from

muscle increases during moderate exercise

and returns to normal immediately on re-

laxation. With maximal, fatiguing exercise,

clearance may remain elevated for some

time after the muscle is at rest.83 Direct

comparisons show that percentage increases

in the post-contraction hyperemia meas-

ured as total flow is much greater than

when measured by clearance.8 These data

also suggest that circulatory readjustments

in active skeletal muscle tend to guarantee

the exact balance between effective blood

flow and the immediate needs of the tissue,

but that total blood flow changes are less

precisely adjusted to the needs of the tissue

and are frequently greater than required.

Apparently excess blood flows through a

by-pass circulation which can not modify

the effective blood flow.

How and if central or humoral factors

alter effective blood flow in active muscle

has most recently been studied by Hir-

vonen and Sonnenschein.8 They measured

both the force of contraction of intermit-

tently stimulated muscle and the blood flow

when the latter was modified by central

influences. The profound decrease in total

flow during stimulation of the sympathetic

constrictors or during intra-arterial adminis-

tration of appropriate doses of the catachol

amines is accompanied by approximately

parallel decreases in the mechanical con-

traction force of the muscle. Stimulating

the autonomic vasodilator system failed to

increase either the total blood flow or the

strength of contraction. Thus, responses of

the vessels in active muscle differ from

those in resting muscle to a large extent

because of the enhanced relative impor-




tance of action and distribution of local

vasodilator substances compared with the

sympathetic vasoactive fibers. In any

event, the locally produced dilators can

apparently achieve maximal perfusion of

the effective circulation in muscle unless

external factors diminish the gross blood

supply to the area.

Results of experiments in several labora-

tories268081 make it clear that the two

circulations through muscle are independ-

ently, or at least differentially controlled.

The cholinergic dilator fibers act almost ex-

clusively on the by-pass circulation, and do

not influence effective blood flow. Folkow8#{176}

suggests that there is actually a relaxation

of arterioles proximal to the terminal vascu-

lar bed which brings a greater than normal

volume of blood at a somewhat higher pres-

sure to the muscle. Since the pre-capillary

sphincters monitor a normal flow into the

effective circulation, an increased perfusion

of the by-pass results. Subsequently, when

the muscle contracts and the pre-capillary

sphincters relax, a more adequate perfusion

of the effective circulation is assured. This

mechanism, and the dilatation of the proxi-

mal arterial segments as suggested by

Hilton29 tend to assure an almost adequate

blood flow during activity. However, in

maximal, fatiguing contractions, in spite of

these mechanisms, effective blood flow

can no longer keep pace with the demand

and a post-contraction hyperemia of the

effective circulation results.

How muscle circulation changes during

prolonged physical training is still not com-

pletely clear. Although resting blood flow

remains unchanged throughout prolonged

periods of intensive training, the immediate

post-contraction hyperemia in a trained

muscle is significantly decreased.888 These

findings have been interpreted as evidence

of an extra increase in blood flow through

the trained muscle during the period of

activity. This long range effect of training

has been confirmed by Rohter and his co-

workers8 who measured the actual rate of

blood flow in a muscle doing standardized

rhythmic exercise at weekly intervals dur-

ing a 7-week-period of intensive training;

and during a subsequent period of detrain-

ing. Resting blood flow through the fore-

arm remains unchanged throughout, but

there is a significant increase in the exercise

blood flows during training. As yet, the in-creased blood flow cannot be partitioned

between the effective and shunt circulation.

However, in direct histological studies

Petr#{233}n9#{176}found the maximum number of

capillaries which can be opened is sig-

nificantly greater in muscles taken from a

trained animal rather than a normal. Per-

haps the pre-capillary sphincters in

trained muscles relax at a lower level of

local metabolites; indeed the whole ques-

tion deserves further intensive study.

In muscle, exercise is a potent vasodilat-

ing agent which for the most part serves to

keep the effective blood flow at the appro-

priate level at each moment. Long range

training of muscle can increase the mean

level of total blood flow through exercising

tissue, however, the mechanisms are not

at all clear. Even with respect to the ad-

justment of the effective circulation in the

contracting muscle there is still some ques-

tion concerning the nature of the agent re-

sponsible for the relaxation of the pre-

capillary sphincters. Conflicting evidence

concerning many individual metabolites has

been set forth, but at the present there is

no agreement about any one of them. At

present, it can be said that there is appar-

ently some locally produced chemical sub-

stance with dilator effect on the local circu-

lation so adjusted as to keep pace with its

rate of formation in the active tissues.

Several studies suggest that the vasodilator

substance can move from ischemic tissue

into the blood stream to be distributed

throughout the body to decrease local re-

sistance in remote areas.91#{176}2

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SUPPLEMENT 677

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SUPPLEMENT 679

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1963;32;671PediatricsChester Hyman

"THE CIRCULATION OF BLOOD THROUGH SKELETAL MUSCLE"

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