Veins and venous tone

Review

Veins

and

venous

tone

Bjiirn Folkow, M.D. Stefan Mellander, M.D. Giiteborg, Sweden

mhe cardiovascular system has many 1 facets, each of which may spellbind an investigator. Thus, to a cardiologist it consists of the Heart, to which there happens to be connected a system of tubes, justified mainly because it allows the output to return to the heart. To the expert on peripheral circulation it consists of a fascinating system of tubes for flow studies, wherein, incidentally, the pressure head is said to have something to do with the heart. Again, to the investigator who is biophysically minded it is an inexhaustible source for the creation of stunning formulae of profound beauty and doubtful applicability. Lastly, to the expert on capillaries it is a vast and delicate exwhich unfortunately change membrane, has to be connected to other, far duller cardiovascular sections for providing the flow needed to put the all-important exchange into action. The only common denominator of these superspecialists would if probably be their raised eyebrows someone dared to suggest that the veins might be important, too. However, such a vein enthusiast has indeed very good reasons for his suggestions, as will be discussed below. These slightly caricatured specialist viewpoints are all somewhat out of foCLls, hut, in ;I ~‘a)‘, the expert on capillaries ma\ claim to be less far away from the truth than the others. This is because, after all,

it is across the capillary walls that the key function of the circulation-the establishment of a dynamic contact between the external and internal environment-is made possible by the maintenance of a capillary blood flow. Ultimately, all other cardiovascular compartments serve to adjust this capillary flow to a level adequate for establishing tissue homeostasis. However, it is equally true that if any of these other “regulatory” cardiovascular compartments should fail, the whole performance of the circulatory system would rapidly deteriorate. Indeed, this would also be the consequence if the veins failed, although admittedly, to please the cardiologists, more quickly if the pump failed. However, it must be admitted at once that the function and control of the venous system has been very little studied and understood even up to this very day. In evaluating to what extent cardiovascular researchers have since Harvey’s days, paid attention to venous function, as compared with other aspects, one can only conclude that the negligence has been monumental, and that the physiologists are mainly to blame. Yet one of William Harvey’s most outstanding pupils, Richard Lower, appears to have had a surprisingly good grasp of the veins and their function, realizing their profound importance in cardiovascular performance, in connection, for example, w4th c-hanges in their tone

l:ron~ the ~)epartment of Physiology. University of Gijteborg, S<,me of the studies discussed were supported in part by Grant “f .i\viation Medicine, and by Grant H-5675 from the Cnited Received for publication Feb. 27. 1963.

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GSteborg, Sweden. AF 61 (052).286 from the CTnited States States Department of Health, Education

Army School and Welfare?.

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or upon exposure to hydrostatic factors. NOW and then during the subsequent centuries excellent studies dealing with one aspect or another of venous function have appeared, but they are indeed rare flowers on the now enormous tree of cardiovascular research grown during the course of the last three centuries. Most investigators seem to have shuddered at the thought of studying the veins, and here methodological difficulties, r&al or imagined, must have played a dominating role. Presumably, this has tended attitude” and to create a “sour-grape hence a perpetuated negligence, now and then possibly stirred by vague feelings of bad conscience. On the other hand, intense effort has been devoted to such aspects as the function and control of the heart, the Windkessel function of the arteries, the regulation of the flow resistance, and the blood pressure, etc. The early investigators certainly believed that the capillaries also deserved much attention, but these were apparently often considered to be too difficult to study. However, at this point the interest in the functionally different cardiovascular sections generally seemed to have reached its limit. To exaggerate a little, the veins were too often considered as admittedly necessary but certainly dull draining pipes, deserving medical attention mainly as suitable places for taking samples or for giving drugs. It is, in fact, only during the last few decades that it has been more generally realized that venous function is indeed so important in cardiovascular performance that it deserves much more intensified research efforts. For the discussion of the functional significance and the control of the veins, it might be advantageous to give some simple introductory definitions bearing on the functional differentiation of the rardiovascular system. \Ve owe to William Harvey the great discovery that the flow of blood proceeds along two main circuits, coupled in series to form a closed system: the pulmonary one for the direct contact with the external environment, and the systemic one for contact with the tissues, the two being perfused by the right and the left sides of the heart, respectively.

Am. licart 1. Scptcmber, 1964

Although the systemic circulation conof “parallelsists of a great number vascular circuits differentiated coupled” to suit the demands of their particular tissues, the pulmonary vascular bed is in this respect fairly homogeneous. HOWever, each individual circuit, pulmonarlor systemic, can, in turn, be divided into functiona number of “series-coupled,” ally differentiated sections, which may be labeled the pump, the Windkesscl vessels, ihe resistance vessels, the sphincter vessels, the exchange vessels (i.e., the true capillaries), the shunt vessels (present in some tissues only), and, last but not least, thr capacitance vessels, connected to the filling side of the other half of the pump. These functionally based definitions (for details see Folkow’ and i’VIellander?j do not, however, coincide exactly with the morphologically delineated sections. E‘or instance, the resistance vessels comprise a major precapillary section (small arteries, arterioles, etc.) and a minor postcapillary section (venules and small veins). The capacitance vessels do largely correspond to the venous sections of the systemic and pulmonary circuits, but not entirely, because the heart itself and also the other vascular sections subserve a capacitance function to some extent. In any case, this makes it quite clear that the venous system must be of great importance in cardiovascular performance, both in contributing to the resistance junction and in being a dominating element in the capacitance function. If we consider first the resistance function of the veins, their quantitative contribution to flow resistance is quite small compared with the precapillary resistance section. However, in this particular case, functional importance can by no means be evaluated only in terms of magnitude. lt is important to realize that the capillaries are situated between two variable resistance sections that can be adjusted by means of their smooth muscles. The cardiovascular s)*stem is so designed that arterial and central venous pressures are normally maintained at fairly constant levels. Therefore, variations in blood Aow will be primarily due to changes in the total resistance of the vascular bed, whereas adjustments of capillary mean hydrostatic pressure will depend upon changes in the

Veins and venous tone

ratio between the precapillary and postcapillary resistances. This latter fact must not be forgotten, since, beside the nutritionally all-important di$usion exchange, a jiltration exchange also occurs across the capillary walls. This, in turn, is to a great extent responsible for the important partition of fluid between the extravascular and intravascular spaces. Thus, if the ratio of precapillary to postcapillary resistance is increased, mean capillary hydrostatic pressure will fall, leading to a net absorption of extravascular fluid to the circulation, and vice versa to outward filtration when the ratio is decreased. Changes in this ratio can be expected, therefore, to constitute one of the main physiologic variables in the filtration exchange, and such changes can be brought about by appropriate adjustments of the smooth muscle activity within the two resistance compartments. In altering this highly important ratio it is obvious that the denominator, the venous resistance, may theoretically exercise as equally profound an influence as the numerator, the precapillary resistance, hence, the great potential importance of the veins also in the resistance function of the vascular bed. Furthermore, the venous system is of dominant importance for the capacitance &n&on of the circulatory system, largely because it contains sotne 65 to 75 per cent of the entire blood volunle.3Js At the same time that it forms the indispensable return route from the capillary section to the heart, it constitutes a voluminous and highly variable blood reservoir or cardiac “forechamber.” It normally appears to be very exactly regulated to meet these demands; even minor adjustments can profoundly affect the filling and, thus, the output of the pump. In their capacitance function the veins of the different circuits subserve, as a unit, the cardiovascular system as a whole rather than any local needs of their particular tissues. It is, for instance, by reflex increases in that a promptly acting, venous “tone” and, in acute situations, very adequate, compensation for loss of blood can be achieved. This capacitance response of the veins can thus be said to form a “first line of defense,” acting in synergism with a pump adjustment for maintaining an

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adequate supply of blood to the tissues. AS a “second line of defense” to combat IOSS of fluid from the circulatory system, concomitant adjustments of the precapillary to postcapillary resistance ratio may be mentioned. When this ratio is increased, a mobilization of tissue Allid into the vascular compartment will ensue, a more slowly acting but nevertheless most important compensatory mechanism. In this type of adjustment the veins are engaged m their role of postcapillary resistance vessels, and such a regulation also serves the cardiovascular system as a whole rather than the immediate local tissue demands. An important “thirrl line of defense” against loss of fluid from the circulation is, of course, constituted by the renal conservation of fluid, but this type of compensation is beyond the scope of the present survey. It is to be expected that the venous system, with its above-mentioned two main functions, serving the circulatory system as a whole, will demand a centrally integrated control for satisfactory performance, and that only minimal interference by local regulatory mechanisms can be tolerated. In approaching the problem of how the venous system is in principle controlled under normal circumstances, one has to take into consideration (a) the functional characteristics of its smooth muscles, (b) the superimposed nervous and hormonal influences, (c) its reflex and central and also (d) the cooperation control, versus competition between neurogenic mechanisms and local factors which influence venous tone. Our knowledge in this field is still fragmentary, to a great extent because the venous system really is difficult to study, at least in quantitative terms. However, quantitative studies are indeed required for a full understanding of the integrated function of the veins. Scattered information, obtained from studies using different techniques in many laboratories during the last few decades, may permit some generalizations concerning the main principles of venous control. How this control may subserve the cardiovascular system as a whole with regard to the regulation of total blood volume, the distribution of available blood volume, the

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return,” etc., will adjustment of “venous be briefly outlined here. No comprehensive review of all the previous literature in the field will, however, be given; for a more complete reference list the reader is referred to other papers.“,‘-” In general, the control of any cardiovascular section tends to be organized at different levels, more and more complexly built extrinsic mechanisms being superimposed on the local factors. The very basis for functional differentiation is, of course, the special design characteristics of the different cardiovascular sections, which, in general terms, are well fitted for the functional demands made upon them. This general principle is certainly true also for the veins. Their thin, distensible walls and wide-bore dimensions, with consequent low resistance and large volume, make them well suited for their capacitance function and their special task in resistance control. It is true that the great distensibility of the veins has considerable drawbacks in some respects, notably in man because of his erect posture, in which case the largest fraction of the venous system is situated below the level of the heart and is exposed to coilsiderable hydrostatic forces, with consequent risks of the pooling of large amounts of blood, thus interfering with venous return. Man’s special situation in this respect is, however, an exception rather than the rule within the animal kingdom, since in the majority of species the heart is placed fairly low in relation to the greater part of the venous system, so that hydrostatic factors thus only slightly impair venous return. Rut, as will be discussed below, fairI\, effective countermeasures have been developed so that even in man venous return is not too badly impaired in this respect. The vascular smooth muscles, as regards their basic characteristics, are evidently not always functionnll~~ unifornl, independent of their location \vithin the WSCIJlar bed. III fact, a c.onsiderabte differentiation -more quantitative than cluatitative in nature-~~~seenis to have taken plaw between the various vascular sections. Smooth muscles often exhibit autolllilticity, a m\,ogenic “tone,” which let us first briefI>. consider as to its extent and toca-

tion within the vascular bed. 'I‘o particularize, an evaluation of its extent within the consecutive vascular sections of one and the same circuit shows that it seenis to beconle gradually nlore dominant the closer the approach to the capillary level. This inherent smooth muscle activity appears, in fact, to be concentrated mainI> in the small precapillary resistance z~ssels and, to a definite, although hemodynamicall? less significant, extent, also in the smallest postcapillarqr vessels (venules).“’ I,et us start, therefore, at the “wrong end” and first deal briefly with solve principles of the control of the resistance vessels, because in many respects it is, for esample, a contrast to that of the capacitance vessels. 1 t appears that the very basis of the “activeI!-” maintained flow resistance is a consequence of such an inherent smooth nluscle activity. It establishes a basal zlascular tone, which in general seenls to be nlore pronounced the wider the range is between the resting and the maxilllal metabolic demands of the particular tissue. This locally established resistance tone creates a kind of “blood f-row reserve” which is easily mobilized whenever CICcumulation of so-called vnsodilator metabolites inhibits the vascular smooth muscles.]’ L%dditionatIy, in nlost circuits the m!vgenie activit) of the resistance vessels can be nlore or less strongly reinforced by the action of centrally controlled constrictor fibers. However, in the intact resting organism it seems as though the normall>, verl* low vasoconstrictor fiber discharge, as compared to the myogenic activit)-, contributes fairly- little to the to/al flo~v resistance. Otherwise it is difficult to explain \vhy the flow resistance in the major parallel-coupled circuits decreases fair-l\. little, virtualI\not at: all in SOJIIC circ&ts, \Vtlen their vessels are acuteI!. deprived of their constrictor fiber influence, provided that factors such as the pressure head are kept essentially- unchnnged.~~ The addition of \Tasoditator drugs or Iljctat)olitrs, 011 the other hand, (x11 in c.ert;lin of thes;cs circuits prxducr ;I ~roio~i~~tl i;lll iii their tlo\\, resistance. Such ;L l)rinciple of :L prinlaril\. local control of the resistance vessels in most s\3tclnic. circuits see,lls 10 be fairI>, logical, &ice these vcsscts Ill;linl\. subserve the nutritional blood suppt>~ (if

lTeins and venous tone

the tissues. This by no n1e;ms denies the fact that in states of emergency the superimposed constrictor fiber influence, which in Illany circuits is potentially very powerful, can produce a drastic restriction of flow upon increased sympathetic discharge. Here it should be remembered, however, that the supply of constrictor nerves seems to be more pronounced the less vitally important and the less sensitive to ischemia the respective tissues are. Therefore, in states of a failing cardiac output, for example, an intensified constrictor fiber discharge will direct the blood flow in the first place to the central nervous system and the myocardium; this is a kind of centrally governed rationing of supply in time of need. In contrast to these principles governing the control of the jlow resistance, wherein a myogenic activity appears to be a fairly dominating feature, the situation on the venous side is strikingly different.lO In all probability there is some myogenic activity present here as well, but it is largely confined to the venules on1y.13s14 Thus, when considered in terms of its capacitance function, venous control is not dependent on such a locally originating mechanism but appears to be almost entirely dominated by its extrinsic nervous ~upply.‘~ As will be further discussed below, the vasoconstrictor fiber control on the venous side is so dominating that it is able to overrule other types of influences, such as local vasodilator factors, to a considerably greater extent than that which is possible with regard to the precapillary resistance vessels. One may ask why the veins show such a contrast to the precapillary resistance vessels in the matter of the balance between local and nervous mechanisms. It ma\’ be recalled that another functionally specialized vascular section-the arteriovenous anastomoses of the skin-is characterized by an almost complete lack of inherent smooth muscle activity, but is, instead, directed by a powerful and dominating vasoconstrictor fiber influence.15-” It appears as though the vascular smooth muscles of this specialized section, as well as those of the venous capacitance section, have become differentiated in a direction similar in the organization of their control

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to that of the intrinsic smooth muscles of the eye, or, more extremely so, the skeletal muscles. A shift from a mainly local effector control to a centralized one is the natural development, of course, whenever a particular function has to be central13 integrated to subserve the organism in the best way. This is the case with both venous capacitance function and the function of the cutaneous arteriovenous shunts. The veins here subserve the integrated cardiovascular performance as an adjustable “forechamber” for maintaining the pump output at an adequate level, and the arteriovenous shunts subserve the centrally integrated regulation of temperature of the organism. Another difference between the capacitance and the resistance vessels of any given vascular circuit is revealed when they are both exposed to a gradually increased vasoconstrictor fiber activity..* If the stimulation frequency is plotted along the abscissa for a stepwise increase in the rate of constrictor fiber excitation, and the effector response is plotted in percentage of the maximal effect along the ordinate, it is found that this frequencyresponse curve for the capacitance vessels is quite clearly placed to the left of that for the resistance vessels. In other words, the curve rises more steeply at lower frequencies but levels off at a lower frequency range than does that for the resistance vessels. This implies that even if the gradual reflex increase in sympathetic discharge is entirely uniform in rate, e.g., in response to bleeding, the constriction of the capacitance side of the vascular bed will tend to precede that of the resistance side. Such an adjustment compensates, of course, more adequately for a loss of blood than does a primary restriction of the blood supply. The flow resistance will increase more strikingly first when additional bleeding causes more intense sympathetic discharge and the neurogenic capacitance depot mobilization begins to reach its limits. Such a difference in the responses of the capacitance and resistance neuroeffectors may be simply and adequately explained by the difference in the wall to lumen ratio between arterial and venous vessels.’ In general, with an increase in neurogenic resistance another important phenomenon

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iucrease in the follows, viz., ;I progressive ln-ecapillary to postcapillary resistance ratio and a consequently intensified mobilization of interstitial fluid to the circulatory system.2 It is interesting to note in this connection that some recent studies in this department indicate that the most sensitive baroreceptor-determined modulation of flow resistance in the major systemic vascular circuits appears to take place within the skeletal muscle area, at least in cats.18Jg In combination with such reflex shifts in muscle blood flow resistance, especially pronounced shifts seem to occur in the precapillary to postcapillary resistance ratio. This causes relatively large variations in the mean hydrostatic capillary pressure in the skeletal muscles and thus in a filtration transfer in this particular tissue.lg It might be emphasized that the skeletal muscles form one of the few tissues in the body which is substantial enough to allow for any more considerable drainage of interstitial fluid into the circulation and has, conversely, a high capacity for lodging the fluid during outward filtration from the vascular compartment. In the splanchnic area, on the other hand, the precapillary to postcapillary resistance ratio generally does not seem to be more significantly altered in connection with more prolonged neurogenic changes in resistance. Therefore, neurogenic adjustments of the vessels of this area, which in other respects is most important hemodynamically, appear to affect its filtration equilibrium only insignificantly under normal circumstances.1g The results of the above-mentioned studylg may suggest that the relatively preferential reflex constrictor fiber adjustment of the precapillary to postcapillary resistance ratio taking place in the skeletal muscles is not primarily designed for maintaining total flow resistance at a given level-as it here contributes relatively little except during more intense sympathetic activity. It seems to be rather more important as a reflexly directed regulator of the distribution of fluid between the intravascular and extravascular compartments of the extracellular space, i.e., helping to maintain the plasma volume constant. Here again the veins, in their role of postcapillary resistance vessels,

Am. Heart J. Sefitember, 1964

seem to participate in it centrally. directed homeostatic mechanism. There is evidence to indicate also that the “hormonal link” of the sympathoadrenal system usually has an effect on the zlenOu$ system similar to that of the constrictor nerves. Epinephrine, which in low concentrations is a potent dilator of the resistance vessels in skeletal muscle, thus appears to exert a pure constrictor action on the corresponding capacitance vessels.2 In general, however, the constrictor effects of “physiologic” amounts of the catecholamines, whether released by activation of the sympathetic adrenal medullary nerves or infused into the blood stream, are far weaker in extent than those exerted by the direct vasoconstrictor fiber innervation.? In this connection, it might be interesting to note that some pharmacologic agents seem to produce different response patterns in the resistance and in the capacitance vessels of the same tissue. Thus, whereas acetylcholine2tZ0 and isopropylnoradrenaline are potent dilators of both these sections, histaminez2 and hydralazinezO almost exclusively dilate the resistance vessels, and nitrites,?O on the other hand, have their main dilator action on the capacitance vessels. Again, angiotensin has been found to exert a much more pronounced constrictor effect on precapillary than on postcapillary vesselsX3 The dual control of the peripheral vascular bed, exercised by locally produced metabolic factors, on the one hand, and by the centrally governed sympathetic constrictor fiber system, on the other, implies that, in many situations, the “tone” of the vascular smooth muscles will depend on a competition between these two opposing forces. For instance, it has been shown that in skeletal muscle the precapillary vessels (precapillary resistance vessels and especially the sphincter vessels) are more sensitive to the dilator metabolites than are the postcapillary vessels (postcapillary resistance vessels and main capacitance vessels} when both are simuitaneously exposed to a constrictor fiber influence.24 The functional significance of such an organization is not immediatelv obvious in the resting equilibrium. It will become definitely apparent, however, in situations in which there is concomitantly-

Veins and venous tone

in extreme accumulation of vasodilator metabolites and a pronounced increase in the constrictor nerve fiber discharge. Such situations are met with, for instance, in hemorrhagic shock with a reduced supply of blood to the tissues,24z25 or during exercise with increased muscle metabolism.?6 This general tendency of the metabolites to overrule the neurogenic tone in the precapillary section helps to maintain a nutritional flow of blood relative to the prevailing local metabolic demands. It further tends to distribute the available blood stream over a greater capillary surface area, which allows a more uniform capillary exchange within the tissue. The relative dominance of the centrally directed constrictor fiber influence on the capacitance vessels, on the other hand, will in such situations prevent peripheral pooling of blood and help to ensure the maintenance of an adequate “venous return” by mobilization of blood from the constricting veins. In most cases of such an accumulation of vasodilator metabolites the normal ability of the constrictor nerves to maintain or even to increase the precapillary to postcapillary resistance ratio can largely be upheld, thereby allowing for an absorption of extravascular fluid if the constrictor fiber activity is intense enough.2*1g It is only in extensive muscular work or under exceptional circumstances, for example, late in the course of hemorrhagic hypotension, that a shift toward an outward filtration can occur. The precapillary resistance response to sympathetic activation then becomes almost abolished, whereas the postcapillary resistance response, i.e., that of the veins, is somewhat better maintained. This will lead to a decrease in the precapillary to postcapillary resistance ratio, a consequent net rise in capillary pressure, and, hence, an outward filtration.24J5 It is noticeable that at such an advanced stage of shock the sympathetic nerves are no longer able to act in their normal compensatory manner for combating the circulatory insufficiency, but may, in fact, help to produce a progressive derangement because of such a continuous transcapillary loss of fluid from the circulation. Again, the functional characteristics of the veins and their

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specialized control are of great importance in this complex integration. As mentioned above, the great distensibility of the veins may in some situations be disadvantageous to the cardiovascular system, for example, in the erect position, unique to man and some primates, The major circulatory changes which occur when a shift is made from the supine or four-limb position to the erect position are connected with the great hydrostatic load that is suddenly exerted on the capillaries and the large fraction of the distensible venous side that is then situated below the level of the heart. Several counteracting mechanisms are, however, brought into play to decrease the tendency of transcapillary loss of fluid and venous pooling of blood. In the abdomen, the hydrostatic “tissue” pressure of the soft internal organs is likely to be closely similar to that produced if the abdomen were filled with fIuid.27-‘s This creates an extramural pressure that almost exactly balances the raised intravascular pressure. In the extremities, venous pooling is, of course, to some extent similarly prevented in this case by the external support exerted by rigid enclosing structures, such as skeletal muscle, fasciae, etc. Moreover, valves which are here situated at strategic points in the veins not only prevent backflow, but may also interrupt the continuous column of blood, at least intermittently. With continuous venous flow, on the other hand, the valves are open and then the hydrostatic load of a continuous column of blood is transmitted to the lowest parts of the circulatory system. An important countermeasure here is the pumping action of contracting skeletal muscles which will temporarily diminish the hydrostatic increment of venous and mean capillary pressures and thereby help to counteract pooling of blood and outward filtration. Also of utmost importance during postural changes is the action of the vasomotor nerves, which mediate reflex constriction of the capacitance vessels in the erect position, opposing the distending forces in the dependent regions.2~7~30-32Moreover, the reflex activation of the vasoconstrictor nerves accomplishes a certain mobilization of reservoir blood from other less dependent regions, both in the lesser and the systemic

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SO tl~t central venous prescirculation, sure and “venous return” are not interfered witI1 too nluch. The inlportancc of the v;~somotoi- control of the capacitance vessels in this connection is readily understood from the pronounced orthostatic symptoms seen in subjects deprived of their sympathetic innervation by surgical or pharmacologic methods. Protection against too serious a rise in capillary pressure in dependent regions during erect posture is also accomplished on the precapillary side. For instance, the precapillary to postcapillary resistance ratio will become increased, partly because of the action of the sympathetic nerves, and partly because of probable intensification of the myogenic automaticity of the precapillary resistance vessels. Such a facilitation of their myogenic activity may be expected to occur wherever their transmural pressure is raised in dependent vascular areas.“‘J3 Even more important in this connection is the effect of the reinforcement of the myogenic automaticity on the precapillary sphincters which occurs when transmural pressure is raised. This leads to closure of a number of sphincters so that blood flow is “shunted” through fewer capillaries than normally. With this, the capillary surface area available for flow, and, hence, for filtration exchange, is reduced. The “functional” capillary surface area in the human foot has been shown to decrease to one third to one eighth of normal on shift of the body to erect posture, and the tendency for filtration loss of fluid correspondingly decreased.33 This is probably one of the most important mechanisms which protects against the formation of edema in dependent regions. Mention has been made of some circulatory adjustments, e.g., during hemorrhage and during postural changes, etc., when a reflex increase in the sympathetic vasoconstrictor fiber discharge occurs. Thus, it seems to be well established that both the aortic and carotid baroreceptors, and also the chemoreceptors, participate in the regulation of both the resistance and the capacitance vessels.9.‘“.3”-3Y Changes in the baroreceptor activity during arterial hypertension and hypotension will thus help to adjust the venous blood capacity in relation to the demands for maintaining

31 df3~~1atc VCI~US returil. U’hethcr Ihc~ influence of this reflex control is entirel\. unifornl with respect to the c~onstrictor fiber discharge to the resistance end the capacitance side of the circulation is so far not known for certain”“; some data 11~~ suggest that this is not necessarily the case, but it is at present premature to give any definite statements. It has ahead) been outlined how the precapillaq7 and postcapillary resistance vessels are reflexly affected to a different extent in various tissues.” However, these differences are not necessarily a consequence of distinct differentiations in constrictor fiber discharge. They may well be a matter ot’ quantitative regional differences in the effector sensitivity to the opposing effects of the constrictor mediator and local vasodilator influences. Reflexes elicited from the low-pressure regions of the circulation might well deserve special attention with regard to the regulation of venous tone,. It has been demonstrated that activation of central venous, cardiac and pulmonary receptors may lead to bradycardia, arterial hypotension, and venodilatation.40-“” \&Te have, however, still no clear evidence as to the quantitative influence of such reflexes on the precapillary and postcapillary side of the circulation. At first sight it might seem to be an attractive hypothesis that such low-pressure receptors, particu1arlJr those activated by distention of the central veins and the atria of the heart, might be more preferentially engaged in the control of the veins. As strategically well-placed receptors they would then be able to adjust central venous pressure and also prevent overloading of the heart by relaxing the venous side of the vascular bed when necessary. However, if such a h~.pothetical preferential reflex engaged the entire venous side, this would also include the postcapillaq. resistance vessels. Then it would at the same time tend to increase the precapillaq- to pOstcapillary resistance ratio. This would, in turn, increase the intravasCII~X fluid volume by causing an “inward filtration,” but this would hardly be rational in the situation. Obviously, hypotheses in this complex field run the risk of being invoked too early, and more experimental work is badly needed before more

Veins and venous tone

definite statements can be made. It is unfortunate that an adequate and, at the same time, selective stimulation of these low-pressure receptors often seems to involve serious interference with normal cardiac performance. It is also very difficult to avoid a secondary interference with the arterial receptor mechanisms. Therefore, hitherto available results of such experiments can hardly be interpreted in quantitative terms with respect to the reflex effects on total flow resistance, precapillary to postcapillary resistance ratio, and capacitance function. Much more could be said about these complex and interesting questions but it would lead us too far away from the point. It is also beyond the scope of the present survey to discuss the interesting finding that cardiac receptors may control the fluid volume of the organism via different renal mechanisms. This problem is discussed in detail by Gauer, Henry and Sieker.46 Beside these examples of visceromotor reflexes, elicited from receptors situated within the cardiovascular system, venous adjustments seem to occur in connection with reflexes emanating from sites outside the circulation. Thus, it has been established that Group III muscle afferents, which probably convey deep pain, produce at the bulbar level a reflex inhibition of the tonic sympathetic discharge, together with a vagal activation. This reflex response leads to bradycardia and to pronounced arterial hypotension which is caused largely by a dilatation of both the resistance and the capacitance vessels.47A similar reflex pattern may also be elicited from what is thought to be similar afferent fibers, emanating from visceral organs in the abdomen.“” It has been suggested that such dramatic changes in cardiovascular dynamics, which thus also engage the venous side, may be responsible for initiating the type of syncope that sometimes occurs in connection with blunt trauma to skeletal nluscle or internal organs. l
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on exposure to cold and exercise30 or to hyperventilation and mental excitation.7 It seemsreasonable to conclude that most stimuli which, by the vasomotor pathways, affect the resistance side of the circulation will concomitantly influence the venous system in a similar direction, but possibly not always to the sameextent. It is evident from what has been said that the vasomotor center in the oblongata medulla, by its spontaneous tonic discharge, steadily modified by the cardiovascular receptors, and sometimes also by other receptors, will be a major determinant of venous tone. As also mentioned, the nervous control may, relatively speaking, be even more dominating on the capacitance vessels than on the resistance vessels, partly because of the fact that their curve of frequency response to sympathetic activation has a different shape, and partly because the veins exhibit far less inherent myogenic activity and are relatively less affected by opposing chemical factors. It may then be questioned whether, beside such a differentiation at the neuroeffector level, special structures might also exist at higher levels of the central nervous system which preferentially, or even exclusively, affect the venous compartment to ensure immediate mobilization of the peripheral depots. As yet, it has not been possible to detect ;my functionally separate i‘venomotor center,” and the vasomotor fibers normally seem to be engaged in certain patterns rather than working selectively. Evidence is now accumulating to show that highly differentiated patterns of response, with regard to reactions of the resistance and capacitance vessels, can sometimes be elicited from centers above the brain stem. To exemplify, it is known that topical stimulation in the hypothalamic sympathetic vasodilator area produces a pronounced dilatation of the resistance vessels of the skeletal muscles 1)~ \vay of sympathetic cholinergic WSOdilator fibers distributed only. to this tissue. The muscle capacitance vessels are, however, not dilated; on the contrary, such stimulations generaIl\. produce :\. definite constriction of the muscle capacitance vessels,4gand also produce tac.hycardia and constriction of both the resist-

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ante and capacitance vessels in most other tissues.50 In all probability, this is due to an engagement of the adrenergic sympathetic constrictor and accelerans fiber system, concomitantly with the cholinergic fibers, to the resistance vessels in the skeletal muscles. As suggested by Abrahams, Hilton and Zbrozyna,51 the sympathetic vasodilator system stems to be engaged in the alarm-defense reaction, which would provide in a moment the all-out increase in blood flow to the skeletal muscles required in such emergency situations. It seems natural that such a dramatic redistribution of blood to the skeletal muscles and the consequent increase in cardiac output calls for a simultaneous constriction of the resistance vessels in other regions and for a neurogenic constriction of all capacitance vessels, including those of the skeletal muscle. Some areas within the cerebral cortex have been shown to exert excitatory or inhibitory influences upon subordinated autonomic structures.16*50 It is believed that the cardiovascular adjustments which can be elicited here are part of more complex somato-visceromotor reactions, associated with the cortical integration of extroceptive impulses and experienced emotions. The central, sympathoinhibitory influence on lower cardiovascular centers induced from the cingulate gyrus’” may be of special interest in this connection, since such dramatic changes can be evoked that it must be assumed that most cardiovascular compartments are involved in the reactions, including the venous system. This cardiovascular depressor response is characterized by an arterial hypotension, peripheral vasodilatation (including also in all probability a generalized venorelaxationj, and bradycardia. These effects can be shown to be due to a powerful central inhibition of the tonic constrictor fiber discharge, emanating from the medullary vasomotor center. The cortical inhibitory influence is mediated through fibers relaying in, or passing through, the depressor area of the anterior hypothalamu@ and the bulbar depressor area.‘8ajO This vascular response pattern is very similar to, or identical with, the depressor response that can be elicited from Group III muscle afferents47 and relays in an

.4m. Heart Scptcmber,

I.

1963

area situated close to this in the bulb. In addition, it appears to be combined with some inhibition of spontaneous somatomotor behavior and of respiration. It has been suggested, therefore, that these limbic structures may be engaged in emotional situations which sometimes lead to emotional fainting, possibly also to the playingdead reaction in some animal species.‘* In fact, the cardiovascular change induced seems to be closely similar to that seen in emotional fainting in man. It is easy to visualize that a momentary intense inhibition of the central nervous constrictor fiber control, not only of the heart and the resistance vessels, but also of the venous vascular compartment, may have drastic consequences. Especially in subjects in the erect position may such an episode of centrally induced, over-all inhibition of neurogenic drive cause complete circulatory collapse, partly because of the ensuing pronounced pooling of blood in peripheral veins. Our present knowledge about the control of the veins is still fragmentary, and, indeed, this is true in regard to their local and reflex as well as central nervous control. We hope that it is clear from what has been said that there is still far more theory than fact. Yet, intensive work in many laboratories during the last few decades has shed much light on venous function, and it is certainly not true that the veins are merely a passive system of draining tubes. On the contrary, the venous system seems to be a vascular section that is at least as reactive and well controlled as any of the other compartments within the circulation. In most situations it is responsive to the same stimuli and in the same general manner as the arterial vessels, but sometimes, by special organization, the reactions of the veins are certainly different quantitatively, possibly also qualitatively in some respects. Such dissimilarities can be attributed to the special characteristics of the venous design, to the venous smooth muscles themselves, to the competitive effects of metabolic and nervous factors on the smooth muscle effecters, etc. In addition, it is not unlikely that the venous side is influenced by fairly specialized reflex adjustments and is engaged in a differentiated way in some

Volwne Number

68 3

Veins and venous tone

specialized nervous patterns. Such possibilities must be kept in mind when venous control is discussed. From what has been said so far it seems only natural that the functional organization of the venous system in several respects is, at least quantitatively, different from that of other “series-coupled” vascular sections. This is so because its two main dynamic functions, the resistance function-of importance in the regulation of intravascular/extravascular volumeand the capacitance function-of importance in the displacement of blood within the cardiovascular system-both subserve the cardiovascular system as an integrated unit rather than any local tissue demands. At our present stage of knowledge, we can only distinguish some of the fundamental principles in regard to venous tone and its control. Intensified study of venous function will probably be frustrating at times, but certainly in the long run, rewarding, since it will give a better understanding of the functional importance of what we might call the “missing link” on our appreciation of cardiovascular integration and, hence, of the system as a whole.

9. 10.

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12.

13.

14.

15.

16. 17.

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REFERENCES Folkow, B.: The efferent innervation of the cardiovascular system, Verhandl. deutsch. Gesellsch. Kreislaufforsch. 25:84, 1959. Mellander, S.: Comparative studies on the adrenergic neurohormonal control of resistance and capacitance blood vessels in the cat, Acta physiol. scandinav. 50:Suppl. 176, 1, 1960. Green, H. D.: Circulatory system: Physical principles, in Glasser, 0.: Medical physics, Vol. 2, Chicago, 1950, Year Book Publishers, Inc. 3a. Wiedeman, M. P.: Dimensions of blood vessels from distributing artery to collecting vein, Circulation Res. 12:375, 1963. Franklin, K. J.: Monograph on veins, Springfield. III.. 1937. Charles C Thomas Publisher. La&s, E. M., and Hortenstine, J. C.: Functional significance of venous blood pressure, Physiol. Rev. 30:1, 1950. 0. H.: Die Wechselbeziehungen Gauer, zwischen Herzund Venensystem, Verhandl. Kreislaufforsch. 22:61, deutsch. Gesellsch. 1956. Burch, G. E., and Murtadha, M.: A study of the venomotor tone in a short intact venous segment of the forearm of man, AM. HEART J. 51:807, 19.56. 8. Folkow, B.: Nervous control of the blood vessels, in McDowall, R. J. S.: The control of the

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circulation of the blood, Suppl. Vol. 1, London, 1956, Wm. Dawson &Sons, Ltd. Bartelstone, H. J.: Role of the veins in venous return, Circulation Res. 8:1059, 1960. Folkow, B., and ijberg, B.: Autoregulation and basal tone in consecutive vascular sections of the skeletal muscles in reserpine-treated cats, Acta physiol. scandinav. 53:105, 1961. Folkow, B.: Role of the nervous system in the control of vascular tone, Circulation 21:760, 1960. Folkow, B., LGfving, B., Mellander, S., and ijberg, B.: The relative importance of vasoconstrictor fibre influence and “myogenic” activity for blood flow resistance in the resting organism. (To be published.) Wiedeman, M. P.: Effect of venous flow on frequency of venous vasomotion in the bat wing, Circulation Res. 5:641, 1957. Wiedeman, M. P.: Response of subcutaneous vessels to venous distention, Circulation Kes. 7:238, 19.59. StrGm, G.: Vasomotor responses to thermal and electrical stimulation of frontal lobe and hypothalamus, Acta physiol. scandinav. 20: Suppl. 70, 83, 1950. Folkow, B. : Nervous control of the blood vessels, Phvsiol. Rev. 35:629. 195.5. Liifving, g., and Mellander, S.: Some aspects of the basal tone of the blood vessels, Acta physiol. scandinav. 37:137, 1956. LGfving, B.: Cardiovascular adjustments induced from the rostra1 cingulate gyrus, with special reference to sympatho-inhibitory mechanisms, Acta physiol. scandinav. 53:Suppl. 184, 1, 1961. ijberg, B.: Effects of cardiovascular reflexes on net capillary fluid transfer, Acta physiol. scandinav. 62:Suppl. 229, 1, 1964. Ablad, B., and Mellander, S.: Comparative effects of hydralazine, sodium nitrite and acetylcholine on resistance and capacitance blood vessels and capillary filtration in skeletal muscle in the cat, Acta physiol. scandinav. 58:319, 1963. Folkow, B.: Effects of catecholamines on consecutive vascular sections, in Ciba Foundation Symposium on Adrenergic Mechanisms, London, 1960, J. & A. Churchill, Ltd., p. 190. Haddy, F. J.: Effect of histamine on small and large iesseipressures in the dog foreleg, Am. J. Phvsiol. 198:161. 1960. Folkow, B., Johansson, B., and Mellander, S.: The comparative effects of angiotensin and noradrenaline on consecutive vascular sections, Acta physiol. scandinav. 53:99, 1961. Lewis, D. H., and Mellander. S.: Competitive effects of sympathetic control and tissue metabolites on resistance and capacitanre vessels and capillary filtration in skeletal muscle, Acta physiol. scandinav. 56:162, 1962. Mellander, S., and Lewis, D. H.: The effect of hemorrhagic shock on the reactivity of resistance and capacitance vessels and on capillary filtration transfer in cat skeletal muscle, Circulation Res. 13:105, 1963. Kjellmer, I.: Studies in cats on work hyper-

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Aviado, I). M., Jr,, and Schmidt, C. F.: KeHexes from stretch receptors in blood vessels, heart and lungs, Physiol. Rev. 35:247, 195.5. 41. .\lexander-, R. S.: Reflex alterations in venomotor tone produced by venous congestion. Circulation Res. 4:49, 1956. 42. Folkow, R., Johansson, B., Mellander, S., and ijberg, B.: ,%pects of the reflexogenic control of the capacitance vessels, Acta physiol. scandinav. 5O:Suppl. 175, 51, 1960. 43. Salisbury, I’. F., Cross, C. E., and Rieben, 1’. i\.: ReHex effects of left ventricular distention, Circulation Res. 8:530. 1960. 44. Neil, E., and Joels, N.: The impulse activity in cardiac afferent vagal fibres, Naunyn-Schmiedberg’s .Qch. exper. Path. u. Pharmakol. 240:453, 1961. C. J.. and Braunwald, E.: ‘4.5. Ross, J,, Jr., Frahm, The intluence of intracardiac baroreceptors on venous return, systemic vascular volume and peripheral resistance. J. Clin. Invest. 40:563, 1961. 46. Gauer, 0. H., Henry, J. I’., and Sieker, H. 0.: Cardiac receptors and Huid volume control, Prog. Cardiovas. Dis. 4:1, 1961. B.: Circulatory responses to stimu47. Johansson, lation of somatic afferents, with special reference to depressor effects from muscle nerves, Acta physiol. scandinav. 57:Suppl. 198, 1, 1962. B., Gelin, L. E., Lindell, S.-E., Sten48. Folkow, berg, K., and Thor&, 0.: Cardiovascular reactions during abdominal surgery, rlnn. Surg. 156:905, 1962. 49. Folkrnv, B., Mellander, S., and iiberg. B.: The range of effect of the sympathetic vasodilator fibres with regard to consecutive sections of the muscle vessels, .\cta physiol. scandinav. 53:7, 1961. 50. I’\n&. B.: Central cardiovascular control, in Handbook of Physiology, Section 1, Vol. 2. p. 11.31, Baltimore, 1960, Williams & Wilkins Compan~~.

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Xbrahams, 1:. C., Hilton, S. M., and Zbrozyna, .\. : :\ctive muscle vasodilatation produced by stimulation of the brain stem: its significance in the defense reaction, J. Physiol. 154:491, 1960. Folkoxv, B., Johansson, B., and ijberg, B.: X ,hTpothalamic structure with a marked inhlbltory effect on tonic sympathetic activity. r\c-ta physiol. scandina\r. 47:262, 1959.