Pharmac. Ther. Vol. 38, pp. 201 to 214, 1988 Printed in Great Britain. All rights reserved
0163-7258/88 $0.00+0.50 Copyright © 1988 Pergamon Press plc
Specialist Subject Editor: E. SCHONBAUMand P. LOMAX
RESPONSES OF THE MICROCIRCULATION HOT AND COLD ENVIRONMENTS
J. GRAYSON Department of Physiology, University of Toronto, Ontario, Canada
1. INTRODUCTION The term microcirculation is used in the present context to describe capillaries, arterioles and metarterioles. Figures 1, 2 and 3 illustrate the microcirculation in the splanchnic area. The detailed configuration varies in different tissues, but the principles are the same. As arteries get smaller they become more numerous and in most tissues the smaller vessels are arranged in networks, arteries being joined to arteries by anastomotic vessels (Fig. 1, from Barlow et al., 1951). In turn the arterial network gives rise to smaller vessels frequently termed arterioles though they are really only small arteries. They are arranged in networks and, unlike capillaries, have smooth muscle in their walls. They respond to neural and to endocrine stimuli and are the main vessels which regulate blood flow into capillaries (Fig. 1). The metarterioles are small muscular arteries which directly link arterioles and venules, but also give rise to smaller vessels and capillaries (Fig. 2, from Zweifach, 1949). In addition there are arterio-venous anastomoses (Fig. 3, from Barlow, 1951) which can shunt blood from the smaller vessels and permit a local increase in blood flow without involving capillary exchange. Then there are the capillaries proper, which are those vessels of the circulation which, being lined only by thin endothelial cells, act as the interface between the blood and the interstitial fluids of the body.
y FIG. 1. Diagram of the vascular arrangement in the stomach wall of man. The mucosal arteries, M, arise from the left gastric artery outside the stomach wall. A, anastomosis between two mucosal arteries; D, Network in glandular aspect of the muscularis mucosa and from which the capillaries of the mucosa arise; A.V.A., arterio-venous anastomosis; P, submucous plexus of arteries and arterioles; S, subsidiary anastomotic channels. Reproduced from Barlow (1951; Fig. 2 Courtesy Cambridge University Press). 201
FIG. 2. Schematic representation of the structural pattern of the capillary bed in the mesentery of the rat. The distribution of smooth muscle is indicated by the dark semicircles in the vessel wall. Simple arterio-venous anastomoses are also shown. Reproduced from Zweifach (1949) with permission.
FIG. 3. Arterio-venous anastomoses in submucosa of the human stomach. Arteries dark, veins light. Similar arrangements occur in many tissues including skin. Reproduced from Barlow et al. (1951) with permission of Surgery, Gynecology and Obstetrics. 2. F U N C T I O N A L A N A T O M Y O F T H E M I C R O C I R C U L A T I O N The capillary network (Fig. 1) is dense and complex. It allows the exchange of fluids, electrolytes, fuels and the raw materials for growth and other functions. Capillaries take up the by-products of metabolism, including metabolically generated heat. The amount varies greatly with the metabolic activity (including exercise) of the body. A near constant blood temperature, however, is an essential feature of homeostasis and it is maintained by a complex system which is probably mainly centrally regulated, with the hypothalamus being the ultimate control center. Capillaries are involved in the process in two ways. Firstly they take up metabolically generated heat from internal organs and mediate the beginning of its convective transfer to the surface of the body. Then in the skin, they lose heat to the environment either by direct conduction or radiation, or when the need for heat loss is greater, by the transfer of fluid to the sweat glands and the evaporation of sweat. Sweat glands have a rich blood supply and depend on the microcirculation for their function. Arterioles and metarterioles are larger than capillaries. They are usually considered as part of the microcirculation although the larger arterioles may be just visible to the naked
Microcirculation responses to hot and cold environments
eye. They are important since they give rise to the capillaries and are the main vessels concerned in regulating capillary blood flow. In general arterioles are intermediate in size between capillaries and small arteries. They have walls which contain both muscle and elastic tissue and which are thick in comparison with the lumen size. There is good evidence that arterioles as small as 21 # can constrict in response to norepinephrine or sympathetic activity. They are supplied with alpha receptors (altura, 1972). In some tissues they also have beta receptors (Altura and Zweifach, 1965). At the point of origin of the precapillary vessels it was once thought that innervated precapillary sphincters existed and that much capillary flow was regulated through their action. This is now thought to be unlikely and vessels smaller than 20/~ do not respond to nerve action--nor do venules (Altura, 1981). As we have seen, metarterioles (Fig. 2) are arterioles which, like arterio-venous anastomoses run directly from arteriole to venule. However, they are muscular, innervated and give rise to pre-capillary vessels or capillaries. Arterioles and metartefioles alike contain vascular smooth muscle and exhibit vasomotion--a topic to which I shall return. Mean arteriolar and metarteriolar diameter control capillary blood flow. Arterioles can respond to activity of noradrenergic sympathetic nerves or circulating adrenaline through activation of the alpha or beta receptors. Many arterioles, particularly in the skin, are supplied with receptors which utilize acetylcholine as the neurotransmitter. Since these are involved in the sweat response they are very important in temperature regulation. In addition to neural factors, arterioles may be affected by endocrine factors, such as circulating adrenaline, noradrenaline, adenosine, and many other agents. Blood flow through the microcirculation depends partly on the immediate needs of the tissue in which they exist. It is also very much linked with the broader function of homeostasis. Thus blood pressure, is greatly affected by cardiac output which may be altered by many things--such as exercise. Blood pressure regulation depends on the constant adjustment of total peripheral resistance, which is a function of arteriolar tone. Both neural and hormonal mechanisms are involved. Core temperature is another aspect of homeostasis which, as we have seen, depends on transfer of heat through capillaries to the blood and loss of heat from the blood, a process which also depends on capillary blood flow. There is a clear overlap between the many aspects of homeostasis and it is probable that the main, integrated control, is hypothalamic, although many different effector mechanisms are called into play. 3. DYNAMICS OF THE MICROCIRCULATION AND THEIR RESPONSES TO TEMPERATURE We should consider briefly the dynamic view of microcirculatory tone, as proposed by Chambers and Zweifach (1944) and further elaborated by Zweifach et aL (1944). Zweifach and his coworkers described the phenomenon of vasomotion according to which arterioles are in constant motion between the fully open and fully closed state. The first observations were made in the mesentery but vasomotion has been observed in many tissues since. For example, it occurs in skin and it may clearly be seen in the human nail bed with a simple microscope and indirect illumination. In this region the capillaries are large, in the form of loops, and easily seen. The pattern of flow distribution between loops is constantly changing and there is a clear picture of a continuously altering microcirculatory pattern. A very similar phenomenon was observed by Knisely in the liver as long ago as 1939 (Knisely, 1939). When blood flow through the tissue is low it used to be thought that this was due to an even, steady vasoconstriction of arterioles matched to the supply needs of the tissue. Now we know that vascular tone must be looked at dynamically. Thus, in a state of low blood flow very few of the arterioles in the vascular bed are actually open at any one time. The number open depends on a dynamic pattern in which some arterioles snap open for part of the time but remain fully closed for most of the time. For the most part those arterioles which are patent are fully open and the remainder are fully closed. The
anatomical pattern is not static, each vascular unit is in a constant state of activity and although the number of arterioles open may remain constant for a long period, it is different arterioles at different times. The determining factor is the rate of vasomotion which varies in response to functional need. In a state corresponding to vasodilatation many arterioles are open at any one time and only a few are closed. The periodicity of vasomotion is slow and vascular units remain open for relatively long periods. Again the basis of the perfusion pattern is dynamic and determined by the activity of vascular smooth muscle. We should note that although vascular tone depends on a dynamic pattern of vasomotion, this does not affect total blood flow which is steady and exactly matched to the functional needs of the organ and to the demands of homeostasis. Thus, we have escaped from the classical view of the microcirculation, in which flow was controlled by a fixed alteration in the calibre of arterioles. However, the terms 'vasodilatation' and 'vasoconstriction' are so firmly entrenched in the language that they continue to be used. We must, nevertheless, concede their dynamic basis and recognize that they are, in fact, describing a dynamic state of affairs. 'Vasodilatation' no longer means a steady dilatation of blood vessels, but a dynamic situation in which a greater number of arterioles are fully open at any one time, and less fully closed. It may result from reduced alpha adrenergic tone (as in the skin during warming), from increased stimulation of beta adrenoceptors (Ahlquist, 1948; Green and Kepchar, 1959), or from activation of cholinergic receptors (Ahlquist, 1948). It may also be brought about by a number of metabolic effects, many of them acting directly on the vascular smooth muscle. Thus when p CO2 rises or p 02 falls vasodilatation occurs. Local glucose levels also have marked effect on blood vessels particularly in liver, gut and muscle, (Grayson and Oyegola, 1983). In the skin one of the more important vasodilator effects is brought on by sweating, as already referred to. There are other causes such as the inflammatory response. Vasoconstriction is usually produced by alpha adrenoceptor stimulation, adrenaline (in the skin) or noradrenaline. There are also metabolic effects which may be related to pCO2, pO2 levels, glucose levels and probably many other effects as well. There are also other causes, often related to cold exposure. One such is Raynaud's phenomenon, but a more serious pathological effect is that which occurs in frostbite. The actual interface between the blood and the extravascular tissues is the capillary membrane. Capillaries are narrow vessels, 5 # to 15 p in diameter lined only by one endothelial layer which, either by direct diffusion, or by diffusion through intercellular spaces or pores, permits passage of many substances including water, electrolytes, nutritional raw materials, etc. As I have already indicated, capillaries are also the main vessels concerned in heat exchange--which occurs within the body and between the body and the environment. Many skin capillaries are very near the surface of the body, between the epithelium and the fat layer. Being only lined with endothelium, little resistance to heat flow is offered and a relatively free exchange with the environment is possible in fully vasodilated skin. However, vasoconstriction reduces or even abolishes blood flow in the superficial layers of skin and withdraws most of the circulation to levels protected by fat from the outer world. In man, heat exchange between body and environment mainly takes place through the capillaries of the skin, but in many animals the lungs also play a major role.
4. MICROCIRCULATION AND HEAT EXCHANGE We should not overlook the variable heat production which accompanies metabolism. During sleep a normal adult male may generate as little as 100 kcals per hour; during extreme exercise this may rise tenfold. Normal wakeful activity generates about double the basal rate. The heat input into the blood is thus very variable and this in turn places a highly variable demand on the heat elimination mechanisms of the body. Arising from these facts the view has been stated that core temperature is largely independent of the
Microcirculationresponses to hot and cold environments
external temperature but is mainly determined by the rate of work in the body as a whole (Snellen, 1966; Nielsen, 1969). This conclusion may be partially correct, but the same workers concluded further that, in contrast, skin temperature is independent of work but solely dependent on environment. This is not the whole truth since the skin plays a crucial role in temperature regulation and its temperature is greatly affected by blood flow and metabolic activity (Kerslake, 1972). The nature of the contact with the external environment is of great interest. Its major importance lies in relation to heat loss from the body, which can take the form either of radiation, conduction or convection--or of evaporation of sweat. Under some environmental conditions, however, heat may actually be taken up by the body--for example, when exposed to the fierce midday sun of the Sahara desert. If equilibrium is to be maintained, this extra heat must also be eliminated, usually by sweating. These are all matters which we shall deal with in relation to the external environment and the effect of external heat and cold on the microcirculation. Although I shall be mainly concerned with the skin, environmental temperature changes do, in fact, have an effect in many other tissues. As we shall see, this is partially secondary to circulatory changes in the skin. But there is also a response to the need for temperature regulation for the metabolic adjustment in internal organs. Two facets of temperature regulation are of current interest, namely heat production and heat loss, and their involvement with the microcirculation. Heat production is, of course, an aspect of metabolism and it is much more concerned with the metabolic needs of the body as they related to states of activity than it is with temperature regulation, although there are direct metabolic reactions to heat and cold. All these functions involve the microcirculation. At rest, about 33% of total heat production in man occurs in the splanchnic area (Durotoye and Grayson, 1971), the gastrointestinal tract and liver. There is a similar heat production in the skeletal muscle and skin. The rest is accounted for by CNS, heart and to a lesser extent by lungs, kidneys, etc. (Forbes, 1949). It is a little known fact that the hottest part of the body is not the liver but the lumen of the stomach and upper part of the small intestine which are distinctly hotter than aortic blood (Grayson and Kinnear, 1962; Grayson and Oyebola, 1983). Even the rectum is hotter than the aorta. This heat production has been shown not to be directly due to the digestive or absorptive functions of the bowel, nor can it all be accounted for on the basis of oxygen uptake. The source of the heat is far from clear but the bowel has recently been shown to have important functions in relation to glucose homeostasis and this may have something to do with the total picture. In this respect gastrointestinal functions are not just related to digestion and absorption but are also closely related to those of the liver (Grayson and Oyebola, 1983). Digestion and absorption do, however, have an effect on heat production and bring about an increase in microcirculatory blood flow; but there is also evidence that gastrointestinal heat production can be directly affected by external temperature. A fall in external temperature of a magnitude great enough to lower the core temperature can lead to an elevation in gastrointestinal temperature. It is not clear to what extent this really depends on a rise in heat production, since external cold and a fall in core temperature have been shown in themselves to produce a fall in gastrointestinal mucosal blood flow (by increased stimulation of alpha adrenoceptors). This alone, would lead to a temperature increase since the bowel is at a higher temperature than its blood supply (Grayson and Kinnear, 1962; Durotoye and Grayson, 1971). A reduction in metabolic heat production in response to heat exposure has been suggested as a factor in adaptation to heat, but again, the effect of blood flow change cannot be ignored. When changes in heat production in internal organs occur they produce changes in the microcirculation which may involve both metabolic and neural factors. These direct metabolic responses to the environment are usually slight. This is due to the fact that behavioral adaptations to adverse temperature conditions, be they heat or cold, are highly developed in man and are usually effective in themselves in protecting the body from exposure to the worst aspects of the actual environment.
J. GRAYSON 5. M I C R O C I R C U L A T I O N A N D T H E C O N T R O L OF H E A T LOSS FROM THE BODY
Regulation of heat loss, by both behavioral and physiological means, is the most important method we have for regulating core temperature, whether the challenge is metabolic or environmental. It is more important than adjusting heat production, which is a by-product of metabolism. Heat is lost from the body in two ways: by radiation and conduction from the skin and by sweating. Both functions depend on capillary blood flow and their effectiveness depends on its fine control. H e a t is lost through the capillaries of the lungs to the lung alveoli. It is the most important route in m a n y animals but it is not very important in man. Small amounts of heat are lost in the excreta and saliva, but this is less important. Convection through the blood stream is the main means o f transferring heat from the deeper organs to the skin where blood comes near to the outside world. Conduction through body tissues has its importance but is a small factor compared with the circulation. Convection, radiation and evaporation of sweat from the skin are by far the most important of the physiological means of regulating heat loss (Kerslake, 1972). Radiation and conduction occur in the skin of the whole body. Curiously, neurological regulation is only well manifested in the distal extremities, the lips and the ears. These are the only sites in which heat loss by these means can be regulated by central control systems. In the skin of the rest of the body such regulation is less marked or absent. Thus placing the feet in cold water produces vasoconstriction in the hands and forearms but not in the skin of the abdomen, nor in the upper arm (Fig. 4, from Grayson and Livingstone, 1976). Such alpha receptors as occur in the abdominal skin or upper arm are not innervated-although the abdominal skin does respond to exogenous administration of adrenaline or noradrenaline. The same would seem also to apply to the face. Sympathetic innervation is present in the lips and ears. However, studies in this field are incomplete. The significance of this distribution has not been precisely delineated, but it is probable that during the evolution of sympathetic control of blood vessels, our ancestors were covered with fur in all parts of the body except the distal extremities. The hairy surfaces could not usefully participate in controlled radiative heat loss. Similarly in a cool climate we wear clothing. All this would negate a physiological effect in controlled radiative heat
Pulsations from Right Index Finger Pulp
Pulsations from Deltoid Skin
iiiiiiiiiiiiiiiiilliiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiill FIG. 4. Effect of cold stimulus on the optical pulse recorded from human skin. Upper tracing, right index finger; lower tracing, deltoid skin. The cold stimulus was immersing the other hand and forearm in water at 5°C. The moment of immersion is indicated by the vertical arrow. Time intervals are 1 sec. Reproduced from Livingstone et al. (1978). Courtesy Canadian Journal of Physiology and Pharmacology.
Microcirculationresponses to hot and cold environments
loss from the covered parts of the body. Accordingly, innervated alpha and beta receptors do not appear to have evolved. This does not apply to sweating, for this is a function affecting all of the body and it is mediated by cholinergically innervated sweat glands. Their metabolic activity produces dilatation of arterioles. A number of possible vasodilator agents (including acetylcholine) have been suggested but there is no certain knowledge. There is one interesting possibility with regard to sweating which may relate to the evolution of temperature regulation. If the vessels of all the skin were supplied with active alpha adrenoceptors, it might be expected that during exercise, which leads to widespread vasodilatation, particularly in muscle, vasoconstriction would occur in all alpha controlled areas to preserve peripheral resistance (a hypothalamic mediated response). If the abdominal or upper limb skin were to participate in such a reaction it would undoubtedly hinder sweating in much of the skin when exercising in a warm environment. Bearing in mind that sweating is the only avenue of heat loss available under such circumstances there would be a conflict of physiological interest, so to speak, and temperature might well rise uncontrollably. From the point of view of survival it may be just as well that vasoconstriction of neural origin occurs only in the distal extremities, the hands and the feet, for the distal extremities do not participate in controlled sweating. This is highly speculative but, if true, the relative scarcity of innervated alpha receptors in much of the skin might reflect a genetic adaptation to the need for sweating in heat loss. Figure 7 shows the effect on hand blood flow of raising the external temperature. There is a passive vasodilatation in the hands (and in the feet) until the environmental temperature reached core temperature. This is due to removal of the cold stimulus needed to activate alpha receptors. It is a passive effect (Grayson, 1949). In these experiments there was a brief period of renewed vasoconstriction accompanying the activation of heat receptors. Despite this, core temperature rose slightly and sweating commenced. This brought core temperature under control and the metabolic effects of the sweating produced a further vasodilatation. This served, presumably, to supply the sweat glands with the blood needed to provide the fluid required for sweating. Other experiments show that a similar extra vasodilatation also took place, not just in the distal extremities, but in all parts of the skin involved in sweating. 6. MICROCIRCULATION IN THE COLD Figure 4, to which reference has already been made, compares optical plethysmograph observations on the hand with those in the deltoid skin of the upper arms. It shows clearly that cold induced vasoconstriction is limited to the distal extremities in the normal subject. The cold stimulus was immersion of the feet in cold water. It will be seen that the skin of the upper arm did not show vasoconstriction, indeed there was frequent vasodilatation, presumably a homeostatic correction of total peripheral resistance. As we shall see this distribution of innervated alpha receptors has a great deal to do with the sites subject to frostbite. Microcirculatory adjustment to cold exposure is thus seen to be mainly vasoconstriction limited to the hands and feet with some metabolic increase in heat production in the gastrointestinal tract and, sometimes, in muscle. Shivering is an effective means of increasing heat production in muscle and is elicited by cold exposure. There is evidence that people who live in cold climates shiver more than others. LeBlanc (1969) quotes evidence indicating that the shivering response to cold is more pronounced in the Innuit than in the Kalahari bushman. Then there is the question of nonshivering thermogenesis. This is the term used to describe cold induced heat production by mechanisms other than shivering. The principal tissue which has been identified in the process is brown adipose tissue (brown fat). There can be no doubt that in some animals brown adipose tissue plays an important part in metabolic adjustment to cold (Pag6 and Babineau, 1950; Schrnbaum et al., 1966; Leduc et al., 1969; Himms-Hagen, 1969; Briick, 1970). Brown fat appears to have two actions. One is the direct generation of heat through lipolysis (Smith and Horwitz, 1969), the other J.P.T. 38/2--F
is through the direct release of norepinephrine (Bligh et al., 1971) which has a general metabolic effect on the body. Brown fat is important in many animals and is also probably very important in the newly born human subject. It becomes increasingly difficult to identify in older subjects and its importance in temperature regulation in the adult human is doubtful. As homeotherms, man could not survive either the cold or the heat without the elaborate physiological mechanisms I have outlined. Nevertheless we must recognize that our physiology could not function were we not able to protect ourselves from the extremities of the climate by the making of clothing, fire, shelter, shade, etc. Man's ability to make fire, to make and use clothing and to make shelter are functions which depend on the brain and the ability to communicate with other human beings. They depend equally on the possession of hands with opposable thumbs, and the upright posture which frees the hands for purposes other than walking. These factors permit survival in many parts of the world. Physiological mechanisms, alone, would be of no avail in the Arctic, or indeed, in any part of the world except, perhaps, equatorial regions. Even there behavior plays a big part in survival. In the days before so-called civilization came, the Innuit in the Arctic were already expert in survival in highly adverse circumstances. They had excellent clothing made from Caribou skins, having two layers of fur, one next to the skin and one in contact with the outside air. the Innuit winter dwellings (igloos) were superbly designed with entrances below ground. They were constructed from snow and ice and even the dwellings intended for the whole winter season could be built by experts in a very short time. They were heated by blubber-fueled heaters. The internal temperatures were as high as 26°C. Even with external temperatures of well below -50°C, this temperature was maintained and babies and children could play nearly naked on the Caribou skins which covered the floor. For the Innuit, or anyone who dwells in the severe cold, preservation of adequate circulation to the hands at all times is more important than conservation of heat in the fingers. Figure 5 shows responses to immersion of the legs in cold water of Caucasians, Innuit and Chinese (mainly from Hong Kong). It will be seen that vasoconstriction occurred in the Caucasians, more marked vasoconstriction in the Chinese and no vasoconstriction in the Innuit. Similarly direct immersion of the hand in iced water elicits
34 V 32
FIG. 5. Mean finger temperature changes which occured in Innuit, I, Caucasian, C, and Oriental (mainly Chinese), O, groups when their feet were immersed in water at 10°C. Each vertical bar shows the standard error of the mean value at each reading. The horizontal bar above the time axis indicates the duration of cooling, after which the feet were removed from the cold water and dried. Reproduced from Livingstone et al. (1978). Courtesy Canadian Journal of Physiology and Pharmacology.
Microcireulation responses to hot and cold environments
281 26 24
~ 22 20
~. 18 16 14 12 10
finger into ice
10 12 Time (min)
FIG. 6. The effect on skin temperature of the finger of placing it in iced water at 1°C. The graph connecting the closed circles shows a normal finding in a Caucasian (either male or female) subject. Temperature drops at first, then slowly rises to its initial levels. There is a further fall, which is also followed by a rise---not shown in this graph. The extent and number of these swings is variable, the example shown is, however, typical. This is Lewis' hunting reaction, The line connecting the closed squares shows a typical result in a subject who has been treated with an alpha blocking agent. The initial fall is greatly reduced and very brief. Lewis' hunting reaction does not occur. Most Innuit tested show this type of response. Reproduced from Livingstone et al. (1978). Courtesy Canadian Journal of Physiology and Pharmacology.
Lewis's hunting reaction in Caucasians (Lewis, 1927). This is a phenomenon in which vasoconstriction occurs in the fingers. It is maintained for about 5 mins, then a secondary vasodilatation occurs as the sympathetic nerve endings become blocked by cold. There follows a chain of vasoconstriction and vasodilatation (Fig. 6, from Livingstone et al., 1978). In some Caucasians and in all subjects tested after alpha adrenoceptor blockade, the initial vasoconstriction did not occur and the hand remained in state of vasodilatation even during ice immersion (Fig. 6). In some individuals, the marked vasoconstriction was exaggerated and secondary vasodilatation did not occur. According to Iampietro et al. (1959), American negroes are usually of this type, showing marked vasoconstriction and no hunting reaction. We obtained similar results in American negro soldiers in the high Arctic (Grayson et al., 1972, unpublished). Such individuals are regarded as 'frost-bite prone'. In contrast, most Innuits do not produce marked vasoconstriction in the cold (Brown et al., 1954). Indeed, most Innuit follow the alpha blocked pattern and generally such evidence as is available suggests that they do not have innervated alpha receptors in the distal extremities. This makes the Innuit highly resistant to frostbite and means that the hand can be used at all times even in the coldest weather. This applies even to modern Innuits who, in fact, are seldom exposed to cold in the way in which their ancestors were. It seems, therefore, that this is a genetic adaptation, which is to say that since the arrival of their ancestors in the North, the individual with inappropriate circulatory responses could not survive. Those with sparse sympathetic innervation to the fingers did, and passed on their genes to their progeny. It should, however, be noted that LeBlanc and his coworkers (1960) observed the finger responses of fishermen in the Gasp6 regionof Canada who must work with bare hands in very cold, wet conditions and he found that most of them did not vasoconstrict in the cold. When his work was published, the role of alpha and beta adrenoceptors was not so well understood as today, but his description fits well the concept of a functional alpha blockade. It seems unlikely that this can be genetic and it is probable that such an adaptation to cold can also develop within the lifetime of an individual. We must, therefore, concede that disappearance of functional alpha adrenoceptor activity may be a factor in cold acclimation. The factors involved in the immobilization of alpha adrenoceptors have not been investigated. The Innuit response to cold does not appear to be a matter of individual adaptation. LeBlanc observed that Innuit women and children who no longer lived the old life and
were exposed to no more cold than the average Caucasian, also showed the same responses (1969). We observed adult male Innuit who no longer lived or worked in the cold. They, too, produced responses similar to the alpha adrenoreceptor blocked reactions seen in Fig. 6. It is our view (Livingstone et al., 1978; Livingstone et al., 1983) that the Innuit responses are, at least in part, genetically determined. The same work also showed that some Caucasians, otherwise normal, showed an exaggerated response to cold. They never produced the secondary vasodilatation characteristic of Lewis' hunting reaction. From observing the results of an airborne exercise in the Arctic it appeared that such a response indicates frostbite-prone subjects. Frostbite is a hazard of northern life which cannot be ignored. It is brought about, usually in the distal extremities where alpha receptors are plentiful, by a marked vasoconstriction, amounting to a total cessation of blood flow in exposed hands and feet. It is maintained and leads to total depletion of microcirculatory blood. It would seem that some factor other than alpha adrenoceptor stimulation is involved in the continuing vasoconstriction which occurs with prolonged cold exposure. However this may be, the vasoconstriction is followed sooner or later by gangrene and can proceed to total loss of a digit or even a hand or a foot. Some of the damage occurs after the digit or limb has thawed, since intense hyperthermia occurs in the parts which are still viable. There is a marked increase in capillary permeability in these areas with oedema and swelling leading to thrombosis and circulatory strangulation which increase the damage caused by cold alone. Another kind of cold damage was reported in the 1914-1918 war, namely 'immersion foot' or 'trench foot'. This was usually associated with severe and prolonged chilling of the limb by exposure to cold water. It was not so severe as frostbite since the cold stimulus was less extreme, but tended to be more widespread and less clearly demarcated. It rarely led to loss of tissue but there was usually blistering, ulceration, oedema and muscle wasting. The Innuit, who do not appear to have many functional alpha receptors in the extremities, are very resistant to frostbite. Since alpha adrenoceptor induced vasoconstriction is the first step in the process leading to frostbite the process might be regarded as being initiated by overactive heat conservation mechanisms. The Innuit do not possess or require them and, as we have seen can conserve heat by behavioral adaptation. 7. H E A T A N D T H E M I C R O C I R C U L A T I O N Heat is, in general, a vasodilator. Local heat, applied anywhere on the body, produces a localized vasodilatation. The effect of raising the environmental temperature is illustrated in Fig. 7. When the environmental temperature rose to about 37°C, vasodilatation occurred in the sympathetically innervated parts of the skin. In these experiments no responses occurred in the skin elsewhere in the body since the rest of the skin was already vasodilated. Grayson (1951) showed that the extent of the peripheral vasodilatation produced by this procedure was the same as that produced by sympathectomy. In modern terms the vasodilatation is thus seen to be the passive result of removing the cold induced sympathetic vasoconstrictor alpha adrenoceptor drive. When the temperature was raised above 37°C there was a brief period during which a further vasoconstriction actually occurred. At this stage, although the environment was actually hotter than the core, core temperature had not had time to change. The vasoconstriction may have been physiological, an attempt to keep out the excess heat, or it may have been a sympathetic vasoconstriction elicited by discomfort. In the final stage of the experiment when the environmental temperature was raised even more, activity of the sympathetic nervous system was blocked. This has been shown to be due to a central effect of hot blood on the vasomotor centres. This blocks reflex vasoconstriction and induces a passive vasodilatation. Cholinergically mediated sweating took over the task of keeping temperature down (the cholinergic centres were not blocked by this amount of heating). It was accompanied by further vasodilatation, presumably metabolically mediated, and having the function of supplying the sweat glands with blood.
Microcirculation responses to hot and cold environments
Environmental Temperature - Blood Flow in Skin i
37 - - Rectal Temp. 36.7
. . . . ~. . . .
Temperature of Cabinet - ° C
FIG. 7. In the experiment shown in this graph, the subject was seated in a chamber with the head out, at room temperature, and the right arm also out but placed in a water bath at constant temperature. The cabinet temperature was raised slowly from 10°C to 50°C. Skin blood flow (and skin temperature--not shown) rose to maximum levels at cabinet temperatures of about 36°C. Thereafter there was a slight decline, until the sweating started when blood flow rose to a final maximum level. Note, during the early warming period, rectal temperature actually fell. It rose, however, when the sweating started.
This experiment does not fully imitate the effects of heat exposure such as that which occurs in the desert or in some industrial situations. It does, however, confirm that the vasodilatation which occurs when the body is exposed to temperatures higher than core temperature is of a different nature from that occurring passively at lower temperatures. It does not occur until the core temperature has risen. When that happens the first effect is to block activity in sympathetic vasoconstrictor centres. Then the cholinergic centres responsible for the control of sweating are activated and sweating begins. At the same time vasodilatation (probably metabolically mediated) occurs in the vessels supplying the sweat glands. It is possible, too, that cholinergic vasodilator endings may play some part in the vasodilatation. There is evidence to indicate that stimulation of warm receptors in the skin can contribute to sweating (Randall et al., 1963). The sweating which occurs in the skin of the hands and feet is probably not primarily related to temperature regulation (Kerslake, 1972). However, sweating in the rest of the body is a mechanism for heat elimination and is controlled by a mechanism which produces metabolic changes in the microcirculation supplying the sweat glands. Indeed, the cutaneous vasodilatation which accompanies the increased sweating is considerable. The question of acclimation to heat is of great interest and is still not fully understood. A major component is an increase in the rate of sweating induced by a given heat stimulus. This increases the efficiency of heat elimination in a hot situation and the ability to carry out work. However, there are limits, as we shall see. One effect of the cutaneous vasodilatation which occurs partially as a result of release of vasoconstrictor drive, partially metabolically in relation to sweating, is that there is an overall increase in blood flow to the skin. A maximum sweat rate (more than double the nonacclimated rate) can be achieved in Caucasian males after full acclimation (Kerslake, 1972). Caucasian women would seem to have lower sweat rates to start with than males and to acclimatize less well. The higher sweat rates reported in acclimated males can be maintained only for short periods. Even so a man working under desert conditions at 40°C can lose 1.5% of his body weight per day. He loses both water and salt. It is interesting to note that the unacclimated man loses both salt and water in such a manner that his osmotic balance is not disturbed. His thirst does not reflect the true water loss (however, to drink just water in response to thirst and not
replace the salt would generate an osmotic imbalance). The heat acclimated man on the other hand produces a diluted sweat. He still loses salt, but not so much, and is much more thirsty than the unacclimated man. Salt is a major factor in heat responses. Though not strictly within the purview of the microcirculation, it is a part of the total picture. If normal physiological balance is to be maintained the salt lost must be replaced. This is not always possible and is a limiting factor in the process of acclimation for the essence of acclimation to heat is an exaggerated rate of loss of a diluted sweat. It needs two things: water to make possible the increase sweat rate; and salt. Excess exposure to heat in the absence of acclimation may lead to the chain of events shown in Fig. 8. Indicated first is the physiological course of events, rising skin temperature, vasodilatation, sweating. These processes may be sufficient to control temperature with no pathological problems. But things sometimes go wrong. The events comprising equilibrium breakdown are indicated. First there is heat syncope. This has a strong psychological ingredient and may have no pathological importance, being merely a reaction to the shear discomfort of being hot. Then comes salt depletion. This is a real problem particularly in industrial heat. Salt is lost through sweating and if not replaced leads first to heat cramps, then to heat exhaustion. It can largely be prevented by eating enough salt to replace the loss. Europeans visiting the tropics are often advised to take salt tablets. Workers in hot situations where the sweat rate may be high are also advised to take salt, either in the form of tablets or liquids (hypertonic solutions). Finally there is the breakdown which leads to heat stroke. This begins with a central effect. The hot blood which perfuses the hypothalamus causes inhibition of the centers and leads to cessation of centrally controlled cholinergic sweating. Water depletion and salt depletion follow a period of prolonged sweating, but when the sweating stops the danger is much greater, for now there is no temperature regulation. Core temperature rises until the subject is in a state of heat stroke which is life threatening.
Heat Stress increased heat loss (radiation, convection)
heat transfer from core to periphery
heat loss by evaporation
rising skin ieiperature
further vasolidation and sweating
Equilibrium Breakdown I
I circulatory ~ ' collapse
/ I7 I
i • ] X
heat I exhaustion/
sweating fat gue
I I I I I I I I I I I
~ ~ reduced sweating
rising core tem peratu re
"~.,.. I "~ "~.~. -,,.~.
cessation of sweating
~"~ ~'~'~" ~"~ "" .~ ...
~ heal stroke
FIG. 8. This shows the sequelae of heat exposure. On first exposure to heat stress there are the usual physiological responses which serve to keep core temperature down. Then equilibrium breakdown may occur as shown. Heat stroke is a serious consequence of excessive heat stress.
Microcirculation responses to hot and cold environments
In a tropical situation a high fever such as tetanus or meningococcal meningitis is more likely to produce death through heat stroke than through the illness itself. There are many questions still to be answered in the question of the physiology of heat acclimation. For our present purposes the microcirculation is heavily involved since sweat glands are clearly central to the process and they cannot function without an adequate blood supply. Acclimation to heat is, however, not so important as was at one time thought. It certainly does occur in some situations, its main feature being an increase in sweat response to a given heat stimulus. Strydom and Wyndham (1963) found little evidence of acclimation in the inhabitants of the Sahara desert. They compared troops fresh out from France with a tribe of desert dwellers, and found no difference in sweat rates. The desert dwellers maintained their temperature behaviorally. They kept in the shelter of their tents during the heat of the day, performing their work at night. They also wore long, loose clothing, to protect themselves from the rays of the sun. This behavior pattern is related to the fact that both water and salt are hard to come by in the desert and, as we have seen, an increased sweat rate requires that both water and salt intake shall be increased. The Kalahari Kung-San (once referred to as the 'bushmen'), who live in an altogether different kind of desert do have access to both water and salt. They hunt and work in the middle of the day and they manifest an increased sweat rate. They are, in fact acclimated to the heat and do not need the shade and shelter required by the Sahara desert dweller. There is also ample evidence that white soldiers, both German and British, operating in the Sahara desert during the last war, could also increase their sweat rates. They had access to ample water and salt and by a process of acclimation increased their tolerance of heat (Edholm, in 1972, made a similar observation on a different group of people indigenous to a hot environment). We should, perhaps, observe that widespread vasodilatation in the skin, such as accompanies sweating, has marked repercussions elsewhere. To compensate the total peripheral resistance changes, vasoconstriction occurs in the bowel and inactive skeletal muscle. The heart rate usually rises to help maintain blood pressure. Metabolic heat production may also fall. If it does, it too must bring about alterations in microcirculatory blood flow. 8. CONCLUSION At this stage this is probably all we can justifiably say about the microcirculation in the heat or the cold. I can only conclude with the statement that the processes of temperature regulation intimately involve the microcirculation, under the control of the hypothalamic centers. They are remarkably efficient, but only over a relatively narrow range of environmental temperature. Under most of the environmental conditions which prevail on this planet they could not operate successfully without the ability, behaviorally, to control our environment and to generate a subtropical environment even when conditions are severe. If it were not for this ability it is hard to imagine how humans could survive anywhere. We see, again, that intelligence and the behavior it generates are probably as important to human survival as physiological mechanisms alone. REFERENCES AHLQUIST, R. P. (1948) A study of adrenotropic receptors. Am. J. Physiol. 153: 586-600. ALrURA, B. M. (1971) Chemical and humoral regulation of blood flow through the precapillary sphincter. Microvasc. Res. 3: 273-276. ALrU~, B. M. (1972) Comparative studies on alpha adrenergic receptors in rat blood vessels. Microvasc. Res. 4: 319. ALTURA, B. M. (1981) Pharmacology of the Microcirculation, In: Microcirculation, Current Physiologic, Medical and Surgical Concepts, pp. 51-105, EFFRIS, R. M., SCHMIDT-SCHONBEIN,H. and DITZEL, J. (eds) Academic Press, New York. ALa'URA, B. M. and ZWEIFACH,B. W. (I 965) Pharmacologic properties of antihistamines in relation to vascular activity. Am. J. Physiol. 209: 550-556. BAI~LOW, T. E. (1951) Arterio-venous anastomoses in the human stomach. J. Anat. 85: 1-5.
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