University of Oxford

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1 1 J. Physiol. (1962), 161, pp. 1-2 With 7 text-ftgure8 Printed in Great Britain THRMAL VASOMOTOR RSPONSS IN HUMAN SKIN MDIATD BY LOCAL MCHANISMS BY G. W. CROCKFORD, R. F. HLLON AND J. PARKHOUS* From the Medical Research Council Unit for Research on Climate and Working fficiency, Department of Human Anatomy, University of Oxford (Received 31 May 1961) The vasodilatation which occurs when the skin of the arm is heated by infra-red radiation has recently been shown to extend beyond the heated area for distances as great as 12 cm (Crockford & Hellon, 1959) and in the present paper it is shown that a similar reaction also follows heating of the skin with water. The evidence of Crockford & Hellon (1959) suggested that a neural mechanism was involved, since vasodilatation occurred simultaneously in the heated and unheated regions. It seemed improbable that vasodilator substances could diffuse sufficiently fast to account for the rapidity of the response, and direct conduction of heat was excluded. The most likely explanation appeared to be either an axon reflex or an ipsilateral spinal reflex. The main purpose of the present experiments was further to elucidate the mechanism whereby certain local stimuli, such as infra-red radiation and heating with water, give rise to vasodilatation beyond the boundaries of the stimulated area. By using cutaneous nerve block techniques and by studying patients with sympathetic and/or somatic denervation evidence has been obtained which indicates that no known system of nerve fibres is responsible for this spreading vasodilatation. In fact, the mechanism shows many similarities to the arterial conducting system suggested by Hilton (1959) to account for the dilatation of the femoral artery in the cat following contraction of the leg muscles. Some additional experiments on cats have enabled this analogy to be more closely drawn. MTHODS xperiments on human subjects Blood flow in the forearm was measured with mercury-in-rubber strain gauge plethysmographs (Whitney, 1953; Clarke & Hellon, 1957) which do not significantly shield the skin from radiation. Two plethysmographs were used on the heated forearm at distances of 5 cm above and below the mid point. The validity of this technique for detecting local * Nuffield Department of Anaesthetics, Radeliffe Infirmary, Oxford.

2 VASOMOTOR CONDUCTION IN SKIN changes in blood flow has been discussed previously (Crockford & Hellon, 1959). In all experiments control measurements of blood flow were made on the unheated arm to ascertain that changes observed in the experimental arm were not due to a general alteration in vasomotor activity. Three 75 W tungsten-filament lamps were used as the infra-red source, placed radially round the forearm and at a distance of 22 cm from it. Radiation was applied only to the proximal half of the forearm and to the part of the upper arm between the elbow and the venous-occlusion cuff. The lower half of the forearm was carefully shielded from the radiation by an opaque, transverse screen. When water, instead of radiation, was used to heat the skin, the proximal part of the forearm was gently sprayed from both sides so that almost all the skin was wetted: a ring of grease prevented water flowing over the distal half of the forearm. The water temperature could be changed to a new level in about 5 sec. Blood flow was again measured by strain gauges, one in the sprayed proximal region and the other in the dry distal part. To block the nerve supply to the forearm skin, 15-2 ml. of 1 % lignocaine was injected subcutaneously in a ring round the forearm (dholm, Fox & Macpherson, 1957); the solution was used both with and without the addition of adrenaline ( 5 x 1-5). All experiments were performed at a room temperature of C and the subjects rested under these conditions for at least 3 min before observations began. xperiments on cats Cats were anaesthetized with chloralose (8 mg/kg i.v.), after induction of anaesthesia with ether. Following the technique of Hilton (1959) the femoral artery on one side was dissected out and the proximal part enclosed in a small oncometer, leaving a distance of some 1-15 mm between the profunda branch of the artery and the distal end of the oncometer. The sciatic nerve on the same side was ligated and electrodes were placed distal to the ligature. One common carotid artery was cannulated for recording arterial blood pressure, with a mercury manometer and kymograph. Changes in the femoral artery volume were recorded by means of the photo-electric apparatus described by Hilton (1959), and an inkwriting milliammeter. RSULTS xperiments on human subjects Heating with water spray. The proximal half of the forearm of a normal subject was sprayed for 25 min: for the first 5 min with water at 34 C to provide the minimal thermal stimulus; from the 5th to 15th minutes at 39 C to heat the arm; and from the 15th to 25th minutes at 34 C again. Four experiments were performed on two subjects and vasodilatation was found to commence between 1 and 2 min after raising the spray temperature from 34 to 39 C. Figure 1 shows the results from one such experiment. As with infra-red radiation (Crockford & Hellon, 1959) the heated and unheated regions of the forearm dilated simultaneously, but with the water spray the blood flow reached a steady level more rapidly-after about 3 min of heating. When the spray temperature reverted to 34 C the blood flow in both regions declined slowly towards the initial levels, but these were not reached by the end of the experiment. Heating with infra-red radiation. In 8 experiments on three normal subjects 1 % lignocaine with.5 x 1-5 adrenaline was injected sub- 11

3 12 G. W. CROCKFORD AND OTHRS cutaneously in a ring round the forearm immediately below the elbow, and the proximal half of the forearm was heated while the distal half was screened. On all occasions the blood flow below the screen increased at the same time as in the irradiated part of the forearm, as found previously in the unanaesthetized arm (Crockford & Hellon, 1959). The results from one such experiment are plotted in Fig. 2. C - -o - Fig. 1. Blood flow changes in the proximal () and distal () parts of the forearm. ach point is the mean of four readings. The black rectangle indicates heating of proximal half of forearm with water spray at 39 C. At other times water temperature was 34 C. 8 - o C = 6_ -o_ -_ U I 2 4 l l l l l l l l i l l l lli Fig. 2. Blood-flow changes following infra-red heating on the proximal () and distal (-) parts of the forearm with control measurements (A) in the opposite arm. ach point is the mean of four determinations. The black rectangle indicates the period of irradiation. Cutaneous nerve block just below the elbow before the experiment began.

4 VASOMOTOR CONDUCTION IN SKIN 13 In another series of experiments on three subjects the ring of anaesthetic (with adrenaline) was injected at the mid point of the forearm, which was also the position of the screen. This injection prevented vasodilatation in the distal part of the forearm; the heated area responded normally. The results plotted in Fig. 3 are typical of these experiments. In the same three subjects injection of saline and adrenaline at the same site on six occasions also prevented spread of the vasodilator response to the unheated part of the forearm, although it did not produce anaesthesia. This is illustrated in Fig. 4. This blocking action of adrenaline was not due 1 1.r 7 6 U- '- 3 4 o 3 o D 2 t7 &.', 1 oil# Fig. 3. Blood-flow changes following infra-red heating. Conventions as in Fig. 2. Cutaneous nerve block with 1 % lignocaine and adrenaline at mid point of forearm before experiment began. C 12 o 1 - _ 7 T2-11 n - I I I I I I I I I I I I I U Fig. 4. Blood-flow changes following infra-red heating. Conventions as in Fig. 2. Subcutaneous ring of adrenaline solution at mid point of forearm before experiment began.

5 14 G. W. CROCKFORD AND OTHRS to a direct effect, since the blanched ring caused by the adrenaline was only 2-3 cm wide and was not close to either of the strain gauges. Because of this effect of adrenaline, the injections of anaesthetic were repeated, lignocaine without adrenaline being used. Six experiments were performed on five subjects, and in no case did the vasodilatation spread from the heated to the unheated part of the forearm, the results being similar to those illustrated in Figs. 3 and 4. Finally, as a control, similar volumes of isotonic saline were injected on twelve occasions in the same five subjects: the vasodilatation spread in the usual way on nine occasions; in two experiments the response distal to the screen was very much reduced and in one it was absent. xperiments on sympathectomized and denervated forearms. One male patient was available with a long-standing unilateral cervical ganglionectomy performed for Raynaud's disease. The completeness of the sympathectomy was tested by immersing the legs in stirred water at 44 C for 5 min: forearm blood flow, measured with a strain-gauge plethysmograph, showed no change on the operated side despite a fourfold increase in the normal forearm. There was profuse sweating on the normal side but only slight dampness of the sympathectomized arm. The absence of the sympathetic fibres did not affect the vasodilatation in response to infrared radiation in either the heated or the unheated regions of the forearm: the responses to infra-red heating were similar in the two arms, as may be seen in Fig. 5. Three male patients were studied with traction lesions of the brachial plexus. All three had been injured for at least 9 months, and all had complete anaesthesia of the forearm and hand. Tests were carried out in order to ensure that axon reflex pathways were no longer present, since Bonney (1954, 1959) has demonstrated that the sensory fibres in the plexus may tear proximally to the dorsal-root ganglia and thus leave axon reflex pathways intact. Cold vasodilatation tests on the index and little fingers were negative and no histamine flares could be elicited on the ulnar or radial aspects of the forearm. Indirect heating caused sweating and vasodilatation of the affected arm in one patient, but in the other two there was no response. Thus all three patients had complete degeneration of the sensory fibres to the forearm on one side, and two also had degenerated sympathetic fibres. All three patients were found to have similar responses, irrespective of whether the sympathetic fibres were present or not. An experiment on one of these patients is illustrated in Fig. 6 and shows that dilatation occurred in both the heated and unheated areas as with normal subjects. In preliminary experiments on these subjects the denervated arms were cold, andc infra-red heating produced a response confined to the proximal half of the

6 VASOMOTOR CONDUCTION IN SKIN 15 forearm. Accordingly, for the experiments reported above the denervated arms were warmed with a 'hair dryer' until the skin temperature was C; the strain gauges were then quickly placed in position and the distal region of the arm was covered with cotton wool. 4- a 3 -o Fig. 5. Blood-flow changes following infra-red heating. Conventions as in Fig. 2. Sympathectomized subject. (a) Heating of operated arm; (b) heating of normal arm. xperiments on the cat's femoral artery The dilator response of the femoral artery was observed in five cats following a 5-sec tetanus of the leg muscles. Figure 7a shows the type of response, which was very similar to that found by Hilton (1959). After several such dilatations had been recorded a small piece of cotton wool was wrapped round the artery 1-15 mm distal to the oncometer. The wool was then soaked in adrenaline solution (.5 x l-5), care being taken that adrenaline did not run proximally into the oncometer. Tetanus was repeated at 5 min intervals and the dilator response was found to become much reduced after 15-2 min (Fig. 7b). The cotton wool was removed and the artery was washed several times with warm saline. The dilator

7 16 G. W. CROCKFORD AND OTHRS response then returned to approximately its original size (Fig. 7c). In some experiments stronger adrenaline concentrations (1 x 1-5 or 1 x 1-4) were necessary to block the response. 6 :-o -D (~; Fig. 6. Blood-flow changes following infra-red heating. Conventions as in Fig. 2. Patient with somatic denervation. Heating applied to affected arm. _ v Ln > v > C- (a) (b) (c) V%O" S_ Minutes I 15 _ Fig. 7. Cat. Records of femoral artery volurme and arterial blood pressure. Arrows indicate start of a 5 sec period of stimulation of sciatic nerve at 4/sec. (a) Normal response to stimulation; (b) response 15 min after application of adrenaline (.5 x 1-5); (c) response after washing off adrenaline.

8 VASOMOTOR CONDUCTION IN SKIN 17 DISCUSSION The experiments which have been described allow certain conclusions to be drawn regarding the mechanisms by which the dilator response is conducted from the skin of the heated to that of the unheated region of the arm. The experiments in which local anaesthetic was injected just below the elbow, proximal to the heated area, exclude an ipsilateral spinal reflex as the cause of spread of the vasodilatation. However, anaesthetic solution injected between the heated and unheated areas blocked the spread of the response, and the control experiments with injections of isotonic saline showed that this block was not due to the mechanical effect of a subcutaneous ring of fluid. This evidence by itself would suggest that the mechanism is a neural one of the axon reflex type, but this cannot be so, since in patients with denervated arms, where the somatic or sympathetic supply was known to be absent, and even when both had degenerated, the spread of vasodilatation was not affected. It follows that if a neural mechanism is still to be postulated, the fibres concerned must be independent of the somatic system and of the sympathetic neurones with cell stations in the paravertebral ganglia. The possibility remains that fibres arise from peripheral sympathetic cells which would remain functional after sympathectomy, such as those Nelemans (1948) described in the frog's tongue; but the existence of such cells is still in doubt. An alternative explanation for the present results is provided by the work of Hilton (1959). He suggested that the femoral arterial dilatation which followed tetanus of the leg muscles of the cat was mediated by a non-nervous conducting system consisting of the smooth muscle in the vessel walls. The system was not affected by various nerve-section procedures, and was only abolished by degenerative section of the sciatic nerve, which led to total denervation of the limb. Hilton did not make any experiments beyond 18 days after sciatic section, so it is possible that the denervation left the vessels in an abnormal state which temporarily impaired the conducting system and that the dilator response might have returned at longer intervals after nerve section. Hilton discussed this possibility in relation to comparable observations on the frog's web made by Krogh, Harrop & Rehberg (1922). They noted a widespread arterial dilatation in response to a local chemical stimulus, such as a silver nitrate crystal. The spread of this dilatation was only temporarily abolished by sciatic section and returned after about 1 days when there was no evidence of any nerve regeneration. These experiments on the cat's femoral artery appear to bear a striking resemblance to the present results obtained on human skin blood vessels. 2 Physiol. 161

9 AS8 1. W. CROCKFORD AND OTHRS In both situations a vasodilatation spreads beyond the region of its initiation by a mechanism which does not require the normal supply of somatic or sympathetic nerve fibres. The patients examined have included cases of sympathetic denervation alone, somatic denervation alone and total absence of both systems. In the two patients with partial denervation the vasodilator spread was not affected, and this is in agreement with Hilton's cat experiments. The two cases of total denervation had had their lesions over 3 days before being tested and the response to heating was normal. A recent total denervation in the cat did abolish the arterial response, but as previously suggested the effect on the conducting system of complete denervation may only be temporary. Transmission of the dilator response in the cat's artery is blocked by the direct application of local anaesthetic (cocaine) to the artery (Fleisch, 1935; Hilton, 1959). Similarly, in the forearm, injections of lignocaine alone had a blocking effect which need not be interpreted as evidence of a neural mechanism, since local anaesthetics apparently prevent arterial vessels from conducting the dilator response. The blocking action of adrenaline on the spread of the forearm response had no parallel in Hilton's observations on the cat's artery and it was for this reason that additional animal experiments were undertaken. The application of adrenaline to the cat's femoral artery in the same or slightly greater concentration than that used in the forearm produced a reversible block to conduction of the dilator response, which was evidently not able to pass through a constricted region of the vessel. Abolition of the conducted response can also be produced when vasoconstriction in forearm skin is caused by the action of the vasoconstrictor fibres. With a subject in a room at 1 C radiant heating of the proximal part of the forearm causes only a small vasodilatation in that area without any spread distally (Crockford & Hellon, unpublished observations). The facts which have emerged from these experiments provide good evidence for believing that spread of the vasodilatation in forearm skin on heating is conducted as a wave of relaxation passing along the superficial small arteries and arterioles, independently of any activity in nervousconnexions. The velocity of conduction in the cat's artery was about 1 cm/sec, a rate which is too slow for any known nerve-fibre system. It is, however, a speed which would enable the vasodilatation to spread between the plethysmographs on the forearm in about 1 sec and therefore would not be evident from venous occlusions applied every 15 sec. It remains to consider the anatomical basis for this propagated vasodilatation in terms of what is known of vascular patterns in human skin. Clearly, if the dilatation passes for distances up to 12 cm and also does not involve the muscle vessels (Crockford & Hellon, 1959) the main limb

10 VASOMOTOR CONDUCTION IN SKIN 19 arteries are probably not affected. A continuity of subcutaneous arterial vessels is required to explain the phenomenon. Such a network has been described by Spalteholz (1927) and demonstrated radiographically in skin by Woollard & Weddell (1934) and Saunders, Lawrence, Maciver & Nemethy (1957). This network would form a pathway for the conduction of the wave of vasodilatation from the stimulated to the unstimulated areas of skin. SUMMARY 1. xperiments have been undertaken to ascertain the mechanism by which heating the forearm skin produces a vasodilatation not only in the skin region being heated but also simultaneously in adjacent areas of skin. 2. Subcutaneous rings of local anaesthetic proximal to the heated area did not affect vasodilatation in the heated or unheated regions. A spinal reflex mechanism was thus excluded. 3. Subcutaneous rings of local anaesthetic, with or without adrenaline, placed between the heated and unheated areas prevented the spread of vasodilatation. Control experiments with adrenaline in saline also prevented the spread. The injection of comparable volumes of saline did not affect the spread of the dilatation. 4. Patients with cervical sympathectomy or complete brachial plexus tears all showed a vasodilatation in heated and unheated skin, as did normal subjects. An axon reflex or any nervous mechanism is thus unlikely and it is suggested that the mechanism may be one of arterial conduction, being conveyed in the smooth muscle of the vessels of the cutaneous arterial plexus. 5. xperiments on the dilator response of the cat's femoral artery following a brief tetanus of the lower leg muscles have shown that locally applied adrenaline will block the conduction of this response. This is analogous to the action of adrenaline in the experiments on human subjects. We wish to thank Professor A. Heyman and Dr S. M. Hilton for their help with some of these experiments and also Dr Hilton for the loan of apparatus. Mr G. Bonney, Mr P. M. Yeoman and Mr A. S. Till kindly put us in touch with their patients. G. W. Crockford is in receipt of a grant from the British Iron and Steel Research Association. RFRNCS BONNY, G. (1954). The value of axon responses in determining the site of lesion in traction injuries of the brachial plexus. Brain, 77, BONNY, G. (1959). Prognosis in traction lesions of the brachial plexus. J. Bone Jt. Surg. 41B, CLARKT, R. S. J. & HT.ON, R. F. (1957). Venous collection in forearm and hand measured by the strain gauge and volume plethysmograph. Clin. Sci. 16, CROCKORD, G. W. & HLLON, R. F. (1959). Vascular responses of human skin to infra-red radiation. J. Physiol. 149,

11 2 G. W. CROCKFORD AND OTHRS DHOLM,. G., Fox, R. H. & MACPHRSON, R. K. (1957). The -effect of cutaneous anaesthesia on skin blood flow. J. Physiol. 132, 15-16P. FLISCH, A. (1935). Les r6flexes nutritifs ascendants producteurs de dilatation arterielle. Arch. int. Physiol. 41, HILTON, S. M. (1959). A peripheral arterial conducting mechanism underlying dilatation of the femoral artery and concerned in functional vasodilatation in skeletal muscle. J. Physiol. 149, KROGH, A., HARROP, G. A. & RHBRG, P. B. (1922). Studies on the physiology of capillaries. III. The innervation of the blood vessels in the hind legs of the frog. J. Phy8iol. 56, NLMANS, F. A. (1948). Innervation of the smallest blood vessels. Amer. J. Anat. 83, SAUNDRS, R. L. D C. H., LAWRNC, J., MACIVR, D. A. & NMTHY, N. (1957). The anatomic basis of the peripheral circulation in man. In RDISCH, W. & TANGCO, F. F., Peripheral Circulation in Health and Diease, p New York: Grune and Stratton. SPALTHOLZ, W. (1927). Blutgefasse der Haut. In JADASSOHN, J., Handb. Haut- und Geschlechtskrankheiten, vol. 1, p Berlin: Springer. WHITNY, R. J. (1953). The measurement of volume changes in human limbs. J. Physiol. 121, WOOLLARD, H. H. & WDDLL, G. (1934). Arterial vascular patterns. J. Anat., Lond., 69,