Sherrington School of Physiology, St Thomas's Hospital, London

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1 53 J. Physiol. (I955) I29, EFFECT OF ADRENALINE AND NORADRENALINE ON BLOOD VESSELS OF THE HAND BEFORE AND AFTER SYMPATHECTOMY BY R. S. DUFF From the Cardiological Department, St Bartholomew's Hospital and the Sherrington School of Physiology, St Thomas's Hospital, London (Received 6 December 1954) Alterations in the vascular reactivity of laboratory animals following sympathectomy were first detected in relation to adrenaline (Meltzer & Meltzer, 1903; Elliott, 1905). It was later shown that the altered response is not confined to adrenaline (Dale & Richards, 1918; Cannon & Rosenblueth, 1936; Hoagland, 1941), for denervation led to differences in the reactions to acetylcholine and histamine. The occurrence in man of altered reactions to adrenaline in skin vessels surgically deprived of their sympathetic nerve supply has been amply demonstrated (Freeman, Smithwick & White, 1934; Smithwick, Freeman & White, 1934; Fatherree, Adson & Allen, 1940; Doupe, 1943; Duff, 1952), but opinion is divided regarding the time of onset, degree, and duration of the phenomenon. Observations on the response of human blood vessels to noradrenaline have been made in normally innervated subjects (Barcroft & Konzett, 1949; De Largy, Greenfield, McCorry & Whelan, 1950), but precise information on the effect of sympathectomy on these responses is lacking. The present study attempts to assess the influence of sympathectomy on the reactivity of the blood vessels ofthe hand to noradrenaline in comparison with that to adrenaline. MATERIAL AND METHODS Subjects Ten subjects of both sexes between the ages of 18 and 45 years were investigated before and some days after cervicothoracic sympathectomy; the vascular responses in thirteen upper limbs were studied. Relevant information on each is given in Table 1. Although the majority were suffering from Raynaud's disease of the fingers, only four hands had visible ischaemic skin lesions, the remainder having normal appearances between attacks of vasospasm. The type of operation used to sympathectomize each hand was ascertained from the surgeon, and all but three subjects were subjected to a heat test (Landis & Gibbon, 1933; Barcroft & Hamilton, 1948) to establish that all vasomotor pathways to the hands had in fact been interrupted

2 54 R. S. DUFF (Duff, 1951). Following operation every hand exhibited signs characteristic of sympathectomyanhidrosis, increased warmth, and absence or reduction of vasospastic attacks. Other consequences of sympathectomy, such as Horner's syndrome following removal of the upper part of the stellate ganglion, were also noted. TABLE 1. Age, sex and condition of subjects, type of operation to sympathectomize each hand, and date of each postoperative test Age Type of Postoperative No. Subject (yr) Sex Hand Condition operation test at: 11 P.A. 18 F R 2; S.C. 28 il LE LE P 13th 5th day day 3 MS.C. 28 F R RD G 16th day 4 i L ~~~ ~~~~RD G 3rd day 5 M.C 29 F L RD G 4th day 6 A.D. 18 F L RD G 4th day 7 H.M. 39 F R RD P 6th day 8 E.N. 40 F R RD G 6th day 9 C.P. 39 F R RD P 4th day 10 E.W. 22 F R RD G 7thday 11 A.P. 45 M R VR G 6th day M. * B. * 32 M L RD 7th IR day RD P 6th day LE=lupus erythematosus of fingers; RD= Raynaud's disease of fingers; VR =vasospasm of retinal arteries; P= preganglionic decentralization; G= postganglionic denervation. Methods The subject reclined comfortably on a couch in a laboratory kept between 22 and 24 C, for at least i hr before the start of the investigation. During each test the blood flow was invariably measured in both hands by venous occlusion plethysmography, using metal plethysmographs (Barcroft & Edholm, 1943; Duff, 1952) filled with water kept at 34± 1 C. Throughout the entire experimental period the blood flow in both hands was measured simultaneously and regularly each i min using either a smoked drum or a continuous-paper ink-recording kymograph. On the side under study, a needle to which a fine polythene tube had been attached was inserted under local anaesthesia into the brachial artery just above its bifurcation (Duff & Swan, 1951; Duff, 1952), and a continuous saline infusion started. A power-driven infusion apparatus (Duff, 1952) ensured steady delivery of the contents of interchangeable 50 ml. syringes at a constant rate, adjusted for 3 ml./min. The infusion into the artery was maintained at this rate throughout the experiment. At 4 min intervals plain saline (0-9% (w/v) NaCl solution) was alternated with saline containing the requisite amount of the test hormone. The latter solution was freshly prepared by serial dilution just before administration, from synthetic L-adrenaline tartrate (B.D.H.) or L-noradrenaline bitartrate (Bayer). Dilutions were such that 3 ml. of saline containing one of the following amounts of either substance entered the brachial artery each minute: -, 1, j or *,ug. The general procedure was to start with a low concentration of adrenaline and follow with successively higher concentrations, then to give one of the lower concentrations of noradrenaline followed in the same manner by successively higher concentrations thereof. Each drug solution was infused for 4 min. Not every subject received all four concentrations of each hormone; to save time the I itg/min solution was often omitted, but care was taken to ensure that for each individual hand the postoperative tests were replicated in identical order to that adopted for the preoperative investigation of that hand. The blood flow in a pair of hands normally undergoes frequent variable but simultaneous fluctuations usually of about equal degree on both sides. After sympathectomy fluctuation in blood flow is generally greatly reduced though not necessarily abolished. Any investigation of unilateral treatment, especially to a normally innervated hand, must therefore be designed to permit recognition and exclusion of these 'spontaneous' bilateral changes in blood flow. An estimate of the net effect in the hand of a unilateral intrabrachial infusion of a drug may be

3 VASCULAR SENSITIVITY AFTER SYMPATHECTOMY 55 obtained by subtracting, as it were, the spontaneous fluctuation of the contralateral control hand from the blood-flow pattern of the test hand before and during the drug infusion. On this basis the following method of analysis has been found satisfactory. If A and a are the means of the blood flow in the test and control hands respectively during the control period immediately before a specific infusion, and B and b the corresponding values recorded during that infusion, then an estimate (E) of what the flow in the test hand would have been had the drug been omitted is obtained by E=Ab/a. Any difference in excess of experimental error between the observed mean B and the expected mean E is a measure of the net effect of the drug. In the material presented here the mean values A, a are derived from the six i min observations for test and control hand during the 3 min prior to the drug infusion; and the means B, b from the six observations during the first 3 min of the drug infusion. From the difference between B and E a useful expression of drug effect is given by (B - E)/E x 100. Previous studies (Duff, 1952) have shown that changes in this expression of less than 25% usually do not signify a specific drug effect and the drug level producing at least 25% vasoconstriction may be taken as the threshold of the hand vessels for that drug. RESULTS -Preoperative response to adrenaline. Nine hands were studied during infusions of A,ug/min. Not one had any significant change in blood flow, the greatest individual constriction being 17%. With -,ug/min three of the thirteen hands had vasoconstriction of more than 25 %, the mean change for the group being 11 % constriction. With j,ug/min two hands had 25 and 49% vasoconstriction, respectively, the mean for the group being 16% (Table 2). Response to adrenaline after sympathectomy. None of the hands in this series exhibited significant change in flow with A1,ug/min. With A,ug/min, however, eight of the thirteen hands now had 25 % or more vasoconstriction, the mean for the group being 30 %. With i p,g no less than eight of the ten hands tested had more than 25 % vasoconstriction. Thus for the two groups receiving H and i ug adrenaline marked increases in the mean responses from 11 to 30% and from 16 to 44 %, respectively, were observed after sympathectomy. The ratio of postoperative to preoperative mean responses was about the same for both doses (2-7 and 2-8). The increased response after sympathectomy is seen (Table 2) to be due especially to changes in hands 3, 6, 9, 11, 12 and 13, which before operation had minimal constrictions but responded with marked reductions in blood flow after sympathectomy. The altered behaviour of two of these hands is portrayed in Figs. 1 and 2. Although some of the other seven hands also showed increased vasoconstriction with a given dose of adrenaline after sympathectomy this increase was less notable. The paired differences between the hands before and after sympathectomy are significant at the A.g/min (t = 3-03, P < 0-02), and the i,ug/min (t = 3-55, P < 0-01) levels. Of the six hands manifesting notable increases in sensitivity to adrenaline three were sympathectomized by preganglionic section and three by ganglionectomy. Two of the postoperative tests were done on the fourth

4 56 R. S. DUFF day thus providing evidence that increased sensitivity may develop well before the end of the first week. Of the remaining hands, which gave little or no evidence of an increase, four were sympathectomized by ganglionectomy and three by preganglionic section. TABLE 2. Comparison of adrenaline effects in thirty-two paired tests. The paired differences between preand postoperative responses are significant at the A jug (t= 3.03, P < 0.02) and *iug levels (t= 3.55, P < 0.01) Before sympathectomy Mean blood flow (ml./100 ml./min) Test hand Control hand Hand, - no. A B a b E Mean Mean Mean After sympathectomy, ~~~AI Mean blood flow (ml./100 ml./min) Test hand Control hand E X100 A B a b E Adrenaline -i1/min % Adrenaline tjg/min % 11-3 Adrenaline i,g/min % 9-9 B-B 0 B xloo % % % A, a= means of the six observations of blood flow during 3 min prior to start of adrenaline, in test and control hands, respectively; B, b= corresponding means during first 3 min of adrenaline period; E=Ab/a.

5 VASCULAR SENSITIVITY AFTER SYMPATHECTOMY Miss A. D.-left Preoperative ~10 I'~~~~~~~~~~~~~~~~~~~~~~~~~~~~P E 5 \,#',I.6 It '4v 3.1 ~d r. -J Adr. Adri or. r.1 No. o 0 Co ~~~~~~Fourdays after ganglionectomy Minutes Fig. 1. Blood flow in tested left hand (heavy line) and control right hand (interrupted line) of a young woman with Raynaud's disease before (upper half) and after sympathectomy (lower half). On both occasions three concentrations each of adrenaline (Adr.) and noradrenaline (Nor.) were given during the course of continuous saline infusions into the left brachial artery. Marked fluctuations in blood flow occurred in both hands before operation, irrespective of the unilateral drug infusions. After operation notable unilateral vasoconstriction results from these infusions. Mr M. B.-right Preoperative E D / E > d.' Adrj Ad. or.j1 Nr I Six days after preganglionic section Minutes Fig. 2. Blood flow in tested right hand (heavy line) and control left hand (interrupted line) of young man before and 6 days after preganglionic sympathectomy for Raynaud's disease. On both occasions solutions of adrenaline (Adr.) and of noradrenaline (Nor.) were infused into the right brachial artery. Before operation these had little effect, but after operation distinct vasoconstriction resulted from each infusion.

6 Response to noradrenaline before operation. At the lowest concentration (6k4Lg/min) at least one of the tested hands showed significant vasoconstriction, and the mean change for the group was 14% compared with 4% for adrenaline. TABLE 3. Comparison of noradrenaline effects in thirty-four paired tests. The paired differences between pre- and postoperative responses are significant at the, ug (t= 2-22, P < 0.05) and *,Zg levels (t=2-23, P=0-05) Before sympathectomy After sympathectomy Mean blood flow (ml./100 ml./min) Mean blood flow (ml./100 ml./min) A Test hand Control hand Test hand Control hand Hand, B - Ex 100 no. A B a b E E A B a b E E XlOO Noradrenaline -1- Kg/min Mean % % Mean Mean 58 R. S. DUFF Noradrenaline A ug/min P; S ' ' ] I ' ) Si ( ) i ' E3v i ' ) % 11-7 Noradrenaline u,ug/min ; ) S) : c d I ( L L-O ( ) IF ', E ( ) , % 10-6 Abbreviations are as in Table % %

7 VASCULAR SENSITIVITY AFTER SYMPATHECTOMY 59 With u,g noradrenaline four of the thirteen hands had over 25 % vasoconstriction, the mean for the entire group being 19% compared with 11 % for adrenaline. With the highest noradrenaline level (I,g) five of eleven hands had over 25% vasoconstriction, the mean for the group being 26% compared with 16% for adrenaline (Tables 2 and 3). Noradrenaline therefore had consistently greater constrictor effect than adrenaline in these hands at all dose levels. TABLE 4. Mean change in flow, in groups of hands, with adrenaline and noradrenaline, o1vvbipg/min Concen- Adrenaline Noradrenaline tration r A A r, A_A (ug/min) Preoperative Sympathectomized Preoperative Sympathectomized ^ No Mean S.D *9 S.E. 3*7 3* No Mean S.D *7 S.E. 4* i No Mean S.D S.E No. = number of tests; mean= mean percentage effect [(B - EIE) x 100] for group; S.D. = standard deviation of group; s.e. = standard error of mean. Response to noradrenaline after sympathectomy. Although a slight increase in mean response was observed with noradrenaline g,ug/min a much greater change was seen, as with adrenaline, at the 1,ug level. Of the thirteen hands eight had over 25 % vasoconstriction compared with four before sympathectomy. Likewise with i jug/min ten of the eleven hands had more than 25 % vasoconstriction, compared with five before operation. The mean vasoconstriction at these two levels rose from 19 to 34 % and from 26 to 49 %, respectively. The paired differences between the hands before and after operation are significant at the 1,ug (t = 2-22, P < 0-05) and u,ug levels (t = 2.23, P = 0.05). It is seen (Table 3) that the main cause of the greater noradrenaline response after operation was the development of increased constrictor sensitivity in hands 3, 6, 9, 11, 12 and 13-the same hands as exhibited enhanced sensitivity to adrenaline. After sympathectomy the mean vasoconstriction for the groups tested at the I and j,ug levels remained somewhat greater for noradrenaline than for adrenaline (Table 4), but the increase in sensitivity was distinctly greater for adrenaline ( ) than for noradrenaline ( ). The dose-response curves for the two drugs (Fig. 3) show that the responses are roughly proportional to the log, dose, especially for adrenaline.

8 60 R. S. DUFF DISCUSSION The present findings with respect to adrenaline may be compared with earlier data obtained under very similar conditions (Duff, 1952). In preoperative tests of a group of ten hands, most, like the present, with Raynaud's disease, adrenaline A,g/min caused an average vasoconstriction of 12% compared with 11 % for the present series; and with i,ug/min the constriction was the same, 16 %, for both. After sympathectomy the ten hands of the earlier series exhibited mean vasoconstriction of 36 % with A ug/min, compared with 30% Adrenaline Noradrenaline i 40,0 20 (10 >~~~ A q. ~ ~ ~ ~ ~~~~~~~1 6 a) /~ /tg/min jag/min 8 64 i Fig. 3. Mean reduction in blood flow [(B - E)/E x 100)] in thirteen hands tested before and after sympathectomy in response to different concentrations of adrenaline and noradrenaline in intra-arterial infusions. Noradrenaline is seen to have a greater constrictor effect than adrenaline in normally innervated hands. After sympathectomy the response to both agents is augmented. The effects are roughly proportional to the log, concentration against which they are graphed. for the present group; and j pg/min caused 55 and 44% respectively. The slightly smaller increase in response of the present group after operation is in line with the finding that it included a smaller proportion of hands developing notable supersensitivity (six of thirteen compared with six of ten). In the earlier series five of the six supersensitive hands had been sympathectomized by preganglionic section, while two of the four failing to manifest greater sensitivity had been sympathectomized by ganglionectomy. In the present study seven of the thirteen hands were sympathectomized by ganglionectomy, of which three developed increased sensitivity; while three of the six having preganglionic section became more sensitive.

9 VASCULAR SENSITIVITY AFTER SYMPATHECTOMY 61 Information on the actual incidence of sensitivity following either type of sympathectomy in man is scanty but a failure to detect changes in a proportion of subjects has been noted (Stein, Harpuder & Byer, 1949). In laboratory animals the amount of sensitivity has been commonly thought to be greater after postganglionic denervation than after preganglionic decentralization (LeCompte, 1941; Cannon & Rosenblueth, 1949). In man, however, the assumption that ganglionectomy causes more sensitivity has been challenged (Fatherree & Allen, 1938; Millonig, Harris & Gardner, 1950; Stein et al. 1949; Duff, 1952, 1953) and the present results further conflict with that assumption. The onset of increased sensitivity has been closely studied in animals and found to occur very soon (LeCompte, 1941) or even immediately (Deterling & Essex, 1949) after interruption of the sympathetic pathway. In man Freeman et al. (1934) failed to detect changes before the 8th day. In the present study two patients tested on the 4th day were more sensitive. In normally innervated subjects noradrenaline has generally been thought to cause more vasoconstriction than adrenaline (Goldenberg, Pines, Baldwin, Greene & Roh, 1948; Barcroft & Konzett, 1949) and the present study confirms this. At the two higher concentrations noradrenaline has been shown (Table 4) to cause, respectively, 70 % and 60 % more constriction. After sympathectomy the effect of noradrenaline was usually enhanced but the increase was not quite so great as that recorded with adrenaline. Differences in the responses of sympathectomized smooth muscle to different sympathomimetic amines have been noted in experimental animals (Lockett, 1950; Innes & Kosterlitz, 1954) but these have still to be fully elucidated (Wakim & Essex, 1952). According to Cannon's 'law of denervation' (Cannon & Rosenblueth, 1949) sympathectomy necessarily results in vascular supersensitivity, and when the sympathetic pathway is cut distal to the ganglionic synapse (postganglionic denervation) the increase in sensitivity is much greater than that following preganglionic section. Two of the present findings are, therefore, in direct conflict with this: (1) that increased sensitivity was not demonstrable in a proportion of effectively sympathectomized hands; and (2) that ganglionectomy tended to cause no more sensitivity than preganglionic section. With respect also to sensitivity of vessels in muscular segments of limbs recent evidence (Duff, 1953) has revealed no notable difference between the two types of sympathectomy. The accumulation of such evidence must soon lead to a reexamination of the validity of Cannon's hypothesis. Closely related is the problem of the return of tone in vessels following the marked vasodilatation accompanying sympathectomy. Perhaps the most prevalent hypothesis attributes the restoration of tone to the development of increased sensitivity to circulating adrenaline. Vasodilatation of the hand begins to diminish 2 or 3 days after sympathectomy and has largely

10 62 R. S. DUFF disappeared by the end of a week (Barcroft & Walker, 1949; Duff, 1951). The demonstration of distinctly increased sensitivity as early as the 4th postoperative day is compatible with this hypothesis, as is the finding of about equal increases in sensitivity with both types of operation, for it has already been shown (Barcroft & Walker, 1949; Duff, 1951) that return of tone is about equal after both operations. But tone returns to the vessels in all sympathectomized hands while some of these hands do not develop supersensitivity. Evidence in further conflict with the hypothesis is provided in Table 2- supersensitivity was often present in hands during their hyperaemic phase; indeed the average control level of flow in the postoperative hands was regularly greater than in the same hands before operation. The process of tone recovery is more or less complete within a week or so, but the increased sensitivity of vessels in skin and muscle persists much longer, even for a year or more (Duff, 1952, 1953). Thus although the sensitivity theory of return of tone is compatible with some of the above findings it conflicts with the majority. It is appropriate to consider briefly the question of the nature of the process underlying vascular responses to circulating hormones. In Tables 2, 3 and Fig. 3 it is shown that normally noradrenaline is a more powerful constrictor than adrenaline. For example, at the I pg level adrenaline in contrast to noradrenaline had virtually no effect even after sympathectomy. This may indicate a lower threshold of skin vessels to noradrenaline or may merely reflect the opposing influence of the adrenaline dilator effect in vessels of the skeletal muscles of the hand. After sympathectomy the increased mean response to noradrenaline was not significantly greater than with adrenaline. This may be interpreted as a lowering of the threshold to about the same level for both substances. Individual hands became distinctly more sensitive either to both or to neither substance. The presence or absence of the phenomenon (as measured by (B-E)/E x 100) seemed to bear little relation to the level of blood flow in individual hands (Tables 2 and 3), which would seem to indicate some purely biological change in the reactivity of cells in the vessel walls, independent of the physical phenomena associated with the increased flow through the sympathectomized vasculature. A connexion between contractility and tone of smooth muscle sphincters may well contribute to the increased reactivity of sympathectomized vessels, but information on the nature of that relationship is at present too scanty to justify further speculation. SUMMARY 1. The effects on hand blood flow of infusing separately adrenaline and noradrenaline into the brachial artery have been measured in ten patients by venous occlusion plethysmography.

11 VASCULAR SENSITIVITY AFTER SYMPATHECTOMY In thirteen hands of subjects mostly suffering from Raynaud's disease the responses to graded amounts of the two substances have been compared before and some days after surgical sympathectomy. 3. Before operation noradrenaline caused on average more constriction than equal amounts of adrenaline at all dose levels. 4. After sympathectomy the average constriction of the hands with both adrenaline and noradrenaline was increased. The mean increase for the group was about threefold for adrenaline and twofold for noradrenaline. 5. The increased sensitivity to both adrenaline and noradrenaline was confined largely to six of the thirteen hands, three of which were sympathectomized by preganglionic section and three by ganglionectomy. 6. In the remaining seven hands definite evidence of enhanced sensitivity was not obtained. Four of these hands were sympathectomized by ganglionectomy and three by preganglionic section. 7. Two subjects tested as early as the 4th postoperative day had demonstrable increased sensitivity to adrenaline and noradrenaline. 8. The findings have been discussed with particular reference to increased sensitivity and recovery of tone in vessels following sympathectomy. I am indebted to Prof. H. Barcroft for valuable help and for access to his laboratory, to Prof. Sir J. Paterson Ross for making special apparatus available, and to Mr M. P. Curwen for statistical advice. I am most grateful to the surgeons who permitted me to study their patients: Sir J. Paterson Ross, Mr J. B. Kinmonth, Mr E. G. Tuckwell, Mr D. J. Robertson and Mr G. W. Taylor. It is a pleasure also to acknowledge the kindness and encouragement of Dr Geoffrey Bourne, Dr G. W. Hayward and Prof. R. V. Christie; and the valuable technical and secretarial assistance rendered by the staff of the Cardiological Department and Professorial Units of St Batholomew's Hospital and the Sherrington School of Physiology, St Thomas's Hospital Medical School. REFERENCES BARCROFr, H. & EDHOLM, 0. G. (1943). The effect of temperature on blood flow and deep temperature in the human forearm. J. Physiol. 102, BARcRoFf, H. & HAMLTON, G. T. C. (1948). Results of sympathectomy of the upper limbs. Lancet, 254, BARCROFT, H. & KONZETT, H. (1949). On the actions of noradrenaline, adrenaline and isopropyl noradrenaline on the arterial blood pressure, heart rate and muscle blood flow in man. J. Physiol. 110, BARCROFT, H. & WALKER, A. J. (1949). Return of tone in blood-vessels of the upper limb after sympathectomy. Lancet, 256, CANNON, W. B. & ROSENBLUIETH, A. (1936). The sensitization of a sympathetic ganglion by preganglionic denervation. Amer. J. Phy8iol. 146, CANNON, W. B. & ROSENBLUIETH, A. (1949). The Supersensitivity of Denervated Structures. New York: MacMillan. DALE, H. H. & RIcHARDs, A. N. (1918). The vasodilator action of histamine and of some other substances. J. Physiol. 52, DETERIaNG, R. A. & EssEx, H. E. (1949). Studies on peripheral circulation and epinephrine sensitization following sympathectomy. Amer. Heart J. 38, DOUPE, J. (1943). Studies in denervation: observations concerning adrenaline. J. Neurol. 6, DUFF, R. S. (1951). Circulatory changes in the forearm following sympathectomy. Clin. Sci. 10,

12 64 R. S. DUFF DUFF, R. S. (1952). Effect of sympathectomy on the response to adrenaline of the blood vessels of the skin in man. J. Phygiol. 117, DuFF, R. S. (1953). Effect of surgical sympathectomy on the sensitivity to epinephrine of the blood vessels of muscular segments of the limbs. J. clin. Inve8t. 32, DUFF, R. S. & SWAN, H. J. C. (1951). Further observations on the effect of adrenaline on the blood flow through human skeletal muscle. J. Physiol. 114, ELLIOTT, T. R. (1905). The action of adrenalin. J. Physiol. 32, FATHERREE, T. J., ADSON, A. W. & ALLEN, E. V. (1940). The vasoconstrictor action of epinephrine on the digital arterioles of man before and after sympathectomy. Surgery, 7, FATHERREE, T. J. & ALLEN, E. V. (1938). The influence of epinephrine on the digital arterioles of man; a study of the vasoconstrictor effects. J. clin. Invest. 17, FREEMAN, N. E., SMITHWICK, R. H. & WHITE, J. C. (1934). Adrenal secretion in man. The reactions of the blood vessels of the human extremity, sensitized by sympathectomy, to adrenalin and to adrenal secretion resulting from insulin hypoglycemia. Amer. J. Physiol. 107, GOLDENBERG, M., PINES, K. L., BALDWIN, E. DE F., GREENE, D. G. & ROH, C. E. (1948). Hemodynamic response of man to norepinephrine and epinephrine and its relation to the problem of hypertension. Amer. J. Med. 5, HOAGLAND, H. (1941). Sensitization of blood vessels to acetylcholine by sympathetic denervation. Proc. Soc. exp. Biol., N. Y., 48, INNES, I. R. & KOSTERLITZ, H. W. (1954). The effects of preganglionic and postganglionic denervation on the responses of the nictitating membrane to sympathomimetic substances. J. Physiol. 124, LANDIS, E. M. & GIBBON, J. H., jun. (1933). A simple method of producing vasodilatation in the lower extremities. Arch. intern. Med. 52, DE LARGY, C., GREENFIELD, A. D. M., MCCORRY, R. L. & WHELAN, R. F. (1950). The effects of intravenous infusion of mixtures of L-adrenaline and L-noradrenaline on the human subject. Clin. Sci. 9, LECOMPTE, P. M. (1941). Observations on the return of vascular tone after sympathectomy. Amer. J. Physiol. 135, LOCKETT, M. F. (1950). The effect ofdenervation on the responses of the cat's nictitating membrane to sympathomimetic amines. Brit. J. Pharmacol. 5, MELTZER, S. J. & MELTZER, C. (1903). The share of the central vasomotor innervation in the vasoconstriction caused by intravenous injections of suprarenal extract. Amer. J. Physiol. 9, MILLONIG, A. F., HARRIS, H. E. & GARDNER, W. J. (1950). Effect of autonomic denervation on nasal mucosa. Arch. Otolaryng., Chicago, 52, SMITHWICK, R. H., FREEMAN, N. E. & WHITE, J. C. (1934). Effect of epinephrine on the sympathectomized human extremity. Arch. Surg., Chicago, 29, STEIN, I. D., HARPUDER, K. & BYER, J. (1949). Reactivity of blood vessels in the sympathectomized human leg. Amer. J. Physiol. 158, WAKIM, K. G. & EssEx, H. E. (1952). Comparison of the circulatory effects of epinephrine and norepinephrine. Circulation, 5,