The Vasoconstrictor and Piloerector Effect in Human Skin of Dopamine and Normetanephrine as Compared with Noradrenaline*

Vol. 44, No. 2

THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

Copyright

Printed in U.S.A.

1965 by The Williams & Wilkins Co.

THE VASOCONSTRICTOR AND PILOERECTOR EFFECT IN HUMAN SKIN OF DOPAMINE AND NORMETANEPHRINE AS COMPARED WITH NORADRENALINE* HALVOR MOLLER, M.D.

Noradrenaline (norepinephrine), the main

prepared with saline freshly before use. Fivefold

transmittor at postganglionic sympathetic nerve terminals, is a powerful vasoconstrictor and piloerector. The minimal concentration for eliciting vasoconstriction after intracutaneous injection Was recently reported by Stoughton

serial dilutions were prepared from 1/1,000 to 1/3,125,000. In some cases dopamine 1/1,000 was

injected also with the addition of NSD 1055, an

inhibitor of dopamine-j3-oxidase.' One ml syringes and needles no. 18 18 (gauge (gauge 25) 25) were used and 0.05 ml was injected intracutaneously. Twelve healthy volunteers (medical students) were injected with

et cxl. cii. (1) (1) to to be be 10. 10. From the aspect of the test solutions in vertical rows on the back molecular structure those authors concluded

alongside the vertebral column. The position of that the presence of at least one free hydroxyl the rows was changed from one case to another. Reactions were read 30 minutes later. In order group on the phenyl ring was required for the compound to induce a considerable vasocon- to enhance the contrast between a blanched area and the surrounding skin this latter was painted striction. with a vasodilating solution containing tetra-

It was the aim of the present study to hydrofurfuryl nicotinate (Trafuril®, Ciba) ;

this

further evaluate the relationship between the treatment did not influence the cutaneous effect of molecular structure of noradrenaline and its the injected compounds. The injected areas were for vasoconstriction evidenced by blanchactivity in the skin. For that purpose the inspected ing and for piloerection evidenced by follicular vasoconstrictor and piloerector effect in man reaction, "cutis anserina". For an exact estimate of intracutaneously injected noradrenaline was of the blanched areas their contour was copied compared with those of its precursor dopamine on a thin plastic film, which was photographed and its main metabolite normetanephrine. For the biosynthesis of noradrenaline the amino acid 3, 4-dihydroxyphenylalanine

(DOPA) is first decarboxylated to dopamine

(Fig. 1). This reaction is catalyzed by the enzyme DOPA decarboxylase. Dopamine is

against a millimeter graph paper. The picture obtained was magnified, cut out and weighed, and the area was calculated after comparison with a standard. RESULTS

Intracutaneously injected noradrenaline in-

further hydroxylated to noradrenaline by duced vasoconstriction in the minimum condopainine-/3-oxidase. Noradrenaline is metabo- centration of 1/625,000 in 7 of the 12 subjects lized mainly by catechol-O-inethyl transferase studied; in 1/125,000 in the other 5. The mean to form normetanephrine. This sequence of of the lowest amounts of noradrenaline eliciting formation and breakdown of noradrenaline may blanching of the skin in this study corresponds evidently take place in the skin proper, since to 0.12 pg. The log dose-response curve is given the activity of DOPA decarboxylase (2), in Figure 2. The lowest concentration of noradrenaline dopamine-/3-oxidase (3), and catechol-O-methyl transferase (4, 5), has recently been demon- provoking vasoconstriction and piloerection as strated in that tissue. compared with that of dopamine and normetammephrine is shown in Figures 3 and 4. VasoMATERIAL AND METHODS

constriction was induced with dopamine in a

Doparnine hydrochloride, 1-noradrenaline hi- minimum concentration about 80 times stronger tartrate and normetanephrine base were used; all than that of noradrenaline and with normetavalues given refer to the base. All solutions were nephrine about 500 times stronger than that

of noradrenaline. With the concentration of

* From the Department of Dermatology, Uni-

1/1,000 the mean values of blanched areas were,

versity of Lund, Lund, Sweden. Received for publication February 17, 1964.

for noradrenaline 114.0

11 sq mm, for

'NSD 1055 was kindly furnished by Mr. D. J. 3 sq mm and for normetaDrain, Smith & Nephew Research, Ltd, Harlow, dopamine 16.9 nephrine 13.8 3 sq mm. England. 83

84

JOURNAL OF INVESTIGATIVE DERMATOLOGY

fflSCUSS0N fflSCUSSON

HO

HO(D-CH2-CH—NH2 HO(D-CH2_CH—NH2

DOPA

The strong vasoconstrictor effect of noradrenaline, the postganglionic sympathetic transmittor, was confirmed in the present

COOH

work. The relationship in the log dose-response

HO1

HO-CH2-CH2-NH2

DOPAMINE

HO!

HO-CHOH-CH2-H2

NORADRENALINE

curve was next to linear (Fig. 2). In the skin the site of action of topically applied catechol arnines seems to be the precapillary sfincter, presumably at the level of the metarteriole (6). A venoconstriction in the subpapillary plexus probably occurs as well (6).

Normetanephrine was a very poor vasoconstrictor when injected into human skin (Fig. NORMETANEPHRINE

1. The structural formulas of DOPA, dopaFIG. 1. mine, noradrenaline and normetanephrine.

3). The methylation of one of the two hyOF

NO.

SUBJECTS

2 DOPAMINE

CO NC.

I0

/Iooo

8

6 4

'25p00

2

n

ri

'625,0O0

NORADRENALI NE

I0

20 40 40 60 60 80 80 20

100 120

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SQ.MM. FIG. 2. 2. Blanched Blanched areas induced by different concentrations of noradrenaline after intracutaneous

injection in man. Mean values from twelve subjects

4

nil

2

are pointed out and connected. The bars

indicate standard errors of the mean.

For each substance tested, slightly higher minimum concentrations were needed to induce piloerection than vasoconstriction (Figs. 3 and 4). Comparing noradrenaline and dopamine as

for piloerector potency, the difference was a little less than for vasoconstrictor capacity. The reverse may be said for the difference between noradrenaline and normetanephrine: in seven of the twelve subjects tested no piloerection at all was observed with normetanephrine 1/1,000.

NO R U E tA N £PHRIN E

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The addition of NSD 1055 to dopamine did FIG. 3. The distribution among twelve subjects not influence the vasoconstrictor and piloerec- of the minimum concentrations of doparnmne, noradrenaline and normetanephrine giving vasocontor effect of this amine.

stnction in the skin.

CUTANEOUS EFFECTS OF DOPAMINE AND NORMETANEPHRINE

85

droxyl groups in the phenyl ring thus imun- accordance with the present finding in human plies an effectivc inactivation. The weak vaso- skin of a vasoconstrictor potency of normetanorinetaactive effect of this methylated derivative of nephrine about 500 times weaker than that of noradrenaline is fully comparable with that of noradrenaline.

histamine (7). Normetanephrine has earlier

A definite vasoconstrictor effect of intra-

been tested in man for its general vaso- cutaneously injected doparnine about 80 times pressor effect by intravenous infusion. With a

weaker than that of noradrenaline, was regisdose of 1 mg/mm. no change in the arterial tered (Fig. 3). Since dopamine may be blood pressure was, however, obtained (8). In metabolized to noradrenaline by skin tissue animal experiments the vasopressor effect of (3) this vasoconstriction might possibly be norinetanephrine has been reported to be con- caused by newly formed noradrenaline. The siderably weaker than that of noradrenaline: effect, however, was not abolished by an in the dog 500 times (8) in the cat 600 times inhibitor of dopamine--oxidase, and thus in the (9); in the rabbit rabbit 800 800 times times (9); in the rat seemed to be due to the action of dopamine 1000 times 1000 times (10). (10). These These results are in good itself. The vasoactivity, in general, of dopamine NO. OF

seems more complex than that of nor-

sue JECTS DO PA M IN E

adrenaline. Thc effect of dopamine evidently

possesses a constrictor as well as a dilator

I0

component. This pressor-depressor response is dependent upon the dose, low doses giving a depressor response and high doses vasopression 4

(11, 12). In man the effect of dopamine on

nfln

arterial blood pressure has been reported to be about 50 times weaker than that of noradrenalme (11). The influence on peripheral resistence

was rather a moderating one, in contrast to that of noradrenaline. By intravenous injection

12 NOR AOR ADA C N AL NE NE

of dopamine, no skin pallor indicative of cutaneous vasoconstriction was observed. This

discrepancy, in comparison with the present results obtained by intracutaneous injection of

S

S

dopamine, may be explained by the low amounts doparnine,

4

reaching the skin vessels following an intravenous administration.

2

2 NORMETANEPHRINE 10

There was an approximate parallelism between the concentrations of the three amines tested giving piloerection (Fig. 4) and those giving vasoconstriction (Fig. 3). The slightly weaker piloerector effect of the compounds may be explained by the registration method being less distinct. Confusing results were recently reported after intra-arterial injections of dopamine in man (11) : piloerection was recorded in the forearm with dopamine dopamine but but not with other catechol ainines in spite of the fact

that these amines are piloerector by intraI

I

I

I

(000

5000

25p00

•25P00

I

cutaneous injection.

625000 CONe.

It may be concluded that the strong vaso-

Fm. 4. The distribution among twelve subjects

constrictor and piloerector effect of nor-

of the minimum cDncentrations of dopamine, nor- adrenaline is dependent to a larger extent upon adrenaline ana nrmetanephrine giving piloerectwo free hydroxyl groups on the phenyl ring tiort in the skin.

86

JOURNAL OF INVESTIGATIVE DERMATOLOGY

of catechol-O-rnethyl transferase and monoamine oxidase. Acta Dermato-vener. (Stock-

than on the hydroxyl group of the side-chain.

With regard to the two effects tested, 3-0methylation of noradrenaline implies an effective inactivation. SUMMARY

The vasoconstrictor and aid piloerector piloerector effect in man of noradrenaline was compared with those

holm), 43: 552, 1963.

6. DEMIS, DEMIS,D. D.J., J.,ZIMMER, 0., VERHONICK, VERHONICK, ZIMMER, J. 0., PH. J. AND CATALANO, PH. M.: The pharmacology of human skin. I. Epinephrine and norephinephrine; catecholamine-serotonin combinations. combinations. J. J. Invest. Invest. IDerm., IDerm., 39: 419, 419, 1962.

7. ASPEGREN, N. AND AND RORSMAN, RORSMAN, H.: The exudaASPEGREN, N.

tory and vasodilatatory effects in human

of its precursor dopamine and its main metabolite normetanephrine. norrnetanephrine. In comparison with noradrenaline, dopamine was about 80 times weaker and normetanephrine about 500 times

skin of 1 -methyl-4-beta-arninoethyl imidazole zole (methyl (methyl-histamine). -histamine). J. J. Invest. Invest. Derm., Derm., 37:65, 1961. 37:65, 1961.

8. 8.

weaker.

EvARTS, E. EvARTS, E. V., V., GILLESPIE, GILLESPIE, Jn., JR., L., L.,FLEMING, FLEMING, C.AND AND SJOERDSMA, T. C. Relativelack lack of of SJOERDSMA, A.:A.:Relative action of 3-methoxy analogue pharmacologic pharmacologic

of norepinephrine. Proc. Soc. Exp. Biol.

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