Centrally and locally mediated vasomotor activities in Raynaud's phenomenon.

I OLSEN N. Centrally and locally mediated vasomotor activities in Raynaud's phenomenon. Scand J Work Environ Health 13(1987)309-312. A selective reviewon the attack of Raynaud's phenomenon in primary Raynaud's phenomenon and vibration-induced white finger is presented with special reference to the location of the primary vasospasm, the nature of the dominant pathophysiological mechanism, and the anatomic location of the abnormal link in this mechanism. It is suggested that the primary vasospasm is a total closure of the main digital arteries, that the arterial spasm is mainly mediated through an exaggerated central sympathetic reflex mechanism, and that the abnormal link in this reflex arch could be the smooth muscle cells of the digital arteries. Other anatomic locations of the abnormal link can however not be excluded as yet.

Since Maurice Raynaud (13), in his thesis of 1862, described the disease now nam ed after him , conflicting theories have been advan ced con cernin g the pathophysiology of the characteristic attacks of the disease. In the present paper a selective review o f the topic is given with reference to the att acks in vibration-induced white finger (VWF) and in primary Raynaud' s phenomenon.
Visible symptoms of the attack Raynaud (13) described an exaggerat ed respon se of digital circulation to cold exposur e or mental stress . The response, denoted as Raynaud's phenomenon, is characterized by the appearance of an acral, welldemar cated blanching or cyano sis in the skin of the finger. It has often been the rule for writers to stat e that the sequence of colors displa yed in the att ack is first white, then blue, and finally red in the stage of recovery. Ho wever Thomas Lewis (4), in 1929, made detailed observation s on the phenomenon and not iced that the attack always started with the cyanotic color in the coo led finger when the finger was held at rest. Microscopically he observed a cessation o f the skin capillary blood flow at this stage. The color could change from cyano sis to white spon ta neo usly or as a result of flexing and extending the finger. Full cyanosis in a cooled finger is thus the cardinal sign of the attack , whereas blanching occurs by passive or active mechanisms secondary to the basic mechanism that produ ces the cyanotic color. The observat ions by Lewis (4)  phenomenon reflect an underlying closure of the larger vessels, followed by a closure of the smaller cutaneous vessels.

Arteriovenous anastomoses
Lewis (5) also discovered the existence of the so-called hunting reaction in norm al subjects. The hunting reaction is a vasodilatation that occurs in the skin of the finger after the latter has been immer sed in cold water for some time. The reaction is believed to be a local prot ective mechanism aga inst overcooling and reflects periods with totally opened arteriovenous ana stomo ses, counteracting the normal sympathetic vasocon strictor response to cold. Lewis (4) also observed that the hunting reaction could always be found in subjects with Raynaud 's phenomenon , although the reaction is far less marked than in normal subjects due to the counteracting spasm of the vessels. An attac k of Raynaud's phenom enon therefo re is not caused by a lack of the hun ting reaction mechani sm. The statement that arte riovenous anastomoses run parallel to the capillaries and not in series with them also shows that closure of the arteriovenou s anastomoses cannot explain the cessation of capillary blood flow in an attack of Raynaud 's phenomenon.

Arterial and venous vasoconstriction theories
Lewis (4) felt that the pr imary vasospa sm was located on the arterial side of the capillaries and that the digital art eries were the vessels primaril y involved . How ever a venous constriction theory also existed and still exists. The microvascular pressure measurements of Landis (3) in 1930casts however considerable doubt on the venous constriction theory and seems to be entirely compatible with the arterial constriction theory. Landis (3) measured capillar y blood pressure dur ing an attack of Raynaud's phenomenon. The capillary blood flow ceased during the attack, and a n abnormally low capillary blood pressure was measured. Recovery was registered as the resumption of capillary blood flow, accompanied by an enormous rise in capillary blood pressure a nd a sudden change in skin color from cyanosis to bright redness, followed by the return of pulse pressure and an increase in skin temperature. If venoconstriction had been prim arily responsible for flow cessation, the capillary blood pressure should have been higher and not lower than the habitual pressure. Closure of the vessels located on the venou s side of the capillary network ma y occur, but is then a closure secondary to the basic closure on the arterial side.

Main digital arteries
From his observations Lewis (4) concluded that the attack was caused by a complete closure of the main digital arteries but was unable to measure it. In 1977 Nielsen & Lassen (8) described a method to measure the vaso con strictor response of the digital arteries to co ld . The systo lic blood pressure of the finger is recorded by this method indirectl y with a cuff a nd strain gauge technique after local cooling of the intermediate phalanx of the finger. The decrease in blood pressure recorded after the cooling is a measure of the increa se in the digit al arterial tone . An attack of Raynaud's phenomenon is reflected as an unmeasurerable recording, a so-called zero pressure , indicating complete closure of all main digital arteries. The method has an acceptable level of reproducibility, sensitivity, and specificity. Olsen & Nielsen (11) first applied a modified form of the method, with finger cooling to 30, 15, and 6°C combined with the body cooling that is generally necessary to provoke an att ack of Raynaud's phenomenon (2), to subjects expo sed to hand-arm vibration. Among fore str y workers the y (12) found that vibratio n-exposed subjects at stage 0 (Ta ylor's index) had a decreased response to cold in comparison to those at stages 2 and 3 but an increased response in comparison with that of referent s. The results indicated that vibration induces a hyperresponsiveness to cold even befo re subjects not ice any att ack of Raynaud's phenomenon. Therefore, after stepwise exclusion of the smaller cutaneous vessels, th e arteriovenou s anastomoses, and the vessels on the venou s side of the capillary network as the location of the primary closure in an attack of Raynaud' s phenomenon, strong indications remain that the primary closure is a complete closure of the main digital arteries and not a closure of the smaller arteries, arterioles, or pre capillary sphincters.

Anatomic changes in the digital arteries
From bioptic material Lewis (6) concluded that, in cases of intermittent vasospasm, exemplified by the 310 mildest form of the so-called " Raynaud's disease" (today denoted as primary Raynaud's phenomenon), there is no more intimal thickening than is found in the arteries of warm-handed people of similar age. Hyperplasia of the med ia was not found in these patients. He found no evidence that attacks of digital arterial spasm lead to thickening of th e medial or intimal coats of th e digital arteries, but did find that , in advanced cases, attacks may lead to thrombotic events. In advanced cases of VWF the episodies of blanching are replaced by a continuous cyanotic appearance of the fingers, the ability of the blood vessels to co nstrict and dilate being lost, but onl y in less than 1 % of patient s does this phenomenon lead to malnutrition, tissue necrosis , and gangrene of th e fingers (14). Ashe & Williams (I) studied biopsies from digital arteries in miners with VWF and in dead referents . Subintimal fibrosis occurred in severe cases but was absent in milder cases and in the referents.
In the cases without subintimal fibro sis a so-called medial hypertrophy was described that was evaluated from the relationsh ip between wall thickness and lumen diameter. The wall thickness was howe ver equal for the miners and referents, whereas the lumen was largest in the referents, the result being a smaller ratio. They concluded that no observable anatomic changes were seen in the arteries in the mild and moderate cases. Therefore, it seems that no anatomic changes occur in mild and moderate cases of primary Raynaud's phenomenon and VWF, the attack of Raynaud' s phenomeno n being a purely vasos pastic phenomenon.

Possible mechanisms in the vasospastic attack
The digital arteri al closure in response to cold exposure might be due to (i) central sympathetic reflex mechanisms, (ii) anatom ic changes of the arterial wa ll or lumen, (iii) local nervous mechanisms , (iv) mechan isms of circulating vasoactive sub stances, (v) mechanisms of locall y released vasoactive substances other th an those released from nerve endings, (vi) intrinsic myogen ic mechanisms, or (vii) intrinsic passive mechanisms.
Centrally med iated vasomotor acti vities are, in the present paper, syno nymous with central sympathetic refle x mechanisms. Locally mediated vasomoto r activitie s are synonymous with the rest of the possible aforementioned mechanisms . Raynaud (13) in 1862 suggested that the vasospas m was mediated through central sympathetic nervous impul ses. Contradictor y to him Lewis (4) ad vanced the theory that the attack in Raynaud's phenomenon is produced directl y by a local mechanism without the intervent ion of centra l symp athetic nervous impul ses. Together the antagonistic hypotheses of Rayn aud and Lewis constitute the classical theories of the pathophysiolo gical mechanism in the attac k of Raynaud 's phenomenon.

Centrally versus locally mediated vasomotor activities
Lewis performed experiments th a t pro vided ob viou s evidence for his theor y. His first direct evidence (4) was the observati on that complete an esthet ization o f the ulna r nerve did not prevent the digital arteries from being subsequently thrown into a complete spasm by local application of cold on the fifth finger. However he only performed this experiment on two of his patients, both severe cases with dr y gan grene o f the fingers. Lewis (4) felt th at , in milder cases o f Raynaud 's phen omenon , th e impo ssibility of provoking an attack dur ing local an esth esia was du e to the lack of a norm al central sympa thetic vasoconstrictor response, but he could not pro ve th is hypothesis by measur ements . Olsen and his co-wo rkers (10) investigated the sympathetic and local vasoconstrictor response to cold in VWF using the Nielsen-L assen method (8) in its modified form (II). The symp ath etic vasoconstrictor response to cold was estimated to be at least twice as large as the locally mediated respon se. Co ntradictory to the findin gs of Lewis (4), a nd in agreement with tho se of Raynaud (13), these results indicated that the digital arterial closure is mainl y mediated through an exaggerated central sympa thetic reflex mechan ism. The same results have been obtained by the same method using stellate blockade in subjects with prim ar y Raynaud' s pheno meno n (9).
Lewis' second direct evidence for a local mechanism in the attack of Raynaud's phenomenon concerned observations on sympathectomized patients (7). He observed a return of the attacks 2 -10 d after the operation in patients with Raynaud's phenomenon with and witho ut nutrition al changes of the skin of the fingers. He also observed that the full vasodilat ation resulting from preganglioni c sympathectomy declines durin g a period of about one week following an o peration. Lewis co ncluded that sympathecto my do es not bring the fingers to a co mmo n state; it relieves in all cases, but can be displayed in a measur e that is relat ed to the abnormality displayed before the operation. It is however important to notice that non e of his cases sho wed attacks on the first day after sympa thectomy. Nielsen et al (9) studi ed two cases of primary Raynaud ' s phenom enon with out trophic changes by measur ement s of systolic blood pressure in the finger du ring combined local and general cooling. Both pati ents underwent bilat eral upp er thoracic sympathecto my. Th e normal respon se on day I after the ope rat ion indicated that the a ttac k is dominated by central sympat het ic reflex mecha nisms. The subsequent return of attac ks may indicate th at other mechan isms then dominat e.
Though a centra l sympathetic mechanism seems to be the dominant mechanism of an attack , locally mediated mechanisms are not necessarily with out influence. It is reasonable to assume that , in milder cases o f Raynaud's phenomenon , the attack is the result of both types. It only mean s that the central sympathetic reflex mechanism makes the greatest and most pathological contibution to the digital arterial constrictor respon se to cold during a vasospastic attack.

Abnormal link in the central sympathetic reflex arch
The "receptor site" of the central sympathetic reflex is probably located in the cutaneous thermoreceptors, as it is necessary to perform a local cooling of the finger to pro voke an attack of Rayn aud's phenomenon. The "effector site" of the reflex is located in the smooth muscle cell of the cooled digital arteries . Thi s reflex arch exists a nd functions in both normal sub jects and in subjects with severe and milder types of Raynaud's phenomenon. The question is now in which part of the reflex arch including receptors and effe ctor s is the fault located in milder cases of Raynaud's phenomenon? Raynaud (13) suggested that the fault was located in the vasomotor centers of the sympath etic nervou s system. Lewis (4), who advanced the theory that the mechan ism was a local one , found that the fault was located in th e digital arteries, probably in the muscular part of the art erial wall. This location is however also exactly where the "effector site" of the central sympathetic reflex ar ch is placed. Ho wever, as seen fro m newer model s of vasoco nstriction (15), the fault may be located in many other anatomic areas of the reflex ar ch, eg, the thermoreceptors, the afferent nerve fibers, the central vasomotor centers, the efferent sympathetic nerve fiber s, and the neuromuscular synapses (including pre-and postsynaptic receptors or inside the smooth muscle cell). A funct ional defect in an y of th e links of the reflex arch ma y theoretically produce an abn ormal contraction of the digital arteries.
The evidence for a central sympathetic reflex mechanism (9, 10) also implie s that the initial basic fault in primary Rayn aud's phenomenon and VWF is not caused by local axon reflexes, circulating or locall y released vasoactive substances, immunologic reactions, viscosity of the blood , systemic blood pressure, or anatomic changes in the intima and lumen of the digital arteries.

Conclusions
The present selective review on prim ar y Raynaud 's phenom enon and VWF leads to t he following conclusion s: 1. The primary vasop asm is a total closure of the main digital arteries with complete cessation of blood flow.
2. Th e art erial closure is mainl y mediated through an exaggerated central sympathetic reflex mechanism.