Cardiovascular responses evoked by mild cool stimuli in primary Raynaud's disease: the role of endothelin

In control subjects and in subjects with primary Raynaud's disease, sudden sound evokes the pattern of the alerting response, which includes cutaneous vasoconstriction and vasodilatation in forearm muscle. However, whereas th is pattern of response habituates on repetition of the sound stimulus in co ntrol subjects, both cutaneous vasoconstriction and muscle dilatation persi st in subjects with primary Raynaud's disease. The aim of the present study was to test whether a similar disparity exists between control subjects an d those with primary Raynaud's disease for the response to mild cool stimul i, and whether the cutaneous response is accompanied by the release of endo thelin-1 (ET-1). In nine subjects with primary Raynaud's disease and in nin e matched controls, the left hand was placed in cool water at 16 degrees C for 2 min five times on each of th ree experimental sessions on days 1, 3 a nd 5, with blood being taken from the venous drainage of the cooled hand be fore and at the end of the second session. In response to the first cool st imulus in Session 1, the subjects with primary Raynaud's disease showed a d ecrease in digital cutaneous vascular conductance (DCVC) in both the right and left hands, as indicated by a laser Doppler recording of erythrocyte (r ed cell) flux divided by arterial pressure, and six of the nine subjects sh owed an increase in forearm vascular conductance (FVC), as indicated by for earm blood flow measured by plethysmography divided by arterial pressure. O n repetition of the stimulus in Session 1, there was no change in the magni tude of the increase in FVC, but the evoked decreases in DCVC became more p rolonged in both the right and the left hand. Similar responses occurred in Sessions 2 and 3; in Session 2, the ET-1 concentration increased from a ba seline value of 2.15 +/- 0.26 fM to 2.72 +/- 0.37 fM after five stimuli. Th ere was no habituation of the increase in FVC over Sessions 1, 2 and 3, jud ging from the mean changes in each session. Control subjects also showed a decrease in DCVC in both hands, and in eight out of nine subjects there was an increase in FVC in response to the first cool stimulus in Session 1. Ho wever, on repetition of the stimulus in Session 1, the increase in FVC habi tuated, while there was no prolongation of the decrease in DCVC; in additio n, the ET-1 concentration did not change in Session 2 in response to the st imulus (2.07 +/- 0.28 compared with 2.29 +/- 0.30 fM). Further, the increas e in FVC habituated over the three sessions, such that there was a mean dec rease in FVC in Session 3. These results indicate that, in subjects with pr imary Raynaud's disease, there is impairment of the ability of the central nervous system to allow habituation of the cardiovascular components of the alerting response evoked by mild cooling, as with the response to sound. W e propose that persistence of the cutaneous vasoconstriction of the alertin g response, coupled with increased release of ET-1 secondary to vasoconstri ction, prolongs such vasoconstriction and eventually leads to vasospasm.