1. The vasospasm of primary Raynaud's disease can be triggered by acute emotional stress. We have studied the pattern of cardiovascular response evoked by acute emotional stress, a sound stimulus of 90 dB, 2 kHz for 30 s, in eight subjects with primary Raynaud's disease and in eight age- and sex-matched controls, the sound being repeated five times on each of days 1, 3 and 5. 2. In controls, the first sound evoked the pattern of the alerting response that is characteristic of acute emotional stress: a rise in arterial pressure and heart rate, a decrease in vascular conductance in the cutaneous circulation of the digit, assessed by laser Doppler recording of erythrocyte (red cell) flux in the digit divided by arterial pressure, and an increase in forearm muscle vascular conductance, assessed from forearm blood flow recorded by venous occlusion plethysmography divided by arterial pressure. 3. In the subjects with primary Raynaud's disease, baselines of arterial pressure, digital cutaneous vascular conductance and forearm vascular conductance were not significantly different from those of the controls and they too showed the alerting response to the first sound, the magnitudes of the changes being comparable to those of the controls. 4. In both the controls and subjects with primary Raynaud's disease, the evoked responses were consistent on repetition of the sound on day 1. In contrast, judging from the means of the changes evoked on each day, the controls showed habituation of the individual components of the alerting response over days 1, 3 and 5, whereas the subjects with primary Raynaud's disease showed no habituation of either the forearm muscle vasodilatation or the digital vasoconstriction. Conversely, the decrease in digital cutaneous vascular conductance evoked by a single deep breath was fully reproducible in both controls and subjects with primary Raynaud's disease when tested at the beginning and end of each experimental day. 5. These results allow the novel conclusion that subjects with primary Raynaud's disease have an abnormality of the central neural modulation of the brain stem areas that integrate the cardiovascular components of the alerting response to acute emotional stress, such that habituation of the vasodilator and vasoconstrictor components of the response on repetition of the stimulus is impaired. We propose that such persistence of vasoconstrictor responses to stressful stimuli predisposes to vasospasm, particularly if neurally mediated vasoconstriction is reinforced by locally released vasoconstrictor factors.
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 this pattern of response habituates on repetition of the sound stimulus in control subjects, both cutaneous vasoconstriction and muscle dilatation persist in subjects with primary Raynaud's disease. The aim of the present study was to test whether a similar disparity exists between control subjects and those with primary Raynaud's disease for the response to mild cool stimuli, and whether the cutaneous response is accompanied by the release of endothelin-1 (ET-1). In nine subjects with primary Raynaud's disease and in nine matched controls, the left hand was placed in cool water at 16 degrees C for 2 min five times on each of three experimental sessions on days 1, 3 and 5, with blood being taken from the venous drainage of the cooled hand before and at the end of the second session. In response to the first cool stimulus in Session 1, the subjects with primary Raynaud's disease showed a decrease in digital cutaneous vascular conductance (DCVC) in both the right and left hands, as indicated by a laser Doppler recording of erythrocyte (red cell) flux divided by arterial pressure, and six of the nine subjects showed an increase in forearm vascular conductance (FVC), as indicated by forearm blood flow measured by plethysmography divided by arterial pressure. On repetition of the stimulus in Session 1, there was no change in the magnitude of the increase in FVC, but the evoked decreases in DCVC became more prolonged 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 baseline value of 2.15+/-0.26 fM to 2.72+/-0.37 fM after five stimuli. There was no habituation of the increase in FVC over Sessions 1, 2 and 3, judging 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. However, on repetition of the stimulus in Session 1, the increase in FVC habituated, while there was no prolongation of the decrease in DCVC; in addition, the ET-1 concentration did not change in Session 2 in response to the stimulus (2.07+/-0.28 compared with 2.29+/-0.30 fM). Further, the increase in FVC habituated over the three sessions, such that there was a mean decrease in FVC in Session 3. These results indicate that, in subjects with primary 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. We propose that persistence of the cutaneous vasoconstriction of the alerting response, coupled with increased release of ET-1 secondary to vasoconstriction, prolongs such vasoconstriction and eventually leads to vasospasm.
Decreases in the infrared spectroscopic amide A frequencies from 3308 to 3291 cm-1 of native purple membrane as a function of pressure are consistent with a gradual αII- to αI-helical conversion for the transmembrane helixes of bacteriorhodopsin. This structural transition reaches completion near 3.7 kbar. Only negligible frequency shifts are observed, however, as a function of pressure in the 1660 cm-1 amide I region, suggesting that additional factors such as hydrogen bonding and helix−helix interactions are important in modulating the frequency of this mode. The pressure dependence of the feature at 2927 cm-1, arising from a Fermi resonance couplet originating from both protein and lipid methyl groups, indicates that global environmental changes occur near 4 kbar.
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