We have recently demonstrated that the vasospastic attacks of Raynaud's disease can be provoked despite digital nerve blockade and that local cooling produces increases in alpha-adrenergic responsiveness not found in normal volunteers. To more precisely determine the etiology of primary Raynaud's disease, it is necessary to determine whether abnormalities of alpha1 receptors, alpha2 receptors, or both are necessary for the occurrence of a vasospastic attack. We propose to examine this question by infusing intraarterially an alpha1 antagonist, an alpha2 antagonist, and both antagonists while provoking attacks with environmental and local cooling (Study 1). Since our investigations have thus far utilized synthetic adrenergic drugs it is important to determine the endogenous vasoconstrictive compound involved in Raynaud's attacks. Since norepinephrine is highly potent at peripheral vascular adrenoceptors, we propose to study its effects in cooled and uncooled fingers of Raynaud's disease patients and controls (Study 2). We have identified abnormalities of alpha-adrenergic receptors in Raynaud's disease patients and have recently demonstrated familial aggregation of this disorder. Since alpha-adrenergic receptors are under genetic control, we propose to see if mutations of these genes are involved in the occurrence of Raynaud's disease (Study 5). We have shown that feedback-induced vasodilation is mediated in part by a nonneural beta-adrenergic vasodilating mechanism and not through changes in plasma catecholamines. A beta-adrenergic vasodilating mechanism having the same time course as feedback-induced vasodilation has recently been demonstrated on vascular endothelium. We propose to determine the involvement of vascular endothelium in feedback-induced vasodilation using a compound that specifically inhibits endothelium- mediated vasodilation (Study 3). Despite much research on temperature biofeedback, little has been done on the brain mechanisms involved. A new MRI (magnetic resonance imaging) method permits the noninvasive measurement of brain blood flow with excellent spatial and temporal resolution. We propose to measure brain blood flow by MRI before and after training in temperature feedback or a credible control procedure (Study 4).

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National Heart, Lung, and Blood Institute (NHLBI)
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Behavioral Medicine Study Section (BEM)
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Wayne State University
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Furspan, P B; Chatterjee, S; Mayes, M D et al. (2005) Cooling-induced contraction and protein tyrosine kinase activity of isolated arterioles in secondary Raynaud's phenomenon. Rheumatology (Oxford) 44:488-94
Freedman, R R; Girgis, R; Mayes, M D (2001) Abnormal responses to endothelial agonists in Raynaud's phenomenon and scleroderma. J Rheumatol 28:119-21
Furspan, P B; Mayes, M D; Freedman, R R (2001) Effect of temperature and modulators of protein tyrosine kinase activity on the reactivity of isolated venules in secondary Raynaud's phenomenon. J Rheumatol 28:2263-8
Freedman, R R; Girgis, R (2000) Effects of menstrual cycle and race on peripheral vascular alpha-adrenergic responsiveness. Hypertension 35:795-9
Freedman, R R; Girgis, R; Mayes, M D (1999) Endothelial and adrenergic dysfunction in Raynaud's phenomenon and scleroderma. J Rheumatol 26:2386-8
Freedman, R R; Girgis, R; Mayes, M D (1999) Acute effect of nitric oxide on Raynaud's phenomenon in scleroderma. Lancet 354:739
Song, J; Ram, J L; Furspan, P et al. (1996) Differences in alpha2-adrenoceptor modulation of calcium channels in vascular smooth muscle cells of male and female rats. Pflugers Arch 433:212-4
Freedman, R R; Mayes, M D (1996) Familial aggregation of primary Raynaud's disease. Arthritis Rheum 39:1189-91
Freedman, R R; Baer, R P; Mayes, M D (1995) Blockade of vasospastic attacks by alpha 2-adrenergic but not alpha 1-adrenergic antagonists in idiopathic Raynaud's disease. Circulation 92:1448-51
Freedman, R R; Keegan, D; Rodriguez, J et al. (1993) Plasma catecholamine levels during temperature biofeedback training in normal subjects. Biofeedback Self Regul 18:107-14

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