The long-term objective is to detect and quantitate differnces in the pathophysiologic determinants of digital blood flow amongst normal subjects, patients with idiopathic Raynaud's disease, and patients with Raynaud's phenomenon secondary to scleroderma. The main thrust is to understand the abnormalities leading to digital artery vasospasm.
The specific aim i s to determine the importance of serotonin in the physiological control of digital blood flow in normal subjects and in the vasospasm of digital vessels in patients with Raynaud's phenomenon. Total fingertip blood flow will be measured by venous occlusion, air plethysmography and capillary flow by the disappearance rate of a radioisotope from a local injection in the fingertip. Arteriovenous shunt flow can be estimated by the difference between the two flows. The effect of intra-arterial 5-hydroxytryptamine on finger flow will be determined in normal subjects to assure that the vascular bed reacts to serotonin. The action of a S2-serotonergic receptor antagonist, ketanserin, on finger flow during reflex sympathetic vasoconstriction will be studied in normal subjects and patients with Raynaud's phenomenon to determine if serotonin is causing vasoconstriction. Experiments will be performed with prazosin to prove that alpha-1 adrenoceptors are not being blocked by ketanserin; dose-response curves to ketanserin will be determined to rule out non-specific effects; the blocking action will be studied in subjects vasoconstricted by angiotensin to determine if only sympathetic vasoconstriction is involved; and other vasoconstrictor agents (clonidine, angiotensin) will be given after ketanserin to determine the specificity of the response. The interaction of norepinephrine and serotonin, which has been shown in in vitro studies, will be studied by administering norepinephrine before and during 5HT intra-arterial infusions. Finger flows will be measured in nerve-blocked fingers before and during local cooling with the administration of 5HT and norepinephrine to look for potentiation of vasoconstrictor responses, and before and during ketanserin and nifedipine to determine the mechanism of vasoconstriction due to local cooling. Finally, patients with platelets depleted of serotonin will be studied to search for the source of the serotonin. These studies should determine if serotonin is involved in the normal physiologic control of finger flow during sympathetic stimulation and local cooling and if it might be involved in pathophysiologic digital vasospasm.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL026320-08
Application #
3338566
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1980-08-01
Project End
1990-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
8
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Boston University
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02118
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Coffman, J D (1994) The diagnosis of Raynaud's phenomenon. Clin Dermatol 12:283-9
Coffman, J D (1994) Effects of endothelium-derived nitric oxide on skin and digital blood flow in humans. Am J Physiol 267:H2087-90
Khan, F; Coffman, J D (1994) Enhanced cholinergic cutaneous vasodilation in Raynaud's phenomenon. Circulation 89:1183-8
Coffman, J D; Cohen, R A (1994) Plasma levels of 5-hydroxytryptamine during sympathetic stimulation and in Raynaud's phenomenon. Clin Sci (Lond) 86:269-73
Khan, F; Palacino, J J; Coffman, J D et al. (1993) Chronic inhibition of nitric oxide production augments skin vasoconstriction in the rabbit ear. J Cardiovasc Pharmacol 22:280-6
Coffman, J D (1992) Alpha-adrenergic and serotonergic receptors and forearm venous compliance in normal human subjects. J Cardiovasc Pharmacol 19:996-9
Coffman, J D (1990) Pathogenesis and treatment of Raynaud's phenomenon. Cardiovasc Drugs Ther 4 Suppl 1:45-51
Coffman, J D; Cohen, R A (1988) Role of alpha-adrenoceptor subtypes mediating sympathetic vasoconstriction in human digits. Eur J Clin Invest 18:309-13
Coffman, J D; Cohen, R A (1988) Serotonergic vasoconstriction in human fingers during reflex sympathetic response to cooling. Am J Physiol 254:H889-93

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