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Raynaud's disease is characterized by excessive cutaneous vasoconstriction in response to ambient cold. A functional disturbance in the local regulation of digital vasomotion has been proposed. The purpose of this study was to determine whether there is an alteration in the postjunctional adrenergic receptors in the digital circulation of patients with Raynaud's disease. Furthermore, we sought to determine whether this abnormality was responsible for the excessive cold-induced vasoconstriction in these patients.Finger blood flow was measured by strain-gauge venous occlusion plethysmography in 10 patients with Raynaud's disease and in 10 normal volunteers in a 22 °C room. Measurements of finger blood flow and mean systemic arterial pressure were made during intra-arterial infusions of the alpha1-adrenergic antagonist, prazosjn, or the alpha2-adrenergic antagonist, yohimbine, at room temperature and during local cooling of the hand. Basal finger blood flow in normal subjects was significantly greater than that of patients (8.6 ± 2.7 vs 1.7 ± 0.5 ml/100 ml per min; normal vs Raynaud's subjects; p< 0.05). In normal subjects, either prazosin or yohimbine induced dose-dependent increases in finger blood flow. The maximal increase in finger blood flow induced by prazosin was significantly greater than that in response to yohimbine (29.2 ± 10.1 vs 2.8 ± 2.1 ml/100 ml per min; prazosin vs yohimbine; p< 0.05). By contrast, in the Raynaud's patients, prazosin or yohimbine induced maximal increases in finger blood flow that were not significant (7.1 ± 1.8 vs 5.0 ± 2.2 ml/100 ml per min; prazosin vs yohimbine; p= NS). The response to prazosin in Raynaud's patients was significantly less than that of the normal volunteers (p< 0.05). In normal subjects, during intra-arterial infusion of vehicle alone, cooling induced a 52.6 ± 5.8% reduction in finger blood flow. This cold-induced vasoconstriction was blunted, but not qualitatively altered, by either adrenergic antagonist. In the Raynaud's patients, during the intra-arterial infusion of the vehicle, cooling induced a 68.2 ± 7.8% reduction in finger blood flow. Infusion of either adrenergic antagonist blunted, but did not qualitatively alter, the response to cold.Finger blood flow is less in patients with Raynaud's disease than in normal subjects when studied in a 22 °C room. In normal subjects, postjunctional alpha1-adrenergic receptors appear to predominate in the control of digital vasoconstriction. Postjunctional alpha1- and alpha2- adrenoceptors play an equal role in adrenergic regulation of finger blood flow in patients with Raynaud's disease. In both normal and Raynaud's subjects, selective antagonism of alpha1- or alpha2-adrenergic receptors does not abolish local cold-induced vasoconstriction. Therefore, it is likely that a nonadrenergic mechanism contributes to local cold-induced vasoconstriction.

Coronary atherosclerosis is characterized by an early loss of endothelium-dependent vasodilation. However, the methods of assessing coronary endothelial function are invasive and difficult to repeat over time. Recently, a noninvasive ultrasound method has been widely used to measure flow-mediated dilation in the brachial artery as a surrogate test for endothelial function. We seek to further validate this method of measuring vascular function.The brachial artery diameters and blood flow of 20 normal volunteers (10 males and 10 females) were measured using high resolution (7.5 MHz) ultrasound and strain gauge plethysmography. Flow-mediated endothelium-dependent vasodilation was measured in the brachial artery during reactive hyperemia after 5 minutes of cuff occlusion in the upper arm. The brachial artery diameter increased maximally by 9.7 ± 4.3% from baseline at 1 min after cuff release and blood flow increased by 1002 ± 376%. Five min of cuff occlusion was sufficient to achieve 97 ± 6% of maximal brachial artery dilation and degree of dilation was not different whether the cuff was inflated proximally or distally to the image site. The intraobserver variability in measuring brachial diameters was 2.9 % and the variability of the hyperemic response was 1.4%. In young, healthy men and women, the baseline brachial artery diameter was the only factor that was predictive of the flow-mediated vasodilation response.The brachial noninvasive technique has been further validated by the determination of flow-mediated dilation. This method of assessing endothelial function may help to determine the importance of vasodilator dysfunction as a risk factor in the development of atherosclerosis.

Intermittent claudication is the most common symptom of peripheral arterial disease (PAD), in part due to an inadequate rise in limb blood flow with exercise. Claudication causes a severe impairment in functional capacity and quality of life in over 3 million Americans. Basic fibroblast growth factor (bFGF) stimulates angiogenesis in vivo and improves limb blood flow in several animal models of hindlimb ischemia. However, the relative safety and efficacy of angiogenic molecules in the treatment of claudication has not been fully evaluated in prospective, blinded clinical trials. In this study, a randomized, double-blind, placebo-controlled, phase II trial of recombinant human bFGF for the treatment of intermittent claudication was performed. bFGF was administered weekly by intravenous infusions of 2 μg/kg for 6 sequential weeks (total dose 12 μg/kg). The primary efficacy endpoint was change in peak walking time (PWT) on a graded exercise treadmill protocol. Secondary efficacy endpoints included changes in functional status as measured by validated questionnaires. The study was stopped prematurely after treatment of the first 24 subjects due to proteinuria in five of the 16 subjects who received systemic bFGF, which exceeded 1000 mg/24 h in four of these five subjects. The small sample size limited evaluation of the predefined efficacy endpoints; however, there was no significant difference between the treatment and control groups for any of the measures of efficacy. In conclusion, intravenous administration of bFGF delivered at low doses weekly for 6 weeks was associated with a high rate of severe proteinuria. It is speculated that bFGF-related proteinuria in this study was primarily related to the systemic route of administration and the frequent dosing schedule. Future clinical trials of bFGF protein should carefully monitor renal function and consider alternative dosing schedules and drug administration routes.