Effect of nitric-oxide-generating system on microcirculatory blood flow in skin of patients with severe Raynaud's syndrome: a randomised trial

Tucker, A.; Pearson, Richard M.; Cooke, E. D.; Benjamin, Nigel

doi:10.1016/s0140-6736(99)04095-7

Cited by 97 publications

(54 citation statements)

References 25 publications

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“…Placebo-controlled studies have demonstrated a vasodilator response of skin vessels, which can be assessed with photoplethysmography or laser Doppler techniques. The application of 5 % sodium nitrite [42] or 2 % glycerol trinitrate (GTN) [43] to the skin of the forearm or fi ngers has been demonstrated to be eff ective in patients with primary RP and limited cutaneous SSc and in healthy control subjects as well. Both sodium nitrite and GTN exert their eff ects by being rapidly converted to nitric oxide, which is a potent natural vasodilator.…”

Section: Other Oral Vasodilatorsmentioning

confidence: 99%

“…Peripheral arterial disease due to atherosclerosis is the most common cause of RP in the elderly. Only recently, Nietert et al demonstrated an association between older RP manifestation age and increased all-cause mortality [ ESM 2,42]. In their analysis, including 830 participants in the Charleston Heart Study who were followed for approximately 20 years, there was a 1.6-fold increase in cardiovascular mortality (HR 1.55; 95 CI 1.10 -2.20).…”

Section: Prognosis and Follow-upmentioning

confidence: 99%

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Raynaud’s phenomenon and digital ischaemia - pharmacologic approach and alternative treatment options

Linnemann

Erbe

2016

Vasa

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Summary:The primary goal of therapy is to reduce the frequency and intensity of Raynaud's attacks and to minimize the related morbidity rather than to cure the underlying condition. Treatment strategies depend on whether Raynaud's phenomenon (RP) is primary or secondary. All patients should be instructed about general measures to maintain body warmth and to avoid triggers of RP attacks. Pharmacologic intervention can be useful for patients with severe and frequent RP episodes that impair the patient's quality of life. Calcium channel blockers are currently the most prescribed and studied medications for this purpose. There has been limited evidence for the effi cacy of alpha-1-adrenergic receptor antagonists, angiotensin receptor blockers, topical nitrates or fl uoxetine to treat RP. The intravenously administered prostacyclin analogue iloprost can reduce the frequency and severity of RP attacks and is considered a second-line therapy in patients with markedly impaired quality of life, critical digital ischaemia and skin ulcers who are at risk for substantial tissue loss and amputation. Phosphodiesterase inhibitors (e.g., sildenafi l) can also improve RP symptoms and ulcer healing whereas endothelin-1 receptor antagonists (e.g., bosentan) are mainly considered treatment options in secondary prevention for patients with digital skin ulcers related to systemic sclerosis. However, their use in clinical practice has been limited by their high cost. Antiplatelet therapy with low-dose aspirin is recommended for all patients who suffer from secondary RP due to ischaemia caused by structural vessel damage. Anticoagulant therapy can be considered during the acute phase of digital ischaemia in patients with suspected vascular occlusive disease attributed to the occurrence of new thromboses. In patients with critical digital ischaemia, consideration should be given to hospitalisation, optimisation of medical treatment in accordance with the underlying disease and evaluation for a secondary, possibly reversible process that is causing or aggravating the clinical symptoms.

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Section: Other Oral Vasodilatorsmentioning

confidence: 99%

Section: Prognosis and Follow-upmentioning

confidence: 99%

Raynaud’s phenomenon and digital ischaemia - pharmacologic approach and alternative treatment options

Linnemann

Erbe

2016

Vasa

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“…In this regard, although abnormalities of both conduit and microvascular endothelial function have been demonstrated in RP, the contribution of these 2 levels of circulation in explaining the differential features in primary and secondary RP requires further definition (3,4,10,11). Recently, a novel circulating endogenous inhibitor of endothelial nitric oxide synthase (eNOS), called asymmetric dimethylarginine (ADMA), has been described (12).…”

mentioning

confidence: 99%

Increased asymmetric dimethylarginine and endothelin 1 levels in secondary Raynaud's phenomenon: Implications for vascular dysfunction and progression of disease

Rajagopalan

Pfenninger

Kehrer

et al. 2003

Arthritis & Rheumatism

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Objective. To compare microvascular and macrovascular functions in a cohort of patients with primary and secondary Raynaud's phenomenon (RP) who were matched for demographic, risk factor, and severity profiles.Methods. Forty patients with primary or secondary RP matched for vascular risk factors and severity scores underwent testing of endothelial function and cold pressor responsiveness of the brachial artery. Microvascular perfusion of the digital vasculature was assessed using laser Doppler fluxmetry in response to reactive hyperemia. Plasma was assayed for endothelin 1 (ET-1), asymmetric dimethylarginine (ADMA), intercellular adhesion molecule 1, vascular cell adhesion molecule 1 (VCAM-1), and monocyte chemoattractant protein 1 (MCP-1).Results. Patients with RP had abnormal vasoconstrictor responses to cold pressor tests (CPT) that were similar in primary and secondary RP. There were no differences in median flow-mediated and nitroglycerinmediated dilation or CPT of the brachial artery in the 2 populations. Patients with secondary RP were characterized by abnormalities in microvascular responses to reactive hyperemia, with a reduction in area under the curve adjusted for baseline perfusion, but not in time to peak response or peak perfusion ratio. Plasma ET-1, ADMA, VCAM-1, and MCP-1 levels were significantly elevated in secondary RP compared with primary RP. There was a significant negative correlation between ET-1 and ADMA values and measures of microvascular perfusion but not macrovascular endothelial function.Conclusion. Secondary RP is characterized by elevations in plasma ET-1 and ADMA levels that may contribute to alterations in cutaneous microvascular function.

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“…This is an unexpected result, since NO is a very potent vasodilator and the present NO-generating system could be expected to yield local concentrations high enough to cause vasodilatation (Tucker et al, 1998). Since the structural characteristics of the dorsal and abdominal epidermis are similar (Peltonen et al, 1998), the barrier to penetration by NO would be similar in these areas.…”

Section: Aspects Of the Local Effects Of No On Skin Blood Flowmentioning

confidence: 82%

“…A gel generating nitric oxide was prepared as described in detail by Tucker et al (1998). Briefly, NO can be generated in Effects of exogenous nitric oxide on skin blood flow in pigeons large amounts through the rapid reduction of nitrite (A) by ascorbic acid (B).…”

Section: Local Stimulation Of Skin Blood Flow By Nitric Oxidementioning

confidence: 99%

Local action of exogenous nitric oxide (NO) on the skin blood flow of rock pigeons (Columba livia) is affected by acclimation and skin site

Peltonen

Pyörnilä

2004

Journal of Experimental Biology

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SUMMARY We studied the blood flow over dorsal and abdominal, non-brooding patch skin of two groups of pigeons: one group was thermally acclimated to cold(winter-acclimatized, WAC) while the other group was acclimated to a mesic environment (thermally non-challenged, NOC). Two bilateral patches at the measurement sites were treated simultaneously with a gel containing sodium nitrate and ascorbic acid, to generate nitric oxide (NO), and a vehicle gel. Blood flow was measured by laser Doppler velocimetry. Changes induced by these treatments were calculated against basic blood flow values for the corresponding patch. The results showed that the basic blood flow over the abdominal skin patches at room temperature was higher than over the dorsal skin in both acclimation states, but comparison revealed a sustainably higher level of basic skin blood flow in the WAC pigeons. The local response to exogenous NO was non-uniform over the two skin areas measured, and a specific vasodilatory action on the abdominal microvessels was recorded in the NOC pigeons. Abdominal vasodilatation in the WAC pigeons seemed to involve other mechanisms as well as local NO-dependent ones, among which the role of cold-induced vasodilatation (CIVD) is discussed here. Interestingly, the dorsal skin seemed to be less responsive to the action of NO, irrespective of the acclimation state. Our results show that acclimation state and skin site affect the action of exogenous NO on local skin blood flow, and we suggest that the differences reflect acclimation-induced changes in the vascularity of the skin and in its sensitivity to thermal stimuli and that the roles of the abdominal and dorsal skin are different with respect to environmental changes.

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Effect of nitric-oxide-generating system on microcirculatory blood flow in skin of patients with severe Raynaud's syndrome: a randomised trial

Cited by 97 publications

References 25 publications

Raynaud’s phenomenon and digital ischaemia - pharmacologic approach and alternative treatment options

Raynaud’s phenomenon and digital ischaemia - pharmacologic approach and alternative treatment options

Increased asymmetric dimethylarginine and endothelin 1 levels in secondary Raynaud's phenomenon: Implications for vascular dysfunction and progression of disease

Local action of exogenous nitric oxide (NO) on the skin blood flow of rock pigeons (Columba livia) is affected by acclimation and skin site

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