endothelin-1 and Raynaud-Disease

Current knowledge about the pathogenesis of Raynaud's phenomenon (RP) results in novel approaches for therapy. Vasospasm without endothelial damage is thought to be the main cause for primary RP. The pathogenesis of secondary forms of RP is supposed to be initiated primary by endothelial damage. The aim of the review is to present main groups of medications as well as non-pharmacological regimen, that are used for the treatment of RP. The necessity of immediate assessment and treatment in severe forms of the disease with digital ulcers is highlighted. The mild forms of primary RP can be controlled by non-pharmacologic approaches. If the effect is insufficient, medications of first choice are calcium channel blockers. In the severe forms of the disorder, intravenous infusion of prostacyclin as well as endothelin-1 receptor antagonists and specific inhibitors of phosphodiesterase-5 are the treatment of choice. Treatment in the future may include selective blockers of alpha-2c adrenergic receptors, inhibitors of protein tyrosine kinase and Rho-kinase, as well as calcitonin gene-related peptide.

Topics: Endothelin A Receptor Antagonists; Endothelin-1; Epoprostenol; Humans; Randomized Controlled Trials as Topic; Raynaud Disease; Receptor, Endothelin A; Treatment Outcome

The endothelium-derived 21 amino acid peptide endothelin-1 is one of the most potent vasoconstrictors. Endothelin-1 exerts its effects upon a variety of vascular and non-vascular cells through a direct interaction with specific receptors. Beyond its vasoconstrictive action on vascular smooth muscle cells endothelin-1 has mitogenic and pro-inflammatory properties. The present review deals with current experimental and clinical evidence for the involvement of endothelin-1 in several cardiovascular disorders with inflammatory components. We further discuss the potential clinical relevance of the endothelin system and therapeutical perspectives of anti-endothelin strategies in the treatment of cardiovascular disease.

Topics: Cardiovascular Diseases; Endothelin-1; Endothelium, Vascular; Humans; Muscle, Smooth, Vascular; Raynaud Disease; Vasoconstriction

The literature on Raynaud's phenomenon (RP) describes a complex and confusing picture of abnormalities that has suggested a multifactorial aetiology. Current research suggests that the underlying disorder is related to a local fault at the level of the digital microcirculation. It is likely that many of the biological changes described in RP are secondary manifestations of this primary abnormality. The strong familial relationship of RP suggests a genetic link although this has not yet been characterized. An overactivity of the sympathetic nervous system appears less likely as a candidate for the primary abnormality and dysfunction at the level of the nerve, and vessel wall may be more important. Digital cutaneous neurones show a deficient release of the vasodilatory calcitonin gene related peptide in PR. This may represent a primary fault that is confounded by other factors, which are influenced by cold or emotional triggers. Vasoconstricting substances such as catecholamines, endothelin-1 and 5-hydroxytryptamine, which may all be released in response to cold exposure, could cause digital artery closure and the associated symptoms of RP. In some cases, this would trigger a cascade of neutrophil and platelet activation, which through the release of inflammatory mediators, contribute to the endothelial damage seen with more severe RP. It is hypothesised that disturbance to the intricate functioning of the endothelium, and secondary compensation at local or systemic level, may appear over time. There is, therefore, still a need to differentiate the true aetiological factors from those that are causal associations with Raynaud's phenomenon. Progress is slowly being made with better understanding of the intricacies between these factors and the microcirculation. Deepening our comprehension of the 'normal' mechanisms that influence microvascular blood flow is necessary to develop a better understanding of the pathophysiology of Raynaud's phenomenon.

Topics: Blood Platelets; Calcitonin Gene-Related Peptide; Endothelin-1; Estrogens; Humans; Microcirculation; Neutrophils; Nitric Oxide; Raynaud Disease

Despite over a century of investigation, the pathophysiology of Raynaud's phenomenon remains an enigma. The two main theories of the cause of digital artery vasospasm are increased activity of the sympathetic nervous system and a local fault in the digital vasculature. An increased sensitivity and/or concentration of alpha-2 adrenoreceptors is suggested. The activation of serotoninergic receptors may play a role in the maintenance of vasospasm. The recently discovered increase in the vasoconstrictive peptide endothelin-1 and the quantitative deficit in the potent vasodilating calcitonin gene-related peptide may lead to a better understanding of vasospasm mechanisms and open the field for new therapeutical approaches to Raynaud's phenomenon.

Topics: Calcitonin Gene-Related Peptide; Endothelin-1; Humans; Raynaud Disease; Receptors, Adrenergic; Receptors, Serotonin; Sympathetic Nervous System

The endothelin family of peptides are extremely potent endogenous vasoconstrictor and pressor agents. Of the 3 isoforms, endothelin-1 is the major isoform produced by the vascular endothelium and is, therefore, likely to be of most importance for regulation of vascular function. Two endothelin receptor subtypes have so far been cloned in mammalian species; ET A, and ET B. Both receptor subtypes are found on smooth muscle cells and mediate the vasoconstrictor and pressor actions of endothelin. The ET B receptor is also found on vascular endothelial cells and mediates endothelin-dependent vasodilatation through release of nitric oxide and prostacyclin. Since their discovery in 1988, the endothelins have been the subject of intense research on their physiological function and potential pathophysiological role in cardiovascular disease. There is now good evidence that endothelin regulates vascular tone and blood pressure, and studies to support the development of endothelin receptor antagonists in conditions associated with chronic vasoconstriction, such as hypertension and heart failure, as well as in vasospastic disorders, such as subarachnoid haemorrhage and Raynaud's disease. There are now a number of selective ET A and combined ET A/B receptor antagonists available for preclinical studies. However, it is still not clear which of these will prove to be of most therapeutic value. Some of these agents are currently being assessed in early phase clinical trials. Endothelin receptor antagonists represent a novel therapeutic approach to a fundamental and newly discovered endogenous vasoconstrictor mechanism. The results of the current clinical trials are awaited with considerable interest.

Topics: Amino Acid Sequence; Animals; Cardiovascular Diseases; Coronary Disease; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Humans; Hypertension; Migraine Disorders; Raynaud Disease; Subarachnoid Hemorrhage

Endothelial and vascular damage are main leading disability in systemic sclerosis (SSc). Raynaud's phenomenon is the early symptom that presents vascular damage. Nailfold capillaroscopy (NFC) is an easily accessible diagnostic tool in secondary Raynaud's phenomenon. Considering the endothelial damage, clinical manifestations, and plasma cytokines was compared with traditionally used NFC parameter for, which to observe the number of capillaries, deletions in 3 mm, apical limb width and the capillary width itself. We hypothesize that a computer-based NFC system can generate a new powerful parameter which predicts the capillary dimension. We investigated the relationship among the plasma endothelin-1 (ET-1), clinical manifestations and quantitative analysis of computerized NFC, and to assess the optimal method in SSc. The level of ET-1 in 60 SSc patients, 30 healthy, and 23 disease controls were measured by enzyme-linked immunosorbent assay (ELISA) kit. We present a significant difference in all parameters of NFC between SSc patients and control groups. ET-1 level was increased in patients with SSc. In SSc group, capillary dimension and loss of capillaries were strongly associated with digital ulceration (p < 0.01) and pulmonary hypertension (p < 0.05). Capillary dimension and ET-1 level was in correlation with skin-hardening grade, and was higher in SSc patients with pulmonary hypertension or digital ulcer. Capillary dimension showed strong correlation with the endothelin-1 in SSc, healthy and disease control groups. (Rs = 0.31/p < 0.05, Rs = 0.82/p < 0.001, Rs = 0.83/p < 0.001). The results suggest that computer-based microscopic analysis of NFC is a useful method that potentially provides information on organ involvement and plasma ET-1. Capillary dimension maybe a powerful parameter possibly applicable in outpatient clinic for assessing SSc patients.

Topics: Adolescent; Adult; Aged; Biomarkers; Capillaries; Endothelin-1; Female; Humans; Image Processing, Computer-Assisted; Male; Microscopic Angioscopy; Middle Aged; Nails; Predictive Value of Tests; Raynaud Disease; Scleroderma, Systemic; Young Adult

Steal syndrome is a well-known complication of arteriovenous shunt placement. Increased frequency of Raynaud's phenomenon (RP) especially concerning shunt limb is reported among hemodialysis (HD) patients. The aim of the study was to assess the relation of impairment of peripheral circulation diagnosed with cold stress test (CST) and thermography to the AV shunt location and markers of endothelial dysfunction in HD patients.. The study group comprised 21 patients (6 male, 15 female, mean age 32.6 +/- 15.0 years) treated with HD for a mean of 69 +/- 54 months. 10 healthy individuals (4 male, 6 female, mean age 38.6 +/- 14.7 years) served as controls. The diagnosis of RP was made upon the results of thermographic measurements during CST. Von Willebrand factor activity and antigen, endothelin-1 and plasma total homocysteine (tHcy) were measured in all subjects.. RP was found significantly more often in HD patients than in controls: 11/21 vs. 1/10 (p = 0.04). RP occurred in both hands in 7/11 (64%) patients. tHcy was higher in HD patients than in the controls (31.7 +/- 13.9 vs. 10.9 +/- 3.2 microg/l, p < 0.0001). tHcy and von Willebrand factor antigen were significantly higher in the RP-positive than RP-negative patients or controls.. Small vessel dysfunction diagnosed as positive RP is a frequent finding in HD patients. It seems that endothelial injury rather than AV shunt steal syndrome is responsible for development of RP in HD patients.

Topics: Adolescent; Adult; Endothelin-1; Endothelium, Vascular; Female; Hand; Homocysteine; Humans; Kidney Failure, Chronic; Male; Middle Aged; Raynaud Disease; Renal Dialysis; von Willebrand Factor

Endothelin-1 (ET-1) has been implicated in the pathogenesis of Raynaud's disease (RD). This study examined the effect of cooling on the response to ET-1 in human microvessels. Subcutaneous small arteries were dissected from gluteal fat biopsies taken from patients with RD (n = 20) and from age- and sex-matched control subjects (n = 17) and were cannulated in a small vessel arteriograph. Cumulative concentration-response curves to ET-1 (10(-12) to 3 x 10(-7) M) were obtained in vessels at 37 degrees C and 24 degrees C, with the endothelium either intact or removed (n = 6 per group). There were no significant differences in responses to ET-1 between RD patients and controls in either intact or denuded vessels, at either 37 degrees C or at 24 degrees C. There was, however, a significant endothelium-dependent interaction between the groups when the effect of temperature on the response to ET-1 was examined (p = 0.01; two-way ANOVA). Whereas cooling tended to reduce the sensitivity in RD, the opposite effect was observed in controls. Measurements of plasma ET-1 did not reveal any significant difference between patients with RD and healthy controls. These results suggest that ET-1 does not play a primary pathophysiologic role in RD. ET-1 might be responsible for mediating the prolonged vasospasm in RD, but secondary to another factor(s), such as impaired endothelium-dependent vasodilation.

Topics: Adult; Arteries; Body Temperature; Endothelin-1; Endothelins; Female; Humans; Male; Middle Aged; Raynaud Disease; Skin; Vascular Resistance

To understand better the role of endothelin-1 (ET-1) in the pathogenesis of primary Raynaud's phenomenon (PRP), we investigated the basal ET-1 plasma levels and changes after whole-body cooling in healthy women and those with PRP. The study was performed as an open parallel-group comparison during the month of February. The Raynaud group included 21 female patients (mean age 45.3 years, range 21-57 years) who had had disabling Raynaud's phenomenon for a mean period of 17 years (range 2-26 years). The control group consisted of 25 healthy women (mean age 43.6 years, range 27-56 years). Plasma levels of ET-1 were measured on two separate occasions: once after 30 min of rest at room temperature and after 40 min of whole-body cooling. There were no significant differences in baseline plasma ET-1 levels between the two groups of women. The plasma ET-1 levels increased significantly in the PRP group after cold exposure (mean difference 0.11 pmol l-1, 95% CI 0.005-0.214, P = 0.012). In contrast, the levels of plasma ET-1 in the control group did not change significantly after cold provocation. In conclusion, no differences in plasma basal levels of ET-1 were observed between the two groups. However, women suffering from Raynaud's phenomenon responded with a slight but significant elevation in plasma levels of ET-1 after whole-body cooling, whereas the healthy control subjects did not. The results from the present study confirm previous observations that endothelial dysfunction may be of aetiological importance in PRP.

Topics: Adult; Blood Pressure; Cold Temperature; Endothelin-1; Female; Heart Rate; Humans; Middle Aged; Raynaud Disease; Smoking

Vibration induced white fingers (VWF) is one form of secondary Raynaud's phenomenon (RP).. Vibration exposed workers with RP and vibration exposed controls without RP participated. Blood samples were collected before and after cold challenge exposure (COP). The concentration of von Willebrand factor (vonWf), thrombomodulin (TM), serotonin (SER), endothelin-1 (ET. The cases showed a significant lower concentration of vonWf before and after COP, a significant increase of ET. vonWf, TM, SER, or ET

Topics: Biomarkers; Calcitonin Gene-Related Peptide; Case-Control Studies; Endothelin-1; Female; Fingers; Humans; Male; Middle Aged; Occupational Diseases; Occupational Exposure; Raynaud Disease; Serotonin; Thrombomodulin; Thromboxane A2; Vibration; von Willebrand Factor

The earliest clinical manifestation of SSc is usually Raynaud's phenomenon, a small-arteries vasospasm driven by vascular tone dysregulation and microcirculatory abnormalities, resulting in digital ulcers (DU) in up to 50% of patients. Many cytokines as well as growth factors have been shown to play a role in promoting vascular smooth muscle cell proliferation and fibroblast activation, leading to ischemic damage as well as skin fibrosis. We aim to investigate a possible difference in venous and arterial blood levels of many cytokines (Th1- and Th17-related), GM-CSF, and endothelin-1 (ET1) in patients with and without DU. In the same patients, the correlations between capillary damage, evaluated by nailfold videocapillaroscopy (NVC), extension of skin fibrosis, calculated by modified Rodnan skin score (mRSS), and cytokines, ET-1, and GM-CSF levels were also measured. Patients with DU showed venous levels of IL-1

Topics: Adult; Aged; Aged, 80 and over; Arteries; Capillaries; Cytokines; Endothelin-1; Female; Fibrosis; Humans; Male; Microcirculation; Microscopic Angioscopy; Middle Aged; Raynaud Disease; Skin; Skin Ulcer; Th1 Cells; Th17 Cells; Tumor Necrosis Factor-alpha; Veins

Raynaud syndrome (RS) manifests as episodes of transient spasms of peripheral blood vessels, most often in response to cold. The reason of that symptom (primary RS (pRS)) usually cannot be found but may be accompanied by some autoimmune diseases (secondary RS (sRS)). In this study, we assessed microcapillary status and serum concentrations of chosen cytokines, adhesive molecules, and nitric oxide (NO) in patients with pRS and sRS in comparison with healthy children. Eighty-six patients with RS were enrolled into the study, including 52 with pRS and 34 with sRS. The control group consisted of 29 healthy children. A decrease in myorelaxative and anticoagulant abilities was observed, with simultaneous prevalence of vasopressor substances and procoagulative activity. Therefore, several important factors such as endothelin-1 (ET-1), E-selectin (E-sel), interleukin-18 (IL-18), and nitrogen oxide (NO) were also analyzed. Two types of capillaroscopy status were determined: normal and microangiopathic. There was a significant relationship between presence of microangiopathy and higher serum ET-1 (p = 0.018) and E-sel (p = 0.021) levels. Similarly, we have found a correlation between presence of ANA and higher ET-1 (p = 0.005), but not E-sel (p = 0.241). In patients with pRS, we found significant relationship between ANA and higher ET-1 (p = 0.008). No such relations were observed in sRS patients. Our data indicates that external factor-induced vasoconstrictive effects dominated in pRS, whereas in sRS in the course of connective tissue diseases, it was accompanied by coexistent vasodilation due to endothelial dysfunction. The latter phenomenon is at least partially dependent on insufficient NO release.

Topics: Adolescent; Case-Control Studies; Child; Connective Tissue Diseases; E-Selectin; Endothelin-1; Endothelium; Female; Humans; Interleukin-18; Male; Microcirculation; Microscopic Angioscopy; Nails; Nitrogen Oxides; Poland; Raynaud Disease

To evaluate the morphological and functional abnormalities of the microcirculation associated with markers of vascular injury in patients with early systemic sclerosis (SSc).. Forty-six patients with early SSc were compared with 80 patients with definite SSc, 40 patients with primary Raynaud's phenomenon (PRP), and 45 healthy subjects. Widefield nailfold capillaroscopy (NFC) (10-25 × magnification), videocapillaroscopy (200 × magnification), and laser Doppler imaging (LDI) assessment were performed in all participants. The number of capillaries/mm, enlarged, giant and ramified capillaries, microhaemorrhages, and the avascular score were determined by widefield NFC and videocapillaroscopy. Fingertip blood flow (FBF) was measured using LDI before and after cold stimulus (CS). Serum endothelin-1 (ET-1), von Willebrand factor (vWF), and transforming growth factor beta-1 (TGF-β1) were measured by enzyme-linked immunosorbent assay (ELISA).. Upon both widefield NFC and videocapillaroscopy, patients with early SSc showed significantly higher numbers of capillaries/mm, lower enlarged and giant capillaries, and a lower avascular score than definite SSc patients (p < 0.001). They also had more enlarged capillaries, microhaemorrhages and a higher avascular score compared to PRP and controls (p < 0.001). FBF before and after CS were significantly higher in controls than in PRP, early SSc, and definite SSc patients (p < 0.001), with no difference between early and definite SSc. Serum levels of ET-1, vWF, and TGF-β1 were similar between early and definite SSc patients.. Early SSc patients showed functional changes and vascular injury marker levels similar to patients with established disease. Nonetheless, the morphological changes were less severe in early SSc, thus providing an opportunity for further prevention of vasculopathy progression.

Topics: Adult; Aged; Autoantibodies; Biomarkers; Cross-Sectional Studies; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Fingers; Humans; Male; Microcirculation; Microscopic Angioscopy; Microvessels; Middle Aged; Raynaud Disease; Scleroderma, Systemic; Severity of Illness Index; Transforming Growth Factor beta1; von Willebrand Factor

Raynaud's phenomenon and digital ulcers (DUs) are frequent among systemic sclerosis (SSc) patients. Our aim was to investigate the diagnostic and predictive value for DU of endothelial dysfunction biomarkers (flow-mediated dilatation (FMD), serum levels of endothelin-1 (ET-1), and ADMA), angiogenic/angiostatic biomarkers (vascular endothelial growth factor (VEGF), endoglin, and endostatin), and nailfold videocapillaroscopy (NVC). We compared our results with a literature review. In a cohort study of 77 SSc patients, we followed two groups of patients: (i) naïve DU patients (39) and (ii) active DU at baseline (38 patients) for 3 years. Telangiectasia (p < 0.001) and diffuse disease subset (p = 0.001) were significantly more frequent in patients with active DU at enrolment. Additionally, NVC late scleroderma pattern (AUC 0.846, 95%CI 0.760-0.932), lower values of FMD (AUC 0.754, 95%CI 0.643-0.864), increased serum levels of ET-1 (AUC 0.758, 95%CI 0.649-0.866), ADMA (AUC 0.634, 95%CI 0.511-0.757), and endoglin as well as low VEGF serum levels (AUC 0.705, 95%CI 0.579-0.830) were significantly associated to new DU events in the 3-year follow-up. Cox regression analysis showed that FMD > 9.41 % (HR 0.37, 95%CI 0.14-0.99); ET-1 >11.85 pmol/L (HR 3.81, 95%CI 1.41-10.26) and late NVC pattern (HR 2.29, 95%CI 0.97-5.38) were independent predictors of DU recurrence. When estimating the probability of occurrence of first DU in naïve DU patients, only late NVC pattern (HR 12.66, 95%CI 2.06-77.89) was an independent predictor factor. In conclusion, late scleroderma patterns in NVC are the best independent predictors of SSc patients who are at risk of developing DU. Endothelial dysfunction assessed by FMD and ET-1 was also found to be an independent predictor of DU recurrence in a 3-year follow-up.

Topics: Adolescent; Adult; Aged; Antigens, CD; Biomarkers; Cohort Studies; Endoglin; Endothelin-1; Endothelium; Female; Fingers; Follow-Up Studies; Humans; Male; Microscopic Angioscopy; Middle Aged; Predictive Value of Tests; Prognosis; Prospective Studies; Raynaud Disease; Receptors, Cell Surface; Scleroderma, Systemic; Ulcer; Vascular Endothelial Growth Factor A; Young Adult

We evaluated endothelin (ET)-1 plasma levels and some clinical measures in patients with primary Raynaud's phenomenon (PRP), and in patients with systemic sclerosis (SSc) and secondary RP (SRP), in the latter according to their different nailfold videocapillaroscopy (NVC) patterns of microangiopathy (early, active, and late).. Ninety-nine patients with SSc, 49 with PRP, and 45 control subjects were studied. NVC was performed in all patients to distinguish the pattern of microvascular damage, and the morphological alterations were scored by a semiquantitative rating scale. ET-1 plasma levels were evaluated in all individuals by ELISA.. ET-1 plasma levels were significantly higher (p=0.001) in patients with both PRP and SRP, compared to controls. A significant positive correlation (p=0.03) was found between ET-1 plasma levels and SRP duration, but not between ET-1 plasma levels and PRP duration. Significant correlations were observed in patients with SSc between ET-1 plasma levels and clinical measures (e.g., digital ulcers), as well as the score value of single NVC measures, such as the number of capillaries, "ramified" capillaries, and enlarged capillaries (p<0.05). Finally, the highest ET-1 plasma levels were found in patients with SSc showing the late pattern of microangiopathy when compared to the early pattern (p=0.03) and to controls (p=0.003).. Highest ET-1 plasma levels were detected in the more advanced stage of the SSc microangiopathy, namely the late NVC pattern, characterized by capillary loss and increased tissue fibrosis; this might support the involvement of ET-1 in the progression of the microvascular/fibrotic SSc damage.

Topics: Adolescent; Adult; Aged; Capillaries; Endothelin-1; Female; Humans; Male; Microscopic Angioscopy; Middle Aged; Raynaud Disease; Scleroderma, Systemic; Skin; Young Adult

Systemic sclerosis (SSc) is characterized by both vasculopathy and autoimmunity. The interplay between these pathogenetic links requires further exploration. The aim was to assess the interrelationship of endothelin-1 (ET-1), a vasoconstrictor peptide, whose levels are usually elevated in the plasma of the patients with SSc and the function of monocyte-derived dendritic cells (MDDCs), which serve as organizers of the immune response. MDDCs were grown from 5 patients with SSc and severe Raynaud's phenomenon and 5 healthy volunteers. The cells were further stimulated by synthetic ET-1, lipopolysaccharide (LPS) or both. The production of endogenous ET-1, TNFalpha and IL-12 was assessed by RT-PCR and/or ELISA. The plasma levels of ET-1 were significantly higher in patients with SSc compared to healthy controls (p = 0.0005). The production of ET-1 by MDDCs was negligible in all examined conditions, while the release of TNFalpha and IL-12 was stimulated by LPS but not by ET-1. The in vitro concentration of the exogenous ET-1, where added, was comparable to the plasma levels of ET-1 in patients with SSc. High plasma levels of ET-1 are characteristic for the patients with SSc and severe Raynaud's phenomenon. An in vitro model with concentrations of ET-1 comparable to those in the plasma of SSc patients has been elaborated. The examined function of MDDCs from SSc patients and healthy volunteers did not differ under these conditions and was not dependent on the presence of ET-1.

Topics: Adult; Dendritic Cells; Endothelin-1; Female; Humans; Interleukin-12; Male; Middle Aged; Monocytes; Peptides; Raynaud Disease; Scleroderma, Systemic; Tumor Necrosis Factor-alpha

The authors review 20 cases of segmental arterial mediolysis (SAM) including 3 newly reported cases. SAM developed in areas of vascular distention in 2 of the latter cases: 1 in utero in the heart of a recipient of a twin transfusion syndrome and the other in the jejunum secondary to partial venous obstruction. In the third case, it occurred in a patient with Raynaud disease. Characterizing SAM are injurious and reparative lesions that occur in the media and/or at the adventitial medial junction. Four distinctive alterations are recognized: (1) mediolysis, (2) a tearing separation of the outer media from adventitia, (3) arterial gaps, and (4) a florid reparative response that replaces zones of mediolysis and fills areas of medial adventitial separation. The repair can transform SAM into lesions indistinguishable from common types of fibromuscular dysplasia (FMD.) A venous angiopathy involving large and medium-sized veins accompanies SAM. It features medial muscle vacuolar change with lysis leading to apparent separation of residual muscle bundles. Immunostaining shows endothelin-1 (ET-1) decorating adventitial capillaries in SAM and neighboring arteries, in capillaries of adjoining tissues, and outlining smooth muscle cell membranes in adjacent veins including those of the venous angiopathy. The significance of these changes is uncertain. Vasospasm is believed to cause SAM, but ET-1 is not the direct pressor agent responsible for this condition. The reason(s) for synthesis and release of ET-1 in SAM are still hypothetical, but local perturbations in vascular tone may be an important factor. ET-1 may be indirectly play a role in SAM by cross-talking and potentiating the activities of other vasoconstrictors such as norepinephrine and by orchestrating its reparative phase.

Topics: Adult; Arteries; Arteritis; Biomarkers; Coronary Vessels; Dilatation, Pathologic; Endothelin-1; Female; Fetal Diseases; Fetofetal Transfusion; Humans; Jejunum; Male; Middle Aged; Muscle, Smooth, Vascular; Peripheral Vascular Diseases; Pregnancy; Raynaud Disease; Tunica Media; Veins

To describe the effect of bosentan and its dual inhibition of endothelin-1 ETA and ETB receptors on digital ulcers in patients with systemic sclerosis (SSc).. Patients receiving bosentan for SSc-related digital ulcers were identified in eight centers, and their characteristics and follow-up were recorded.. Nine (six with diffuse and three with limited cutaneous forms of SSc) patients (median age: 54 years) had received bosentan for digital ulcers. Complete healing occurred in seven (median time to improvement: 4 weeks). Another experienced a significant decrease in the number of ulcers (from 22 to 5) in 8 weeks, while one had no improvement. After a median follow-up of 24.3 months, only one recurrence was observed. Raynaud phenomenon improved in all but one patient.. These data suggest that some patients may benefit from bosentan to treat digital ulcers. The short time to healing in these patients with rather chronic ulcers argues strongly in favor of its use. These results also strengthen the evidence that endothelin-1 plays an important role in the vascular manifestations of SSc.. Bosentan can be effective in the treatment of digital ulcers in some SSc patients with SSc, probably especially those involving substantial ischemia. Bosentan is not a first-line drug in this indication yet and must be carefully used by specialists in SSc. Forthcoming results from the international RAPIDS-2 study should clarify the indications for bosentan in the treatment of SSc-related digital ulcers.

Topics: Adult; Aged; Antibodies, Antinuclear; Bosentan; Endothelin-1; Female; Fingers; Follow-Up Studies; Humans; Ischemia; Male; Middle Aged; Raynaud Disease; Scleroderma, Systemic; Skin Ulcer; Sulfonamides; Time Factors; Treatment Outcome

In the pathogenesis of Raynaud's phenomenon humoral and immunoinflammatory agents are involved. The aim of this study was the assessment of the level of endothelin-1 (ET-1), tumor necrosis factor (TNF-alpha), interleukin-6 (IL-6), soluble IL-6 receptor (IL-6sR), von Willebrand's factor (vWF) and platelet factor 4 (PF-4) in patients with Raynaud's phenomenon associated with systemic connective tissue diseases.. The examined group consisted of 32 patients (24 women and 8 men) with Raynaud's phenomenon associated with selected connective tissue diseases, aged 28-50 years. A control group consisted of 13 healthy volunteers. Immediately after a cold provocation test venous blood was taken in order to assess serum concentrations of: TNF-alpha, IL-6, IL-6sR, vWF, PF-4, antinuclear antibodies (ANA), antineutrophil antibodies (c-ANCA).. In the group of patients with Raynaud's phenomenon mean serum concentration of ET-1, TNF-alpha, PF-4, and vWF was significantly greater than in the healthy group. In contrast, serum IL-6 and IL-6sR concentrations did not differ significantly between the diseased and healthy groups. In a subgroup of Raynaud's phenomenon patients showing particularly high concentration of serum ET-1 (twice as much as mean control concentration), the increase in IL-6, IL-6sR, vWF and c-ANCA concentration exhibited statistical significance in comparison with patients with lower serum ET-1 concentration. The vWF concentration exhibited positive correlation with time interval between the occurrence of clinical symptoms and serum ANA antibodies concentration. The increase in ET-1 synthesis in Raynaud's phenomenon patients is dependent on the increase in IL-6 level and c-ANCA antibodies level.. The patients with Raynaud's phenomenon show an increase in ET-1 and TNF-alpha concentrations. An enhanced ET-1 synthesis is dependent on the augmentation of serum c-ANCA antibodies and IL-6 concentrations.

Topics: Adult; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Antinuclear; Biomarkers; Connective Tissue Diseases; Cytokines; Disease Progression; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Humans; Interleukin-6; Male; Middle Aged; Platelet Factor 4; Raynaud Disease; Receptors, Interleukin-6; Severity of Illness Index; Tumor Necrosis Factor-alpha; von Willebrand Factor

Topics: Blood Platelets; Endothelin-1; Humans; Raynaud Disease

To compare thirst, drinking behaviour, and endothelin-1 (ET-1) plasma levels between vasospastic and non-vasospastic subjects.. We compared 67 subjects with a primary vasospastic syndrome with 64 age- and sex-matched non-vasospastic control subjects. A detailed medical history was recorded, including a questionnaire containing queries about thirst and drinking behaviour, history of migraine or unspecific headache, history of episodes of low blood pressure, and smoking habits. Body mass index (BMI) was calculated and blood samples were drawn for ET-1 measurements.. Subjects with a vasospastic syndrome reported a reduced desire to drink and a lower estimated quantity of daily fluid intake, more often forgot to drink, more often had both migraine and unspecific headache, more often had episodes of low blood pressure, and had an increased plasma level of ET-1. These features differed statistically significantly between the two groups. There was also a non-significant trend among vasospastic subjects to smoke less and to have a smaller BMI.. A reduced desire to drink is found frequently among vasospastic subjects.

Topics: Adult; Aged; Aged, 80 and over; Body Mass Index; Drinking Behavior; Endothelin-1; Female; Glaucoma; Humans; Male; Middle Aged; Raynaud Disease; Surveys and Questionnaires; Syndrome; Thirst; Vasodilation

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.. 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).. 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 nitroglycerin-mediated 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.. Secondary RP is characterized by elevations in plasma ET-1 and ADMA levels that may contribute to alterations in cutaneous microvascular function.

Topics: Adult; Arginine; Brachial Artery; Chemokine CCL2; Cold Temperature; Disease Progression; Endothelin-1; Female; Humans; Laser-Doppler Flowmetry; Male; Microcirculation; Middle Aged; Raynaud Disease; Vascular Cell Adhesion Molecule-1; Vascular Resistance; Vasoconstriction

Cold water-immersion induces vasoconstriction with an elevation of blood endothelin-1, which is a potent vasoconstrictor peptide, in patients with primary Raynaud's phenomenon (PRP). However, physiological involvement of endothelin-1 in cold-induced vasodilation (CIVD) remains to be elucidated.. We monitored changes of finger blood flow during cold water (10 degrees C) immersion and assayed blood endothelin-1 in 7 PRP patients and 7 workers with vibration-induced white finger (VWF) and in the respective control subjects.. While significant reductions in finger blood flow at 2 min after the immersion were observed in PRP patients and VWF workers, its elevation at 4 min, which was considered to reflect CIVD, was recognized only in PRP patients. In healthy controls, blood endothelin-1 increased at 4 min and returned to the basal level immediately after the immersion. The increase in blood endothelin-1 at 4 min in PRP patients was greater than that in controls, and continued even after the immersion. Conversely, the increase neither at 4 min nor after immersion was seen in VWF workers. Local vascular changes produced by repetitive vibration may be responsible for the attenuated CIVD and unchanged blood endothelin-1 during cold water-immersion in VWF workers.. Our results showing elevated blood endothelin-1 during and after immersion in PRP contrast with that in VWF suggesting that endothelin-1 is related to sympathetic hyperactivity which is more involved in PRP rather than VWF. It seems unlikely that endothelin-1 is functionally or directly associated with CIVD.

Topics: Adult; Endothelin-1; Female; Fingers; Humans; Hypothermia, Induced; Immersion; Male; Middle Aged; Occupational Diseases; Peripheral Vascular Diseases; Raynaud Disease; Vasodilation; Vibration

Infants with severe atopic dermatitis (AD) sometimes have cold and pale fingers and toes as observed in patients with Raynaud-like phenomenon (RP). We tried to clarify the physiological mechanism of secondary RP in patients with AD. The correlation between serum endothelin-1 (ET-1) or nitrate (NO3) levels and the severity of AD was examined in 37 patients. As a result, RP was observed in 5 boys younger than 6 months of age and with severe AD. These 5 infants had high serum ET-1 levels. However, serum NO3 levels were only mildly elevated. These results suggest that secondary RP in AD may occur with elevated ET-1 caused by stressed and/or damaged endothelium in infants with severe AD.

Topics: Child, Preschool; Dermatitis, Atopic; Endothelin-1; Female; Humans; Infant; Male; Nitrates; Raynaud Disease

Endothelin is an endogenous vasoconstrictor and plays an important role in pathogenesis of Raynaud's phenomenon. Plasma endothelin-1 (ET-1) and von Willebrand factor (vWF) concentrations following cold exposure in 52 patients with Raynaud's phenomenon were measured. Statistically significant increase of ET-1 and vWF was found in the study group in compare to healthy volunteers. There was positive correlation between ET-1 and vWF in those cases. The dates suggest that ET-changes indicates a vasospastic effect on vascular injury. Treatment with endothelin-receptor antagonist may prevent structural changes in vessel well.

Topics: Adult; Aged; Endothelin-1; Endothelium, Vascular; Female; Humans; Male; Middle Aged; Raynaud Disease; von Willebrand Factor

To evaluate the relative roles of endothelium and platelets in the pathogenesis of primary RP and RP secondary to SSc.. Endothelial derived ET-1, t-PA, PAI-1, and platelet derived beta-TG, PDGF, TGF-beta were measured in 36 patients with primary RP, 14 patients with RP secondary to SSc and 30 age and sex matched controls.. A significative increase of ET-1, t-PA, PAI-1, TGF-beta, and beta-TG were the most relevant changes in patients with RP secondary to SSc with respect to the controls. Less relevant increases of t-PA, PAI-1, PDGF, and beta-TG levels were observed in patients with primary RP vs controls.. These data seem to confirm the involvement of endothelial cells and platelets in the pathogenesis of RP, with mild changes in primary RP and more relevant changes in RP secondary to SSc.

Topics: Adult; beta-Thromboglobulin; Biomarkers; Endothelin-1; Endothelium; Female; Humans; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Platelet Activation; Platelet-Derived Growth Factor; Raynaud Disease; Scleroderma, Systemic; Tissue Plasminogen Activator; Transforming Growth Factor beta

To determine circulating endothelin-1 levels (ET-1) in patients with primary or secondary associated Raynaud's phenomenon (RP) under resting conditions and in response to cold provocation.. Patients were categorised as primary RP (18) or scleroderma associated RP (14). Finger blood flow was measured by venous occlusion plethysmography at finger temperatures of 32 degrees C and 24 degrees C. Vasospasm was detected as a finger systolic pressure of 0 mm Hg after standardised provocative cooling. Severity of vasospasm was assessed by the level of cooling required to provoke spasm. Plasma ET-1 levels were measured in antecubital blood withdrawn under baseline conditions (finger 32 degrees C) and at the point of vasospasm. Measurements were also made in 19 matched control subjects.. Finger blood flow was lower in patients with RP than in controls, with no difference between the two RP groups. Vasospasm occurred in all patients with RP but not in any control subjects and a grading system of severity was established. Baseline plasma ET-1 levels were similar in patients with RP and controls. Increases in ET-1 levels at the point of vasospasm in patients or corresponding timepoint in controls were also similar. There was no significant difference between the ET-1 levels in the two RP subgroups when the fingers were warm or when vasospasm was present.. These results do not support the hypothesis that ET-1 plays a part in the pathogenesis of RP. Objective testing is a useful adjunct to the clinical diagnosis of RP and allows assignment of a severity grade.

Topics: Adult; Case-Control Studies; Cold Temperature; Endothelin-1; Female; Fingers; Humans; Laser-Doppler Flowmetry; Male; Middle Aged; Plethysmography; Raynaud Disease; Regional Blood Flow; Severity of Illness Index; Vasoconstriction

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 thre

Topics: Adult; Aged; Cold Temperature; Endothelin-1; Female; Forearm; Hand; Hemodynamics; Humans; Male; Middle Aged; Raynaud Disease; Regional Blood Flow; Skin; Vasoconstriction

To elucidate possible genetic factors involved in the pathogenesis of primary Raynaud's phenomenon (RP) and to determine the demographic features.. The allele frequencies of known polymorphisms in four vasoactive candidate genes, eNOS, BKRG, ET-1 and the ETA receptor genes, were compared in a phenotypically homogeneous group of patients with primary RP and a normal control population.. In patients with primary RP, there was a higher reporting of both a family history of RP than in controls (45.3% vs 3.1%; P<0.0001) and a personal history of migraine (32.6% vs 7.2%; P<0.0001). No significant differences in allele frequencies of the candidate genes were found.. These findings support the concept that genetic susceptibility exists in primary RP. The high prevalence of migraine suggests that primary RP is part of a more widespread disorder of vascular tone. These findings do not suggest that common molecular variants of these candidate genes are involved in primary RP.

Topics: Adult; Case-Control Studies; Endothelin-1; Female; Gene Frequency; Genetic Markers; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Raynaud Disease; Receptor, Endothelin A; Receptors, Bradykinin; Receptors, Endothelin

Raynaud's phenomenon has been suggested as a predisposing factor for pulmonary vasospasm which may lead to pulmonary hypertension, but the occurrence of cold stimulus-induced pulmonary vasospasm has been inconsistent. Such inconsistent pulmonary vascular responses may be caused by differences in the production of endogenous vasodilators and vasoconstrictors among patients. Fourteen patients with Raynaud's phenomenon associated with mixed connective tissue disease (n=10) or systemic sclerosis (n=4) participated in the study. Right heart catheterization was performed before and after a cold pressor test, immersing a hand in cold water (15 degrees C) for 5 min. Plasma levels of 6-keto prostaglandin (PG)F1alpha, thromboxane (TX)B2 and endothelin (ET)-1 in the mixed venous blood were measured. Mean pulmonary artery pressure increased after the cold pressor test in five of 14 patients, and the patients were divided into those with pulmonary vasospasm (responders) and those without vasospasm (nonresponders). After the cold pressor test, levels of 6-keto PGF1alpha increased significantly in nonresponders (p<0.01) and decreased significantly in responders (p<0.05). The ratios of 6-keto PGF1alpha to TXB2 significantly increased in nonresponders (p<0.01) but not in responders and the difference between responders and nonresponders after the cold pressor test was also statistically significant (p<0.05). No significant change in plasma ET-1 levels occurred in either responders or nonresponders. The results suggest that an impaired production of prostaglandin I2 and an imbalance between prostaglandin I2 and thromboxane A2 are associated with the occurrence of pulmonary vasospasm induced by Raynaud's phenomenon.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Cold Temperature; Endothelin-1; Female; Hemodynamics; Humans; Male; Middle Aged; Pulmonary Artery; Pulmonary Veins; Raynaud Disease; Respiratory Function Tests; Spasm; Thromboxane B2; Vascular Diseases

Topics: Adult; Cold Temperature; Endothelin-1; Female; Humans; Male; Middle Aged; Raynaud Disease; Scleroderma, Systemic

The present study was designed to examine the role of endothelin-1 (ET-1), an endothelium-derived potent long-acting vasoconstrictor peptide, in vascular acrosyndromes with hypersensitivity to cold. Plasma ET-1 concentration was measured, before and after cold test, in 12 subjects with "a frigore" vascular acrosyndromes (9 females and 3 males, age range 17-59 years), of whom 6 were with primary Raynaud's phenomenon and 6 with essential acrocyanosis, and in 6 controls (5 females and 1 male, age range 21-37 years). Cold stimulation was performed by immersion of one hand into a water bath at 13 degrees C for 5 minutes. Blood samples were simultaneously drawn from an antecubital vein in the cooled side and in the contralateral arm at baseline, at the stop of cooling, at 10 and 90 minutes from the beginning of the cold challenge. Mean (+/-SD) baseline ET-1 plasma levels, as measured by radioimmunoassay, were higher in patients with "a frigore" vascular acrosyndromes (4.8 +/- 0.3 pmol/l) than in control subjects (1.9 +/- 0.1 pmol/l, p < 0.001). After hand cooling ET-1 rose in patients with "a frigore" vascular disorders to a peak value of 7.0 +/- 0.4 pmol/l, which was much greater than that observed in healthy subjects (2.7 +/- 0.4 pmol/l, p < 0.001). Absolute increase in ET-1 plasma concentrations from baseline to peak value was significantly higher in patients with "a frigore" vascular acrosyndromes than in normal subjects (2.2 +/- 0.3 vs 0.8 +/- 0.2 pmol/l, p < 0.001), being only in the former group the rise in ET-1 still detected 90 minutes after cold test. Plasma levels of ET-1 in the controlateral arm raised in a similar fashion, but absolute values were lower than in cooled arm. Circulating ET-1 levels in patients with primary Raynaud's phenomenon and essential acrocyanosis showed a similar pattern during the study. Our data demonstrate that in patients with "a frigore" vascular acrosyndromes baseline and cold-stimulated plasma ET-1 concentrations are increased. Further, in these vascular disorders, exaggerated ET-1 response to cold is prolonged. These findings suggest that increased ET-1 may contribute to an imbalance between vasoactive mediators in the cutaneous blood vessels contributing to the abnormal vasoconstriction to cold in these disorders. Alternatively, the increment in ET-1 release may represent a marker for endothelial cell damage in "a frigore" vascular acrosyndromes.

Topics: Adolescent; Adult; Cold Temperature; Endothelin-1; Female; Humans; Male; Middle Aged; Raynaud Disease; Syndrome; Vascular Diseases