endothelin-1 and Peripheral-Vascular-Diseases

The need of blood flow to different organs varies rapidly over time which is why there is sophisticated local regulation of blood flow. The term dysregulation simply means that blood flow is not properly adapted to this need. Dysregulative mechanisms can lead to an over- or underperfusion. A steady overperfusion may be less critical for long-term damage. A constant underperfusion, however, can lead to some tissue atrophy or in extreme situations to infarction. Unstable perfusion (underperfusion followed by reperfusion) leads to oxidative stress. There are a number of causes that lead to local or systemic vascular dysregulation. Systemic dysregulation can be primary or secondary of nature. A secondary dysregulation is due to other autoimmune diseases such as rheumatoid arthritis, giant cell arteritis, systemic lupus erythematodes, multiple sclerosis, colitis ulcerosa, or Crohns disease. Patients with a secondary vascular dysregulation normally have a high level of circulating endothelin-1 (ET-1). This increased level of ET-1 leads to a reduction of blood flow both in the choroid and the optic nerve head but has little influence on autoregulation. In contrast, primary vascular dysregulation has little influence on baseline ocular blood flow but interferes with autoregulation. This, in turn, leads to unstable oxygen supply, which seems to be a relevant component in the pathogenesis of glaucomatous optic neuropathy.

Topics: Blood Flow Velocity; Blood Pressure; Choroid; Endothelin-1; Glaucoma; Humans; Optic Disk; Peripheral Vascular Diseases; Regional Blood Flow

Peripheral vascular disease can compromise the blood supply to the lower limb with amputation being necessary in severe cases. Reduced blood flow may be due to arterial occlusive disease or constriction of skeletal microvessels with the resultant ischaemia causing pain, tissue damage, ulceration and gangrene. These events are associated with endothelial damage or dysfunction: endothelin-1 is implicated as a mediator via its constrictor, proinflammatory and proliferative actions. Raised plasma and tissue levels of this peptide have been described in various ischaemic conditions, including peripheral vascular disease. Here, the possible role of endothelin-1 in peripheral vascular disease is discussed and potential therapeutic tools are considered.

Topics: Animals; Endothelin Receptor Antagonists; Endothelin-1; Humans; Lower Extremity; Peripheral Vascular Diseases; Reperfusion Injury

The authors present remodelling mechanisms of distal peripheral vessels in vibration disease, caused by endothelium functions disorder (lower NO, increased endothelin-1 and Villebrandt factor), stressed oxidative metabolism in neutrophils, intensified lipid peroxidation, depressed antioxidant defence, activated anti-inflammatory cytokines (TNF-alpha, IL-1beta) and hyperhomocysteinemia. Degree of the changes increases with combination of vibration disease and arterial hypertension. The data justify application of Telmisartan improving functional state of endothelium.

Topics: Angiotensin II Type 1 Receptor Blockers; Benzimidazoles; Benzoates; Cardiovascular Diseases; Endothelin-1; Endothelium, Vascular; Humans; Male; Middle Aged; Nitric Oxide; Peripheral Vascular Diseases; Telmisartan; Vibration

Recent data have addressed the issue of higher levels of homocysteine (Hcy) and endothelin-1 (ET-1) in end-stage renal disease (ESRD) that may be considered an independent predictor for cardiovascular disease. The prevalence of peripheral arterial disease (PAD) in patients with ESRD has been reported to be relevant, highlighting its clinical importance. We aimed to explore the therapeutic role of propionyl-L-carnitine (PLC) in hemodialysis patients with PAD by measuring ankle/brachial index (ABI), ET-1 and Hcy.. Randomized, double-blind, placebo-controlled trial.. Sixty-four patients on hemodialysis with chronic renal insufficiency and PAD were assigned to receive either intravenous PLC (600 mg) or placebo 3 times weekly for 12 months. The ABI and plasma levels of ET-1 and Hcy were measured at baseline, 6 and 12 months.. In the PLC-treated group, progressive increases in ABI were observed, while in the placebo group the reverse trend was seen. Highly significant and progressive reductions in plasma levels of ET-1 and Hcy, compared to baseline, were also seen in the PLC-treated group.. Hemodynamic flow, endothelial profile and Hcy levels were ameliorated by the administration of PLC in hemodialysis patients with ESRD and PAD.

Topics: Ankle; Branchial Region; Carnitine; Double-Blind Method; Endothelin-1; Homocysteine; Humans; Infusions, Intravenous; Kidney Failure, Chronic; Peripheral Vascular Diseases; Placebos; Renal Dialysis

Topics: alpha-Cyclodextrins; Alprostadil; Arterial Occlusive Diseases; Chronic Disease; Cyclodextrins; Drug Administration Schedule; Endothelin-1; Humans; Infusions, Intra-Arterial; Leg; Peripheral Vascular Diseases

Vibration white finger (VWF) is the episodic blanching of the fingers that occurs in response to cold in those who work with hand-held vibrating tools. Clinically the condition differs from primary Raynaud's phenomenon as persistent pain and paresthesia are common in the hands and arms and occur independently of the "white attacks." We have previously reported a decrease in protein gene product 9.5 and calcitonin gene-related peptide-immunoreactive nerve fibers in the digital skin of individuals with VWF. In this study, we have sought to determine whether this deficit of immunoreactive sensory-motor nerves has a functional counterpart in vivo. Histamine produces a rapid wheal and flare response following intradermal injection, whereas endothelin-1 (ET-1) produces a central area of pallor with a surrounding neurogenic flare. In contrast, calcitonin gene-related peptide produces a non-neurogenic erythema. In this study, histamine and ET-1 were injected into the dorsum of the middle phalanx and the local neurovascular response was assessed by measuring the area of the visible flare or pallor. Basal finger blood flow was also measured by laser Doppler flowmetry in each of the digits prior to intradermal injection. The experiments were performed at 21 degrees C and 4 degrees C. Patients with VWF and asymptomatic vibration-exposed workers had significantly lower resting skin blood flow at both 21 degrees C and 4 degrees C than heavy manual workers with no vibration exposure. The size of the histamine- and ET-1-induced flares at both 21 degrees C and 4 degrees C was significantly smaller in patients with VWF when compared with the asymptomatic vibration-exposed workers and heavy manual workers. The size of the ET-1-induced pallor was smaller in patients with VWF when compared with the heavy manual workers at both 21 degrees C and 4 degrees C. In contrast, the area of erythema induced by intradermal injection of calcitonin gene-related peptide at both 21 degrees C and 4 degrees C was of a similar size in patients with VWF and in heavy manual workers. These results indicate that the neuroneal deficit identified by immunohistochemistry in the digital skin of patients with VWF has a functional counterpart in vivo and is evident as a reduced ability to propagate an axon-reflex vasodilator response when challenged with histamine and ET-1. Furthermore, these results enable patients with VWF to be differentiated from both asymptomatic vibration-exposed workers, in whom

Topics: Adult; Calcitonin Gene-Related Peptide; Endothelin-1; Erythema; Fingers; Histamine; Humans; Male; Middle Aged; Nervous System; Occupational Diseases; Pallor; Peripheral Vascular Diseases; Skin; Vibration

BACKGROUND Tourniquet-related complications are a common clinical problem. In the present study, we compared the effects of dexmedetomidine vs. oxycodone in patients undergoing limb ischemia-reperfusion. MATERIAL AND METHODS Fifty-four patients undergoing unilateral lower-extremity surgery under combined spinal and epidural anesthesia were randomly assigned to a control (ischemia-reperfusion, I/R) group, a dexmedetomidine (Dex) group, and an oxycodone (Oxy) group. Tourniquet-induced hemodynamic parameters changes among groups were compared. The serum concentration of malondialdehyde (MDA), superoxide dismutase (SOD), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), fatty acid binding protein 3 (FABP3), endothelin-1 (ET-1), and brain-derived neurotrophic factor (BDNF) were measured using ELISA before anesthesia and at 30 min and at 6 h after tourniquet release. RESULTS In the control group, tourniquet use caused significant increases in systolic arterial pressure (SAP), mean arterial pressure (MAP), diastolic arterial pressure (DAP), and rate-pressure product. Compared with Oxy, Dex significantly decreased heart rate (HR). Both Dex and Oxy lowered SAP compared with the control group. No significant difference was observed in DAP between Dex and Oxy. The levels of MDA, TNF-alpha, IL-6, FABP3, and ET-1 were significantly higher, while the SOD and BDNF were significantly lower compared to baseline in the I/R group, but the variation range of those agents was significantly smaller in the Dex and Oxy groups, and the measured values were comparable between the 2 groups. CONCLUSIONS Compared with Dex, Oxy was not inferior in mitigating tourniquet-induced hyperdynamic response, ameliorating the inflammatory reaction, and protecting remote multiple organs in lower-extremity surgery patients.

Topics: Adult; Aged; Brain-Derived Neurotrophic Factor; China; Dexmedetomidine; Endothelin-1; Fatty Acid Binding Protein 3; Female; Hemodynamics; Humans; Interleukin-6; Ischemia; Lower Extremity; Male; Malondialdehyde; Middle Aged; Oxycodone; Peripheral Vascular Diseases; Prospective Studies; Random Allocation; Reperfusion Injury; Superoxide Dismutase; Tumor Necrosis Factor-alpha

The pathophysiology of sporadic Alzheimer's disease (AD) remains uncertain. Along with brain amyloid-β (Aβ) deposits and neurofibrillary tangles, cerebrovascular dysfunction is increasingly recognized as fundamental to the pathogenesis of AD. Using an experimental model of limb ischemia in transgenic APPPS1 mice, a model of AD (AD mice), we showed that microvascular impairment also extends to the peripheral vasculature in AD. At D70 following femoral ligation, we evidenced a significant decrease in cutaneous blood flow (- 29%, P < 0.001), collateral recruitment (- 24%, P < 0.001), capillary density (- 22%; P < 0.01) and arteriole density (- 28%; P < 0.05) in hind limbs of AD mice compared to control WT littermates. The reactivity of large arteries was not affected in AD mice, as confirmed by unaltered size, and vasoactive responses to pharmacological stimuli of the femoral artery. We identified blood as the only source of Aβ in the hind limb; thus, circulating Aβ is likely responsible for the impairment of peripheral vasculature repair mechanisms. The levels of the majority of pro-angiogenic mediators were not significantly modified in AD mice compared to WT mice, except for TGF-β1 and PlGF-2, both of which are involved in vessel stabilization and decreased in AD mice (P = 0.025 and 0.019, respectively). Importantly, endothelin-1 levels were significantly increased, while those of nitric oxide were decreased in the hind limb of AD mice (P < 0.05). Our results suggest that vascular dysfunction is a systemic disorder in AD mice. Assessment of peripheral vascular function may therefore provide additional tools for early diagnosis and management of AD.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Arterioles; Capillaries; Disease Models, Animal; Endothelin-1; Femoral Artery; Hindlimb; Humans; Ischemia; Mice; Mice, Transgenic; Microcirculation; Nitric Oxide; Peripheral Vascular Diseases; Placenta Growth Factor; Transforming Growth Factor beta1

Endothelin-1 is a strong endogenous vasoconstrictor and is also an agent reducing the ocular blood flow. Patients with retinitis pigmentosa are known to have reduced ocular blood flow. This can be secondary to retinal atrophy, but may also partially result from an additional condition, such as a Flammer syndrome. The aim of the study was to investigate whether the endothelin-1 plasma levels in retinitis pigmentosa patients with and without Flammer syndrome are different.. In the study we included patients with clinical signs and symptoms of retinitis pigmentosa, confirmed by electrophysiological findings. Blood samples were obtained from 6 retinitis pigmentosa patients with and 4 without Flammer syndrome. The results were related to 30 age- and sex-matched control subjects. Endothelin-1 plasma levels were determined by specific radioimmunoassay.. The endothelin-1 plasma levels in retinitis pigmentosa patients with Flammer syndrome were significantly higher than those without Flammer syndrome. The mean (±SD) endothelin-1 levels (pg/mL) in retinitis pigmentosa patients with Flammer syndrome were 4.95 (±1.74), range: (2.37-6.76), whereas in patients without Flammer syndrome they were 1.10 (±0.08), range: 1.00-1.20. Our own normal values are: 1.56 (±0.30), range: (0.90-2.13). All retinitis pigmentosa patients with increased endothelin-1 plasma levels had signs and symptoms related to a Flammer syndrome, such as cold extremities, low blood pressure, reduced feeling of thirst, increased sensitivity in general, e.g., increased sensitivity to certain drugs, increased pain sensitivity and increased sense of smell.. Endothelin-1 plasma levels were increased in retinitis pigmentosa patients with but not in patients without Flammer syndrome. Many questions remain open: Why so many retinitis pigmentosa patients suffer from Flammer syndrome, why is the endothelin-1 level in such patients higher than in healthy subjects with Flammer syndrome, how much of the ocular blood flow reduction is due to retinal degeneration and how much to the Flammer syndrome? We hypothesise that Flammer syndrome leads to an additional increase of the endothelin-1 level and an additional decrease of ocular blood flow in retinitis pigmentosa patients. Further studies are needed to analyse the causal relationship between retinitis pigmentosa and Flammer syndrome and evaluate potential therapeutic implications.

Topics: Adult; Biomarkers; Diagnosis, Differential; Endothelin-1; Female; Humans; Male; Middle Aged; Peripheral Vascular Diseases; Reproducibility of Results; Retinitis Pigmentosa; Sensitivity and Specificity; Syndrome

The study objective is to prove an association among plasma concentration of big endothelin and endothelin-1, other clinical parameters and two frequent polymorphisms - G8002A and -3A/-4A - in the endothelin-1 (EDN-1) coding gene (6p21-23), and among plasma concentration of TNF alpha and gene polymorphisms TNF alpha -308 A/G, -238 A/G, TNF beta Ncol and 3'TACE (tumour necrosis factor alpha converting enzyme) in patients with chronic heart failure (CHF). The second objective is to find an association between polymorphisms G8002A and -3A/4A EDN-1 with diabetes mellitus (DM), peripheral artery disease (PAD) and myocardial infarction (MI) in patients with chronic heart failure (CHF). The study population included 266 patients with symptomatic CHF and proven dysfunction of the left ventricle (LV). Genotyping and plasma concentrations of humoral substances were examined in 224 patients with ejection fraction (EF) below 40%. No associations between plasma concentrations of endothelin-1 and big endothelin and polymorphisms G8002A (p=0.87, p=0.81) and -3A/-4A (p=0.871, p=0.749) in the gene coding endothelin-1 were found. No associations were observed between plasma concentration of TNF alpha and genotypes in four polymorphisms in TNF alpha, beta and TACE genes. A significant correlation was seen between plasma concentration of big endothelin and pulmonary congestion. Patients with ischemic heart disease (IHD) and previous MI showed a difference in the distribution of genotype G8002A for endothelin-1: allele G 0.718 and A 0.282 vs those without MI: allele G 0.882 and A 0.118, (p<0.05). Patients with IHD and DM had allele G in 0.67 and A 0.33, while those without DM had allele G in 0.790 and A in 0.209 (p<0.03). Patients with IHD and concomitant PAD had allele G in 0.718 and A in 0.282 vs those without PAD allele G in 0.882 and A in 0.118 (p<0.0004). Patients with dilative cardiomyopathy (DCMP) showed no differences in genotype G8002A and presence of DM or PAD. It might be speculated that in the case of endothelin-1 and TNF alpha in CHF the genetic determination is not important, and plasma concentrations are influenced more by the disease severity. Ischemics with previous MI, concomitant DM or PAD showed more frequently allele A and less often allele G than those without these diseases. A genotype with allele A is associated with higher risk of concomitant diseases.

Topics: Biomarkers; Chronic Disease; Cytokines; Diabetes Mellitus; Endothelin-1; Female; Genetic Predisposition to Disease; Heart Failure; Humans; Male; Middle Aged; Myocardial Infarction; Peripheral Vascular Diseases; Polymorphism, Genetic; Risk Assessment

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 a hypothesized relationship between optic disc haemorrhages (ODHs) and primary vascular dysregulation (PVD).. Observational case report of a patient with classical PVD and five bilateral recurrent ODHs. The ODHs were superotemporal in the right eye and inferotemporal in the left; the eyes were otherwise normal. Intraocular pressure (IOP) never exceeded 17 mmHg. Visual fields were normal. Increased blood flow resistivity, a reduced blood flow of the extraocular vessels, a low systemic blood pressure, a cold-induced flow stop of the nailfold capillaries, and elevated endothelin-1 plasma levels were found, all confirming the diagnosis of vascular dysregulation.. Optic disc haemorrhages may be due to a disturbed blood-retina barrier rather than to a mechanical rupture of the vessel. This barrier dysfunction may occur in the context of PVD.

Topics: Blood Flow Velocity; Blood Pressure; Blood-Retinal Barrier; Cold Temperature; Endothelin-1; Female; Humans; Intraocular Pressure; Middle Aged; Nails; Optic Disk; Peripheral Vascular Diseases; Philosophy; Regional Blood Flow; Retinal Hemorrhage; Visual Fields

Blood monocytes are the precursors of the lipid-laden foam cells that are the hallmark of early atherosclerotic lesions, and monocyte chemoattractant protein-1 (MCP-1) plays important roles in their recruitment to the vessel wall. In this study, we measured serum levels of MCP-1 in patients with peripheral arterial obstructive disease (PAOD) and investigated whether intravenous prostaglandin E1 (PGE1) treatment, which produces clinical benefits in PAOD, might decrease such levels.. Eight patients with PAOD at Fontaine stage II to IV were treated with a daily intravenous infusion of 10 microg of PGE1 for 7 consecutive days. Blood samples before and after 7-day PGE1 treatment were used for assays of MCP-1, interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), von Willebrand factor (vWF), and endothelin-1 (ET-1).. Serum MCP-1 levels in patients with PAOD were significantly higher than those in healthy control subjects (263.8 +/- 52.8 vs 136.5 +/- 15.0 pg/mL, P =.002). PGE1 administration for 7 days resulted in a significant decrease in the MCP-1 level, from 263.8 +/- 52.8 to 196.1 +/- 25.5 pg/mL (P =.02), whereas levels of IL-6, hs-CRP, and ET-1 and the activity of vWF were not affected.. Serum MCP-1 levels were elevated in patients with PAOD, indicating the involvement of activation of monocytes in the pathogenesis of this disorder. Parenteral administration of PGE1 appeared to decrease circulating MCP-1 levels, which might lead to the suppression of the development of atherosclerotic lesions in patients with PAOD.

Topics: Adult; Aged; Alprostadil; Arterial Occlusive Diseases; Biomarkers; C-Reactive Protein; Case-Control Studies; Chemokine CCL2; Endothelin-1; Female; Fibrinolytic Agents; Humans; Injections, Intravenous; Interleukin-6; Intermittent Claudication; Male; Middle Aged; Peripheral Vascular Diseases; Vasodilator Agents; von Willebrand Factor

After its reintroduction as an arterial graft in coronary artery surgery, the radial artery is now established as an alternative arterial conduit, with good early and midterm patency. However, because of the concern about its vasospasticity, numerous vasodilator strategies have been used. Recently the use of the irreversible alpha-adrenergic antagonist phenoxybenzamine has been proposed. Although this treatment is effective in eliminating the vasoconstriction mediated by noradrenaline, the contribution of other circulating vasoconstrictors to vasospasm could be as important. This study investigates the response of radial arteries treated with phenoxybenzamine to vasoconstrictor stimuli and possible preventative strategies.. In vitro, sections of radial artery, pretreated with phenoxybenzamine after harvesting, were stimulated with maximal concentrations of the vasoconstrictors noradrenaline, vasopressin, angiotensin II, KCl, and endothelin-1. In matched segments of artery, vasoconstrictor responses were recorded in the presence of diltiazem, glyceryl trinitrate, and papaverine and compared with phenoxybenzamine-treated samples.. Phenoxybenzamine-treated radial artery failed to respond to noradrenaline but did respond to vasopressin, angiotensin II, endothelin-1, and KCl. Diltiazem was largely ineffective against contractile stimuli apart from KCl. Glyceryl trinitrate and papaverine significantly reduced responses to all of the vasoconstrictors tested.. In phenoxybenzamine-treated sections of radial artery, circulating vasoconstrictor agonists may still contribute to the induction of spasm. Additional vasodilator strategies may be required to completely prevent vasospasm.

Topics: Adrenergic alpha-Agonists; Aged; Angiotensin II; Coronary Artery Bypass; Diltiazem; Dose-Response Relationship, Drug; Endothelin-1; Humans; Middle Aged; Nitroglycerin; Norepinephrine; Papaverine; Peripheral Vascular Diseases; Phenoxybenzamine; Phosphodiesterase Inhibitors; Radial Artery; Spasm; Time Factors; Treatment Outcome; Vasoconstriction; Vasoconstrictor Agents; Vasodilator Agents; Vasopressins

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

The matrix metalloproteinases (MMPs) and endothelin-1, a potent vasoconstrictor and mitogen for smooth muscle cells, have been shown to be involved in the pathogenesis of various vascular disorders. However, the expression of endothelin-1 and the activation of MMPs have not been fully evaluated in plexogenic pulmonary arteriopathy (PPA). Immunohistochemical and confocal microscopic studies were conducted to evaluate the reactivity of lung tissue from six patients with pulmonary hypertension for alpha-smooth muscle actin (alpha-SMA), desmin, vimentin, factor VIII, endothelin-1, various types of MMPs (MMP-1, MMP-2, MMP-3, MMP-7 and MMP-9), membrane type-MMPs (MT-MMPs), tissue inhibitors of MMPs (TIMPs), and type IV collagen. Four major arterial morphological abnormalities were recognized in PPA: muscularization of pulmonary arterioles, onion-skin lesions, cellular and mature plexiform lesions, and atheromas in elastic pulmonary arteries. Reactivity for MMP-2 and MT-1-MMP was found in endothelial cells and, to a lesser extent, in myofibroblasts proliferating in various lesions of PPA. Increased expression of endothelin-1 was observed in the latter cells and in endothelial cells. Some myofibroblasts were positive for MMP-3 and MMP-7 in the vascular lesions except for mature plexiform lesions. MMP-1, MMP-9 and TIMP-2 tended to be positive only in the atheromatous lesions. Staining for type IV collagen showed focal thinning and discontinuities of the endothelial basement membrane in plexiform lesions. This study demonstrates colocalization of MMP-2 with MT-1-MMP and increased expression of endothelin-1 in various arterial lesions of PPA. These changes may play important roles in the remodeling of arterial structures, particularly of basement membranes, in this disorder.

Topics: Adolescent; Adult; Biomarkers; Collagen Type IV; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Immunohistochemistry; Male; Matrix Metalloproteinases; Microscopy, Confocal; Middle Aged; Peripheral Vascular Diseases; Pulmonary Alveoli; Pulmonary Artery

The distribution of endothelin-1 (ET-1) and its receptors (ET(A)/ET(B)) has been studied in segments of femoral artery obtained from patients undergoing operation for peripheral vascular disease (PVD) using a combination of immunohistochemistry and autoradiography. Both receptor subtypes were located on the tunica media of vessel segments, with ET(A)-receptors predominating. Densitometric analysis showed that there was no difference in receptor binding to proximal/distal arterial segments from PVD patients. High-resolution autoradiography identified ET(B) binding to vascular nerves and vasa vasorum, mainly in distal portions of femoral arteries. Immunoreactive ET-1 was also identified that was associated with the vasa vasorum.

Topics: Autoradiography; Endothelin-1; Humans; Immunohistochemistry; Peripheral Vascular Diseases; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin

The objective of this study was to examine the endothelial function of internal mammary artery in patients with coronary artery disease and in heart transplant recipients. Therefore the response of this artery to increasing concentrations of acetylcholine (1, 10, 20 microg/min for 2.5 minutes each) was assessed in 6 patients in a control group, 16 patients with coronary artery disease (CAD group) matched for risk factors with 16 heart graft recipients (who underwent transplantation for nonischemic heart failure), and 12 patients with coronary artery disease and peripheral vascular disease (PVD group). Diameters of proximal and middle segments of internal mammary artery were measured by quantitative angiography. The responses to the first concentration of acetylcholine were attenuated in these three groups compared with the control group. At the highest concentration of acetylcholine the diameter increase was similar in the control and CAD groups, whereas the responses remained significantly impaired in the transplant and PVD groups. However, after selective infusion of L-arginine (30 mg/min for 11 minutes), the precursor of endothelium-derived nitric oxide, was performed, the responses to acetylcholine were restored in these two latter groups. Endothelin plasma levels were significantly enhanced in the PVD group, which exhibited the most severe impairment in acetylcholine-induced vasodilation. Thus some patients with CAD, mainly those with advanced atherosclerosis, and cardiac transplant recipients exhibit internal mammary artery endothelial dysfunction, and this abnormality seems reversible.

Topics: Acetylcholine; Adult; Coronary Angiography; Coronary Disease; Endothelin-1; Endothelium, Vascular; Heart Transplantation; Hemodynamics; Humans; Mammary Arteries; Middle Aged; Peripheral Vascular Diseases

To determine the effect of chronic cigarette smoking on renal function, a cross-sectional study was carried out with 30 subjects who had no known vascular disease risk factor other than cigarette smoking, and 24 age- and sex-matched controls without any vascular risk factor including cigarette smoking. Renal function by radionuclide studies of renal plasma flow, GFR, and plasma endothelin-1 concentration was determined. Compared with nonsmokers, smokers had a renal function impairment characterized by a normal GFR and a significant reduction in renal plasma flow as reflected by MAG3 clearance (199.20 +/- 58.85 ml/min per 1.73 m2 versus 256.54 +/- 60.14 ml/min per 1.73 m2; t = 3.52, P < 0.001). MAG3 clearance was significantly correlated with age and smoking. The renal dysfunction was associated with an increase in plasma endothelin-1 concentration (21.56 +/- 1.15 pmol/L versus 25.01 +/- 3.21 pmol/L; t = 5.00, P < 0.001). Former smokers as well had similar, although milder, abnormalities. In conclusion, cigarette smokers manifest an impairment of renal function, suggesting that smoke may have a detrimental effect on renal function.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Case-Control Studies; Cross-Sectional Studies; Endothelin-1; Female; Glomerular Filtration Rate; Glycine; Humans; Incidence; Kidney Diseases; Male; Middle Aged; Multivariate Analysis; Peripheral Vascular Diseases; Regression Analysis; Renal Circulation; Risk Factors; Smoking; Time Factors

To assess the effects of picotamide, an antithromboxane receptor and antithromboxane synthase drug, on vascular function and endothelin-1 release, 20 patients with peripheral arterial disease, without hypertension or diabetes mellitus, receiving placebo and picotamide (900 mg/day) were studied. The modifications of vascular parameters were evaluated by arterial distensibility index and postischemic hyperemia test (postischemic perfusion index and recovery time). Endothelin-1, prostacycline, and thromboxane B2 were determined under resting conditions and after treadmill test. Picotamide treatment caused a decrease of resting thromboxane B2 and endothelin-1 concentrations, produced an improvement of the vascular function as seen by the increase of vascular parameters reported, and attenuated the ischemic treadmill-induced increase of thromboxane B2, but not of endothelin-1. These data confirm that the picotamide improved vascular flow by the reduction of thromboxane-mediated effects, reduced resting endothelin-1 levels, but did not attenuate endothelin-1 concentrations induced by the treadmill stress.

Topics: Aged; Endothelin-1; Exercise Test; Female; Humans; Male; Middle Aged; Peripheral Vascular Diseases; Phthalic Acids; Platelet Aggregation Inhibitors; Prostaglandins F; Thromboxane B2; Vasomotor System