Role of vasoactive factors in the pathogenesis of early changes in diabetic retinopathy

Chakrabarti, Subrata; Cukiernik, Mark; Hileeto, Denise; Evans, Terry; Chen, Shali

doi:10.1002/1520-7560(0000)9999:9999<::aid-dmrr157>3.0.co;2-g

Cited by 100 publications

(59 citation statements)

References 179 publications

(323 reference statements)

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“…Macitentan was tested in a rat model of type I diabetes to assess its impact on end-organ damage. Preclinical and clinical data suggest that ET-1 is involved in the pathophysiology of diabetic nephropathy (Schrijvers et al, 2004) and retinopathy (Chakrabarti et al, 2000). Urinary ET-1 levels correlate with the severity of nephropathy in diabetic patients (Lee et al, 1994) and glomerular ET-1, not its receptors, is increased in STZ rats (Fukui et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Pharmacology of Macitentan, an Orally Active Tissue-Targeting Dual Endothelin Receptor Antagonist

Iglarz¹,

Binkert²,

Morrison³

et al. 2008

J Pharmacol Exp Ther

297

298

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Macitentan, also called Actelion-1 or -6-(2-(5-bromopyrimidin-2-yloxy)ethoxy)-pyrimidin-4-yl]-NЈ-propylaminosulfonamide], is a new dual ET A / ET B endothelin (ET) receptor antagonist designed for tissue targeting. Selection of macitentan was based on inhibitory potency on both ET receptors and optimization of physicochemical properties to achieve high affinity for lipophilic milieu. In vivo, macitentan is metabolized into a major and pharmacologically active metabolite, ACT-132577. Macitentan and its metabolite antagonized the specific binding of ET-1 on membranes of cells overexpressing ET A and ET B receptors and blunted ET-1-induced calcium mobilization in various natural cell lines, with inhibitory constants within the nanomolar range. In functional assays, macitentan and ACT-132577 inhibited ET-1-induced contractions in isolated endothelium-denuded rat aorta (ET A receptors) and sarafotoxin S6c-induced contractions in isolated rat trachea (ET B receptors). In rats with pulmonary hypertension, macitentan prevented both the increase of pulmonary pressure and the right ventricle hypertrophy, and it markedly improved survival. In diabetic rats, chronic administration of macitentan decreased blood pressure and proteinuria and prevented end-organ damage (renal vascular hypertrophy and structural injury). In conclusion, macitentan, by its tissuetargeting properties and dual antagonism of ET receptors, protects against end-organ damage in diabetes and improves survival in pulmonary hypertensive rats. This profile makes macitentan a new agent to treat cardiovascular disorders associated with chronic tissue ET system activation.

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Section: Discussionmentioning

confidence: 99%

Pharmacology of Macitentan, an Orally Active Tissue-Targeting Dual Endothelin Receptor Antagonist

Iglarz¹,

Binkert²,

Morrison³

et al. 2008

J Pharmacol Exp Ther

297

298

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“…However, in the Hoorn Study applying the method of flow-mediated vasodilatation, endothelial dysfunctionrelated mechanisms were not clearly associated with retinopathy (27). In the development of retinopathy, vascular endothelial growth factor acts as a primary regulator, and retinal hypoxia and hyperglycemia interact as promoting factors, with possible roles of IGF, transforming growth factor, tumor necrosis factor-␣, and epidermal growth factor (28), as well as cyclooxygenase-2 and nitric oxide (29). Inflammation may be important in the pathogenesis of both macrovascular (30 -34) and microvascular disease (35)(36)(37).…”

Section: Methodsmentioning

confidence: 99%

Retinopathy Predicts Cardiovascular Mortality in Type 2 Diabetic Men and Women

et al. 2007

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OBJECTIVE -To investigate the association of retinopathy with the risk of all-cause, cardiovascular disease (CVD), and coronary heart disease (CHD) mortality in type 2 diabetic subjects in a population-based 18-year follow-up study with particular emphasis on sex differences.RESEARCH DESIGN AND METHODS -Our study cohort comprised 425 Finnish type 2 diabetic men and 399 type 2 diabetic women who were free of CVD at baseline. The findings were classified based on standardized clinical ophthalmoscopy to categories of no retinopathy, background retinopathy, and proliferative retinopathy. The study end points were all-cause, CVD, and CHD mortality.RESULTS -Adjusted Cox model hazard ratios (95% CIs) of all-cause, CVD, and CHD mortality in men were 1.34 (0.98 -1.83), 1.30 (0.86 -1.96), and 1.18 (0.74 -1.89), respectively, for background retinopathy and 3.05 (1.70 -5.45), 3.32 (1.61-6.78), and 2.54 (1.07-6.04), respectively, for proliferative retinopathy and in women 1.61 (1.17-2.22), 1.71 (1.17-2.51), and 1.79 (1.13-2.85), respectively, for background retinopathy and 2.92 (1.41-6.06), 3.17 (1.38 -7.30), and 4.98 (2.06 -12.06), respectively, for proliferative retinopathy.CONCLUSIONS -Proliferative retinopathy in both sexes and background retinopathy in women predicted all-cause, CVD, and CHD death. These associations were independent of current smoking, hypertension, total cholesterol, HDL cholesterol, glycemic control of diabetes, duration of diabetes, and proteinuria. This suggests the presence of common background pathways for diabetic microvascular and macrovascular disease other than those included in the conventional risk assessment of CVD. The sex difference observed in the association of background retinopathy with macrovascular disease warrants closer examination. Diabetes Care 30:292-299, 2007H yperglycemia is the major determinant of the risk of microvascular complications of diabetes (1), whereas the evidence that hyperglycemia is a major risk factor for macrovascular complications of this disease is more limited (2,3). Population-based studies have shown that microvascular complications predict cardiovascular disease (CVD) mortality not only in type 1 (3,4) and type 2 (5-10) diabetic subjects but even in nondiabetic subjects (10) and in general population samples, controlling for the effect of glucose status (11)(12)(13)(14). These observations suggest similar underlying pathogenic processes in microvascular complications and in atherosclerotic CVD in diabetes.It has been suggested that microvascular processes might be especially important in the development of coronary heart disease (CHD) in women (11,13). However, epidemiological data are largely missing with respect to possible sex differences in the association of diabetic retinopathy with CVD. We have performed an 18-year follow-up study of 824 Finnish subjects with type 2 diabetes (425 men and 399 women) who were free of CVD at baseline to evaluate the predictive value of retinopathy for all-cause, CVD, and CHD mortality by sex. RESEARCH DESIGN ANDMET...

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“…VEGF-A not only stimulates the development of new retinal vessels but also plays an important role in the early stages of diabetic retinopathy. It stimulates microaneurysm formation and capillary occlusion with ischemia, as well as promoting increased vascular permeability (Duh and Aiello, 1999;Chakrabarti et al, 2000). Many cell types in the eye produce VEGF-A, including retinal pigment cells, retinal capillary pericytes, endothelial cells, glial cells, Mueller cells, and ganglion cells (Aiello et al, 1994).…”

Section: Diabetes Mellitusmentioning

confidence: 99%