Endothelium-derived hyperpolarizing factor(s): updating the unknown

Mombouli, Jean-Vivien; Vanhoutte, President forPaul M.

doi:10.1016/s0165-6147(97)90633-7

Cited by 198 publications

(156 citation statements)

References 47 publications

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“…A second factor that could contribute to endothelium-dependent relaxation is EDHF (Garland et al, 1995;Mombouli & Vanhoutte, 1997), an unidenti®ed factor which causes relaxation by opening K + channels to cause hyperpolarization. To determine whether the opening of K + channels might be contributing to the endothelium-dependent relaxation we examined the responses to ACh in the presence of a depolarizing concentration of K + (67 mM).…”

Section: Discussionmentioning

confidence: 99%

“…The endothelium regulates vascular tone by the release of a number of factors including endothelium-derived relaxing factor (EDRF), characterized as nitric oxide (NO, Palmer et al, 1987), endothelium-derived hyperpolarizing factor (EDHF, Taylor & Weston, 1988;Furchgott & Vanhoutte, 1989;Komori & Vanhoutte, 1990;Garland et al, 1995;Mombouli & Vanhoutte, 1997) which remains to be identi®ed and prostaglandins such as PGI 2 (Moncada et al, 1976). EDHF opens potassium channels to hyperpolarize cells leading to closure of voltage-operated calcium channels to cause relaxation (Garland et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

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Enhanced role for the opening of potassium channels in relaxant responses to acetylcholine after myocardial ischaemia and reperfusion in dog coronary arteries

Chan

Woodman

1999

British J Pharmacology

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1 Anaesthetized dogs were subjected to 1 h occlusion of the left circum¯ex coronary artery followed by 2 h of reperfusion. Relaxant responses were examined in coronary artery rings removed proximal (nonischaemic) or distal (ischaemic) to the site of occlusion. 2 Relaxant responses to acetylcholine (ACh) were similar in nonischaemic and ischaemic artery rings. In addition ACh-induced relaxation of nonischaemic and ischaemic artery rings was equally susceptible to inhibition of nitric oxide (NO) synthase using L-N G -nitroarginine (L-NOARG, 10 74 M), or to inhibition of soluble guanylate cyclase using 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ, 10 75 M). 3 In nonischaemic arteries, the relaxation to ACh was una ected by high K + (67 mM) but in ischaemic arteries, the maximum relaxation to ACh was signi®cantly reduced from 113+6 to 60+2% (ANOVA, P50.05). Tetraethylammonium (TEA, 10 73 M), an inhibitor of large conductance calcium activated potassium (BK Ca ) channels did not inhibit the response to ACh in nonischaemic arteries but in ischaemic arteries TEA signi®cantly shifted the concentration response curve to ACh to the right (pEC 50 ; nonischaemic, 7.07+0.25; ischaemic, 6.54+0.21, P50.01, ANOVA) without decreasing the maximum relaxation. TEA did not a ect the responses to sodium nitroprusside in either nonischaemic or ischaemic arteries. 4 In conclusion, ischaemia/reperfusion did not change the sensitivity of endothelium-dependent relaxation to L-NOARG or ODQ indicating that ischaemia did not a ect the contribution of NO or cyclic GMP to ACh-induced relaxation. However, in ischaemic arteries the opening of the BK Ca channels contributed to relaxation caused by ACh whereas TEA had no e ect in nonischaemic arteries. The factor responsible for the opening of this potassium channel was a factor other than NO and may be endothelium derived hyperpolarizing factor (EDHF).

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Enhanced role for the opening of potassium channels in relaxant responses to acetylcholine after myocardial ischaemia and reperfusion in dog coronary arteries

Chan

Woodman

1999

British J Pharmacology

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“…The identity of EDHF has been the subject of persistent controversy. It is likely that more than onè EDHF' exists, with substantial species and regional heterogeneity (Mombouli & Vanhoutte, 1997). Therefore, the relative contribution and the nature of the NO-independent vasodilator mechanisms may engender some of the observed discrepancies between the studies.…”

Section: Mechanisms Of Impaired Endothelium-dependent Vasodilatation mentioning

confidence: 99%

Endothelial dysfunction in diabetes

Vriese

Verbeuren

Voorde

et al. 2000

British J Pharmacology

1,015

769

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Endothelial dysfunction plays a key role in the pathogenesis of diabetic vascular disease. The endothelium controls the tone of the underlying vascular smooth muscle through the production of vasodilator mediators. The endothelium-derived relaxing factors (EDRF) comprise nitric oxide (NO), prostacyclin, and a still elusive endothelium-derived hyperpolarizing factor (EDHF). Impaired endothelium-dependent vasodilation has been demonstrated in various vascular beds of di erent animal models of diabetes and in humans with type 1 and 2 diabetes. Several mechanisms of endothelial dysfunction have been reported, including impaired signal transduction or substrate availibility, impaired release of EDRF, increased destruction of EDRF, enhanced release of endothelium-derived constricting factors and decreased sensitivity of the vascular smooth muscle to EDRF. The principal mediators of hyperglycaemia-induced endothelial dysfunction may be activation of protein kinase C, increased activity of the polyol pathway, non-enzymatic glycation and oxidative stress. Correction of these pathways, as well as administration of ACE inhibitors and folate, has been shown to improve endothelium-dependent vasodilation in diabetes. Since the mechanisms of endothelial dysfunction appear to di er according to the diabetic model and the vascular bed under study, it is important to select clinically relevant models for future research of endothelial dysfunction.

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“…This component which is independent of NO synthase and cyclooxygenase is generally accepted to be mediated by EDHF [3]. This EDHF possibly comprises several different factors, with important species and regional heterogeneity [25]. Recently, strong evidence implicated the cytochrome P450 2C8-dependent metabolite 11,12-epoxyeicosatrienoic acid as an EDHF in porcine coronary arteries [26] and in hamster end arteries [27].…”

Section: Basalmentioning

confidence: 99%

The impaired renal vasodilator response attributed to endothelium-derived hyperpolarizing factor in streptozotocin - induced diabetic rats is restored by 5-methyltetrahydrofolate

et al. 2000

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Dysfunction of the endothelium is an early and key event in the development of microvascular and macrovascular complications [1], which account for most of the morbidity and mortality of diabetes. Endothelial integrity is generally assessed by evaluating the vasodilator response of a blood vessel or a vascular bed to an endothelium-dependent agonist [2]. Endothelial cells relax the tone of the underlying vascular smooth muscle cells by releasing a number of vasodi- Diabetologia (2000) Abstract Aims/hypothesis. Endothelial dysfunction contributes to the development of diabetic vascular complications. A better understanding of the pathophysiology of endothelial dysfunction in diabetes could lead to new approaches to prevent microvascular disease. Methods. Endothelium-dependent and endotheliumindependent vasodilator responses were investigated in the renal microcirculation of streptozotocin-induced diabetic rats. We measured renal blood flow changes with an electromagnetic flow probe. In addition, the responses of the different segments of the renal microcirculation were evaluated with videomicroscopy using the hydronephrotic kidney technique. Because endothelial cells release different relaxing factors (nitric oxide, prostacyclin and an unidentified endothelium-derived hyperpolarizing factor), responses to acetylcholine were measured before and after treatment with the nitric oxide synthase inhibitor l-N G -nitroarginine methylester HCI (l-NAME) and the cyclooxygenase inhibitor indomethacin. We evaluated with the effect of 5-methyltetrahydrofolate, the active form of folate, on the responses. Results. The l-NAME-and indomethacin-resistant vasodilation to intra-renal acetylcholine was significantly reduced in the diabetic compared with control rats, suggesting impaired endothelium-derived hyperpolarizing factor-mediated vasodilation. The responses to the nitric oxide donor (Z)-1-[-2-(aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NONOate) and to the K + -channel opener pinacidil were similar in diabetics and controls, indicating intact endothelium-independent vasodilator mechanisms. The contribution of endothelium-derived hyperpolarizing factor to vasodilation induced by acetylcholine was greatest in the smallest arterioles. In diabetic rats, the response to acetylcholine was increasingly impared as vessel size decreased. Defective vasodilation in diabetic kidneys was rapidly normalized by 5-methyltetrahydrofolate. Conclusion-interpretation. Endothelium-derived hyperpolarizing factor-mediated vasodilation is impaired in the renal microcirculation of diabetic rats, in particular in the smallest arteries. Treatment with folate restores the impaired endothelial function in diabetes. [Diabetologia (2000

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Endothelium-derived hyperpolarizing factor(s): updating the unknown

Cited by 198 publications

References 47 publications

Enhanced role for the opening of potassium channels in relaxant responses to acetylcholine after myocardial ischaemia and reperfusion in dog coronary arteries

Enhanced role for the opening of potassium channels in relaxant responses to acetylcholine after myocardial ischaemia and reperfusion in dog coronary arteries

Endothelial dysfunction in diabetes

The impaired renal vasodilator response attributed to endothelium-derived hyperpolarizing factor in streptozotocin - induced diabetic rats is restored by 5-methyltetrahydrofolate

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