Hydrogen Peroxide Is an Endothelium-Derived Hyperpolarizing Factor in Human Mesenteric Arteries

doi:10.1006/bbrc.2001.6278

Biochemical and Biophysical Research Communications

Volume 290, Issue 3, 25 January 2002, Pages 909-913

https://doi.org/10.1006/bbrc.2001.6278 Get rights and content

Abstract

The endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several vasodilating factors, including prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor (EDHF). We have recently identified that endothelium-derived hydrogen peroxide (H₂O₂) is an EDHF in mice. The present study was designed to examine whether this is also the case in humans. Bradykinin elicited endothelium-dependent relaxations and hyperpolarizations in the presence of indomethacin and N^ω-nitro- $l$ -arginine, which thus were attributed to EDHF, in human mesenteric arteries. The EDHF-mediated relaxations were significantly inhibited by catalase, an enzyme that specifically decomposes H₂O₂, whereas catalase did not affect endothelium-independent hyperpolarizations to levcromakalim. Exogenous H₂O₂ elicited relaxations and hyperpolarizations in endothelium-stripped arteries. Gap junction inhibitor 18α-glycyrrhetinic acid partially inhibited, whereas inhibitors of cytochrome P450 did not affect the EDHF-mediated relaxations. These results indicate that H₂O₂ is also a primary EDHF in human mesenteric arteries with some contribution of gap junctions.

References (33)

J.V. Mombouli et al.
Endothelium-derived hyperpolarizing factor(s): Updating the unknown
Trends Pharmacol. Sci.
(1997)
H. Shimokawa
Primary endothelial dysfunction: Atherosclerosis
J. Mol. Cell. Cardiol.
(1999)
S.D. Katz et al.
Acetylcholine-mediated vasodilation in the forearm circulation of patients with heart failure: Indirect evidence for the role of endothelium-derived hyperpolarizing factor
Am. J. Cardiol.
(2001)
Z.S. Katusic
Superoxide anion and endothelial regulation of arterial tone
Free Radical Biol. Med.
(1996)
M. Feletou et al.
Endothelium-dependent hyperpolarization of canine coronary smooth muscle
Br. J. Pharmacol.
(1988)
G. Chen et al.
Acetylcholine releases endothelium-derived hyperpolarizing factor and EDRF from rat blood vessels
Br. J. Pharmacol.
(1988)
M. Rosolowsky et al.
Role of PGI₂ and epoxyeicosatrienoic acids in relaxation of bovine coronary arteries to arachidonic acid
Am. J. Physiol.
(1993)
B. Fisslthaler et al.
Cytochrome P450 2C is an EDHF synthase in coronary arteries
Nature
(1999)
G. Edwards et al.
K⁺ is an endothelium-derived hyperpolarizing factor in rat arteries
Nature
(1998)
J.L. Beny et al.
An evaluation of potassium ions as endothelium-derived hyperpolarizing factor in porcine coronary arteries
Br. J. Pharmacol.
(2000)

H.J. Taylor et al.

Inhibition of the gap junctional component of endothelium-dependent relaxations in rabbit iliac artery by 18-alpha glycyrrhetinic acid

Br. J. Pharmacol.

(1998)

Y. Yamamoto et al.

Endothelium-dependent hyperpolarization and intercellular electrical coupling in guinea-pig mesenteric arterioles

J. Physiol.

(1999)

T. Matoba et al.

Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in mice

J. Clin. Invest.

(2000)

H. Shimokawa et al.

Importance of endothelium-derived hyperpolarizing factor in human arteries

L. Urakami-Harasawa et al.

Importance of endothelium-derived hyperpolarizing factor in human arteries

J. Clin. Invest.

(1997)

H. Miura et al.

Human coronary arteriolar dilation to bradykinin depends on membrane hyperpolarization: Contribution of nitric oxide and Ca²⁺-activated K⁺ channels

Circulation

(1999)

Cited by (248)

Vascular injury associated with ethanol intake is driven by AT1 receptor and mitochondrial dysfunction
2023, Biomedicine and Pharmacotherapy
Renin-angiotensin (Ang II)-aldosterone system (RAAS) is crucial for the cardiovascular risk associated with excessive ethanol consumption. Disturbs in mitochondria have been implicated in multiple cardiovascular diseases. However, if mitochondria dysfunction contributes to ethanol-induced vascular dysfunction is still unknown. We investigated whether ethanol leads to vascular dysfunction via RAAS activation, mitochondria dysfunction, and mitochondrial reactive oxygen species (mtROS).
Male C57/BL6J or mt-keima mice (6–8-weeks old) were treated with ethanol (20% vol./vol.) for 12 weeks with or without Losartan (10 mg/kg/day).
Ethanol induced aortic hypercontractility in an endothelium-dependent manner. PGC1α (a marker of biogenesis), Mfn2, (an essential protein for mitochondria fusion), as well as Pink-1 and Parkin (markers of mitophagy), were reduced in aortas from ethanol-treated mice. Disturb in mitophagy flux was further confirmed in arteries from mt-keima mice. Additionally, ethanol increased mtROS and reduced SOD2 expression. Strikingly, losartan prevented vascular hypercontractility, mitochondrial dysfunction, mtROS, and restored SOD2 expression. Both MnTMPyP (SOD2 mimetic) and CCCP (a mitochondrial uncoupler) reverted ethanol-induced vascular dysfunction. Moreover, L-NAME (NOS inhibitor) and EUK 134 (superoxide dismutase/catalase mimetic) did not affect vascular response in ethanol group, suggesting that ethanol reduces aortic nitric oxide (NO) and H₂O₂ bioavailability. These responses were prevented by losartan.
AT₁ receptor modulates ethanol-induced vascular hypercontractility by promoting mitochondrial dysfunction, mtROS, and reduction of NO and H₂O₂ bioavailability. Our findings shed a new light in our understanding of ethanol-induced vascular toxicity and open perspectives of new therapeutic approaches for patients with disorder associated with abusive ethanol drinking.
Cerium dioxide nanoparticles modulate antioxidant defences and change vascular response in the human saphenous vein
2022, Free Radical Biology and Medicine
Citation Excerpt :
Although we did not find differences in the BKca channels protein expression in the presence of CeO2NPs, these results did not rule out that CeO2NPs were affecting BKca channels activation. Endothelium-derived hyperpolarisation is a mechanism that is related to calcium-activated potassium channels and may or may not involve a factor released from the endothelium [28], such as potassium ion [29,30] or H2O2 [31,32]. Vascular NOX4 produces more H2O2 than O2-, giving it a vascular protective role [8,15,33].
Nanoparticles have a promising future in biomedical applications and knowing whether they affect ex vivo vascular reactivity is a necessary step before their use in patients. In this study, we have evaluated the vascular effect of cerium dioxide nanoparticles (CeO₂NPs) on the human saphenous vein in response to relaxing and contractile agonists. In addition, we have measured the protein expression of key enzymes related to vascular homeostasis and oxidative stress.
We found that CeO₂NPs increased expression of both SOD isoforms, and the consequent reduction of superoxide anion would enhance the bioavailability of NO explaining the increased vascular sensitivity to sodium nitroprusside in the presence of CeO₂NPs. The NOX4 reduction induced by CeO₂NPs may lead to lower H₂O₂ synthesis associated with vasodilation through potassium channels explaining the lower vasodilation to bradykinin. In addition, we showed for the first time, that CeO₂NPs increase the expression of ACE2 in human saphenous vein, and it may be the cause of the reduced contraction to angiotensin II. Moreover, we ruled out that CeO₂NPs have effect on the protein expression of eNOS, sGC, BKca channels and angiotensin II receptors or modify the vascular response to noradrenaline, endothelin-1 and TXA₂ analogue.
In conclusion, CeO₂NPs show antioxidant properties, and together with their vascular effect, they could be postulated as adjuvants for the treatment of cardiovascular diseases.
The homeostatic role of hydrogen peroxide, superoxide anion and nitric oxide in the vasculature
2021, Free Radical Biology and Medicine
Reactive oxygen and nitrogen species are produced in a wide range of physiological reactions that, at low concentrations, play essential roles in living organisms. There is a delicate equilibrium between formation and degradation of these mediators in a healthy vascular system, which contributes to maintaining these species under non-pathological levels to preserve normal vascular functions. Antioxidants scavenge reactive oxygen and nitrogen species to prevent or reduce damage caused by excessive oxidation. However, an excessive reductive environment induced by exogenous antioxidants may disrupt redox balance and lead to vascular pathology. This review summarizes the main aspects of free radical biochemistry (formation, sources and elimination) and the crucial actions of some of the most biologically relevant and well-characterized reactive oxygen and nitrogen species (hydrogen peroxide, superoxide anion and nitric oxide) in the physiological regulation of vascular function, structure and angiogenesis. Furthermore, current preclinical and clinical evidence is discussed on how excessive removal of these crucial responses by exogenous antioxidants (vitamins and related compounds, polyphenols) may perturb vascular homeostasis. The aim of this review is to provide information of the crucial physiological roles of oxidation in the endothelium, vascular smooth muscle cells and perivascular adipose tissue for developing safer and more effective vascular interventions with antioxidants.
Decreased expression of neuronal nitric oxide synthase contributes to the endothelial dysfunction associated with cigarette smoking in human
2020, Nitric Oxide - Biology and Chemistry
Endothelial nitric oxide synthase (eNOS) malfunctioning has been proposed to contribute to the endothelial damage produced by cigarette. Besides eNOS, neuronal NOS (nNOS) is also expressed in most vascular tissues and plays an important role in the endothelium-dependent vascular relaxation. We hypothesize that nNOS may contribute to the endothelium dysfunction produced by cigarette in smokers. Vascular function was assessed in human resistance mesenteric arteries using a wire myograph, the level of protein expression by Western blot, eNOS and nNOS localization by immunofluorescence. Measurement of NO was assessed by fluorescence microscopy. Arteries of smokers showed impaired endothelium-dependent vascular relaxation in response to acetylcholine. Pharmacological nonselective blockade of NOS with l-NAME and selective nNOS blockade with inhibitor 1 reduced the relaxation of the mesenteric artery of both smokers and nonsmokers. Interestingly, the inhibitory effect of NOS inhibitors was greater in nonsmokers than in smokers. The expression of total nNOS and eNOS and the level of phosphorylation at eNOS-pSer¹¹⁷⁷ were reduced in arteries of smokers as compared with nonsmokers. No differences between groups were observed in the expression of total COX-1, COX-2, catalase and SOD-1. Immunofluorescence analysis showed the presence of nNOS in the vascular endothelium in both groups. Acetylcholine-induced NO production was impaired in arteries from smokers as compared to nonsmokers. Selective inhibition of nNOS caused a decreased in NO production, which was greater in nonsmokers than in smokers. Our data show that a decrease in nNOS expression contributes to the endothelial dysfunction caused by cigarette smoking in human.
Catalase blockade reduces the pressor response to central cholinergic activation
2019, Brain Research Bulletin
Intracerebroventricular (icv) injection of hydrogen peroxide (H₂O₂), a reactive oxygen species, or the blockade of catalase (enzyme that degrades H₂O₂ into H₂O and O₂) with icv injection of 3-amino-1,2,4-triazole (ATZ) reduces the pressor effects of angiotensin II also injected icv. In the present study, we investigated the effects of ATZ injected icv or intravenously (iv) on the pressor responses induced by icv injections of the cholinergic agonist carbachol, which similar to angiotensin II induces pressor responses that depend on sympathoexcitation and vasopressin release. In addition, the effects of H₂O₂ icv on the pressor responses to icv carbachol were also tested to compare with the effects of ATZ. Normotensive non-anesthetized male Holtzman rats (280–300 g, n = 8–9/group) with stainless steel cannulas implanted in the lateral ventricle were used. Previous injection of ATZ (5 nmol/1 μl) or H₂O₂ (5 μmol/1 μl) icv similarly reduced the pressor responses induced by carbachol (4 nmol/1 μl) injected icv (13 ± 4 and 12 ± 4 mmHg, respectively, vs. vehicle + carbachol: 30 ± 5 mmHg). ATZ (3.6 mmol/kg of body weight) injected iv also reduced icv carbachol-induced pressor responses (21 ± 2 mmHg). ATZ icv or iv and H₂O₂ icv injected alone produced no effect on baseline arterial pressure. The treatments also produced no significant change of heart rate. The results show that ATZ icv or iv reduced the pressor responses to icv carbachol, suggesting that endogenous H₂O₂ acting centrally inhibits the pressor mechanisms (sympathoactivation and/or vasopressin release) activated by central cholinergic stimulation.
Vasorelaxant and antihypertensive effects of Tianshu Capsule on rats: An in vitro and in vivo approach
2019, Biomedicine and Pharmacotherapy
Both Chuanxiong (Ligusticum chuanxiong Hort) and Tianma (Gastrodia elata Blume) have the effects of vasorelaxation and antihypertension. However, the effects of Tianshu Capsule (TSC, composed of Chuanxiong and Tianma in the mass ratio of 4:1) on antihypertensive activity have not been explored. This study aimed to investigate the eﬀ ;ects of TSC on vascular tension and blood pressure in rats and to explore the underlying mechanisms.
The vasorelaxant effect of TSC was explored on thoracic aortic rings (both intact endothelium and denuded) preincubated with phenylephrine (Phe) or potassium chloride (KCL). The mechanism was investigated in the presence of antagonists or blockers on aorta isolated from normotensive rats. The in vivo antihypertensive effect was assessed using a tail-cuff method on spontaneously hypertensive rats (SHRs).
TSC (0.125–4 mg/mL) produced a concentration-dependent vasorelaxation on aortic rings preincubated with Phe (1 μM) or KCL (60 mM). Removal of aorta endothelium markedly attenuated the TSC activity. Pretreatment of aortic rings with β-adrenoceptor blocker propranolol (1 μM), muscarinic receptor antagonist atropine (1 μM), cyclooxygenase inhibitor indomethacin (IDO, 1 μM), adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purine-6-amine (SQ22536, 100 μM), K⁺ channel blockers 4-aminopyridine(4-AP, 1 mM) or barium chloride(BaCl₂, 1 mM) followed by addition of Phe (1 μM) prior to TSC did not influence the TSC-induced relaxation. In contrast, the vasorelaxant effects of TSC were markedly inhibited by the NO synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME, 10 μM), guanylyl cyclase inhibitor 1H- [1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ, 10 μM), K⁺ channel blockers, glibenclamide (100 μM) and clotrimazole (5 mM). Moreover, TSC (2 mg/mL, 4 mg/mL) inhibited CaCl₂-induced contractions and caused a concentration-dependent rightward shift of the response curves. Additionally, TSC (2 mg/mL, 4 mg/mL) depressed the constriction caused by Phe (1 μM) in the absence of extracellular Ca²⁺. Furthermore, TSC (2.15 g/kg) lowered the systolic blood pressure (SBP), with no alteration in heart rate (HR) in SHRs.
These findings demonstrated that TSC induced vasorelaxant effects via both endothelium-dependent and endothelium-independent pathways. The NO/sGC/cGMP pathway, ATP-sensitive K⁺ channels, Ca²⁺-activated K⁺ channels, inhibition of extracellular Ca²⁺ influx and intracellular Ca2⁺ release were probably involved in this relaxation. The vasorelaxant effects of TSC may make the greatest contribution to the reduction in high blood pressure.

View all citing articles on Scopus

¹: To whom correspondence and reprint requests should be addressed. Fax: +81-92-642-5374. E-mail: [email protected].

View full text

Regular ArticleHydrogen Peroxide Is an Endothelium-Derived Hyperpolarizing Factor in Human Mesenteric Arteries

Abstract

Trends Pharmacol. Sci.

J. Mol. Cell. Cardiol.

Am. J. Cardiol.

Free Radical Biol. Med.

Endothelium-dependent hyperpolarization of canine coronary smooth muscle

Br. J. Pharmacol.

Acetylcholine releases endothelium-derived hyperpolarizing factor and EDRF from rat blood vessels

Br. J. Pharmacol.

Role of PGI2 and epoxyeicosatrienoic acids in relaxation of bovine coronary arteries to arachidonic acid

Am. J. Physiol.

Cytochrome P450 2C is an EDHF synthase in coronary arteries

Nature

K+ is an endothelium-derived hyperpolarizing factor in rat arteries

Nature

An evaluation of potassium ions as endothelium-derived hyperpolarizing factor in porcine coronary arteries

Br. J. Pharmacol.

Inhibition of the gap junctional component of endothelium-dependent relaxations in rabbit iliac artery by 18-alpha glycyrrhetinic acid

Br. J. Pharmacol.

Endothelium-dependent hyperpolarization and intercellular electrical coupling in guinea-pig mesenteric arterioles

J. Physiol.

Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in mice

J. Clin. Invest.

Importance of endothelium-derived hyperpolarizing factor in human arteries

Importance of endothelium-derived hyperpolarizing factor in human arteries

J. Clin. Invest.

Human coronary arteriolar dilation to bradykinin depends on membrane hyperpolarization: Contribution of nitric oxide and Ca2+-activated K+ channels

Circulation

Regular Article
Hydrogen Peroxide Is an Endothelium-Derived Hyperpolarizing Factor in Human Mesenteric Arteries

Role of PGI₂ and epoxyeicosatrienoic acids in relaxation of bovine coronary arteries to arachidonic acid

K⁺ is an endothelium-derived hyperpolarizing factor in rat arteries

Human coronary arteriolar dilation to bradykinin depends on membrane hyperpolarization: Contribution of nitric oxide and Ca²⁺-activated K⁺ channels