Independent blockade of cerebral vasodilation from acetylcholine and nitric oxide

Marshall, J. Jeffrey; Wei, Enoch P.; Kontos, Hermes A.

doi:10.1152/ajpheart.1988.255.4.h847

Cited by 71 publications

(67 citation statements)

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“…23 If this is correct, the effect of H 2 O 2 on EDRF production may be explained because the oxidation of these essential SH groups may render the endothelium unable to produce EDRF. Our findings in the present study and earlier findings 19 are consistent with the possibility that the EDRF from acetylcholine in the cerebral vessels might be a nitrosothiol, which is capable of activating guanylate cyclase directly without the necessity for an interaction with tissue components. Our findings with cysNO support this view.…”

Section: Resultssupporting

confidence: 93%

“…This view is supported by the demonstration of partial restoration of the response to nitroprusside after replenishment of SH groups with A^-acetyl-L-cysteine. The present findings are consistent with earlier results 19 in which we used nitro blue tetrazolium, a dye that oxidizes SH groups, to block the vasodilating effect of nitroghycerin, nitroprusside, and nitric oxide. Nitro blue tetrazolium in these experiments did not influence the response to acetylcholine.…”

Section: Resultssupporting

confidence: 93%

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H2O2 and endothelium-dependent cerebral arteriolar dilation. Implications for the identity of endothelium-derived relaxing factor generated by acetylcholine.

1990

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We studied the mechanism of the vasodilator effect of H2O2 on cerebral arterioles and its effect on endothelium-dependent responses to acetylcholine. Topical application of H2O2 (0.1-1 microM) on the brain surface of anesthetized cats equipped with cranial windows induced dose-dependent arteriolar dilation, which was markedly inhibited by topical deferoxamine, showing that it was probably mediated by generation of hydroxyl radical. Higher concentrations of H2O2 (3 microM) also induced dilation, which was unaffected by deferoxamine, indicating the participation of other mechanisms. After topical application of H2O2, endothelium-dependent responses to acetylcholine were eliminated or converted to vasoconstriction, and in bioassay experiments, acetylcholine-mediated endothelium-derived relaxing factor (EDRF) was absent. Superoxide dismutase plus catalase restored the appearance of transferable EDRF after 1 microM H2O2 but not after 3 microM H2O2. Application of H2O2 in the assay window eliminated the responses to nitroprusside and nitric oxide but did not affect responses to adenosine, to EDRF from the donor window, or responses to S-nitroso-L-cysteine. The inhibiting effect of H2O2 on the response to nitroprusside was partially eliminated after topical application of N-acetyl-L-cysteine. The results show that H2O2 inhibits the vasodilator action of nitroprusside and nitric oxide probably because it oxidizes thiols in vascular smooth muscle and prevents the formation of a nitrosothiol. EDRF from acetylcholine and S-nitroso-L-cysteine still produce dilation in the presence of the blockade induced by H2O2. The findings suggest strongly that the EDRF from acetylcholine in cerebral vessels is a nitrosothiol like S-nitroso-L-cysteine.

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Section: Resultssupporting

confidence: 93%

Section: Resultssupporting

confidence: 93%

H2O2 and endothelium-dependent cerebral arteriolar dilation. Implications for the identity of endothelium-derived relaxing factor generated by acetylcholine.

1990

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“…Production of superoxide anion inactivates NO (Marshall et al, 1988;Rubanyi & Vanhoutte, 1986;Kobayashi & Kamata, 2001) and dismutation of free radicals has generally (Pieper et al, 1996;Hattori et al, 1991;Kamata & Kobayashi, 1996) but not always (Heygate et al, 1995) been found to improve impaired endothelium-dependent relaxation in experimental models of diabetes. Indeed, we recently reported that NO is metabolized by O 2 7 to NO 3…”

Section: Discussionmentioning

confidence: 99%

Effects of chronic administration of the novel endothelin antagonist J‐104132 on endothelial dysfunction in streptozotocin‐induced diabetic rat

Kanie

Kamata

2002

British J Pharmacology

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1 The biosynthesis of endothelin-1 is increased in the diabetic state. So this peptide may cause diabetic vascular complications. We tested this possibility by chronically administering J-104132, a potent orally active mixed antagonist of endothelin A and B (ET A /ET B ) receptors to streptozotocin (STZ)-induced diabetic rats and focusing on changes in endothelial function. 2 The acetylcholine (ACh)-induced endothelium-dependent relaxation was impaired in diabetic rats and this impairment was signi®cantly attenuated following chronic administration of J-104132 (10 mg kg 71 , p.o., daily for 4 weeks).3 In an in vitro experiment using aortae from diabetic rats, the ACh-induced relaxation was not changed by the presence of J-104132 (3610 79 M). 4 The expression levels of the mRNA for endothelial nitric oxide synthase was comparable among aortae from the three groups (control, diabetic and chronically J-104132-treated diabetic). 5 The amount of superoxide anion was signi®cantly greater in aortae from diabetic rats than in controls. Chronic J-104132 treatment signi®cantly decreased the level of superoxide anion in diabetic rats. 6 The expression of the p22phox mRNA for the NADH/NADPH oxidase subunit was signi®cantly increased in STZ-induced diabetic rats and this increase was completely prevented by chronic administration of J-104132. 7 These results suggest that in STZ-induced diabetic rats, ET-1 may be directly involved in impairing endothelium-dependent relaxation via increased superoxide-anion production.

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“…Indeed, a considerable body of evidence now suggests that in type I diabetes, the observed impairment of endothelial function may involve inactivation of NO by oxygen-derived free radicals (Meraji et al, 1987;Hattori et al, 1991;Pieper et al, 1992;Tesfamariam, 1994;Keaney and Vita, 1995;Kamata et al, 1996a;Ooboshi et al, 1997;Kobayashi and Kamata, 1999a, 2002b. In experimental models of type I diabetes, an enhancement of NO production (which in such models is diminished by superoxide anion) and dismutation of free radicals has generally been found to improve impaired endothelium-dependent relaxation (Rubanyi and Vanhoutte, 1986;Marshall et al, 1988;Kobayashi and Kamata, 2001). Convincing evidence indicates that the major enzymatic sources of vascular superoxide are NAD(P)H oxidase, xanthine oxidase, and uncoupled NOS (Landmesser and Harrison, 2001).…”

Section: Mechanisms Underlying Impaired Endothelial Function In Diabementioning

confidence: 99%

The PI3-K/Akt pathway: roles related to alterations in vasomotor responses in diabetic models

Kobayashi

Matsumoto

Kamata

2005

J Smooth Muscle Res

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Macro-and microvascular disease states currently represent the principal causes of morbidity and mortality in patients with type I or type II diabetes mellitus. Abnormal vasomotor responses and impaired endothelium-dependent vasodilation have been demonstrated in various beds in different animal models of diabetes and in humans with type I or type II diabetes. Several mechanisms leading to endothelial dysfunction have been reported, including changes in substrate avail ability, impaired release of NO, and increased destruction of NO. The principal mediators of diabetes-associated endothelial dysfunction are (a) increases in oxidized low density lipoprotein, endothelin-1, angiotensin II, oxidative stress, and (b) decreases in the actions of insulin or growth factors in endothelial cells. An accumulating body of evidence indicates that abnormal regulation of the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway may be one of several factors contributing to vascular dysfunction in diabetes. The PI3-K pathway, which activates serine/threonine protein kinase Akt, enhances NO synthase phosphorylation and NO production. Several studies suggest that in diabetes the relative ineffectiveness of insulin and the hyperglycemia act together to reduce activity in the insulin-receptor substrates (IRS)/PI3-K/Akt pathway, resulting in impairments of both IRS/PI3-K/Akt-mediated endothelial function and NO production. This article summarizes the PI3-K/Akt pathway-mediated contraction and relaxation responses induced by various agents in the blood vessels of diabetic animals.

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Independent blockade of cerebral vasodilation from acetylcholine and nitric oxide

Cited by 71 publications

References 0 publications

H2O2 and endothelium-dependent cerebral arteriolar dilation. Implications for the identity of endothelium-derived relaxing factor generated by acetylcholine.

H2O2 and endothelium-dependent cerebral arteriolar dilation. Implications for the identity of endothelium-derived relaxing factor generated by acetylcholine.

Effects of chronic administration of the novel endothelin antagonist J‐104132 on endothelial dysfunction in streptozotocin‐induced diabetic rat

The PI3-K/Akt pathway: roles related to alterations in vasomotor responses in diabetic models

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