Superoxide dismutase recovers altered endothelium-dependent relaxation in diabetic rat aorta

Hattori, Yoshiyuki; Kawasaki, Hisao; Abe, Kazuhiro; Kanno, Morio

doi:10.1152/ajpheart.1991.261.4.h1086

Cited by 172 publications

(159 citation statements)

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“…Decreased endothelial-dependent relaxation, a common assay for ED in aortic rings (37)(38)(39) and mesenteric microvessels (40,41), indicates that both conductance and resistance vessels are affected. In the diabetic mesentery the vascular tree undergoes hypertrophy preceded by attenuated endothelial dependent relaxation (42,43).…”

Section: Discussionmentioning

confidence: 99%

Inositols prevent and reverse endothelial dysfunction in diabetic rat and rabbit vasculature metabolically and by scavenging superoxide

Nascimento

Lessa

Kerntopf

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Endothelial dysfunction (ED) is an early feature of cardiovascular risk and diabetes. Hyperglycemia and hyperlipidemia are causative factors. Excessive endothelial mitochondrial superoxide (ROS) production with hyperglycemia and hyperlipidemia is a key mechanism. Inositol components of an insulin inositol glycan mediator, D-chiro-inositol (DCI) and 3-O-methyl DCI (pinitol), decrease hyperglycemia and hyperlipidemia. We tested whether these, myoinositol and dibutyryl DCI (db-DCI), would prevent or reverse ED in diabetic rats and rabbits. Oral inositols reduced hyperglycemia and hypertriglyceridemia with different potencies and prevented ED in rat aortic rings and mesenteric beds. Inositols added in vitro to five diabetic tissues reversed ED. Relaxation by Ach, NO, and electrical field stimulation was potentiated by inositols in vitro in rabbit penile corpus cavernosa. Inositols in vitro restored impaired contraction by the eNOS inhibitor L-NAME and increased NO effectiveness. DCI and db-DCI decreased elevated ROS in endothelial cells in high glucose and db-DCI reduced PKC activation, hexosamine pathway activity, and advanced glycation end products to basal levels. Xanthine͞xanthine oxidase generated superoxide was reduced by superoxide dismutase or inositols, with db-DCI efficacious in a mechanism requiring chelated Fe 3؉ . Histochemical examination of rat aortic rings for protein SNO demonstrated a decrease in diabetic rings with restoration by inositols. In summary, inositols prevented and reversed ED in rat and rabbit vessels, reduced elevated ROS in endothelial cells, potentiated nitrergic or vasculo-myogenic relaxations, and preserved NO signaling. These effects are related to their metabolic actions, direct superoxide scavenging, and enhancing and protecting NO signaling. Of the inositols tested, db-DCI was most effective.I nositol phosphoglycans (IPGs) are potentially important putative intracellular mediators of insulin action (1, 2). Separate classes have been identified (3), one containing D-chiro-inositol (DCI) and galactosamine (4) and a second containing myo-inositol (myo-INS) and glucosamine (1-5). Generated rapidly from lipid and͞or protein precursors in response to insulin, they have insulin-like effects in vitro and in vivo (1, 2, 4, 6, 7). Myo-INS phospho-glycans have been prepared by enzymatic cleavage of protein precursors and chemically synthesized (7-9). They have dose-dependent insulinlike effects on isolated adipocytes, cardiomyocytes, and diaphragms including increased glucose transport (7-9). One DCI containing IPG has been isolated from liver, and its structure has been determined and chemically synthesized (10). It is active in vivo; lowering elevated blood glucose when administered intravenously to diabetic rats (10-12). In vitro, it enhances insulin to stimulate [ 14 C]glucose incorporation into glycogen in H4IIE hepatoma cells (10). It activates pyruvate dehydrogenase (PDH) phosphatase (10), phosphoprotein phosphatase PP2C directly (13), and PP1 indirectly (4,14). Both PDH and glyco...

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Section: Discussionmentioning

confidence: 99%

Inositols prevent and reverse endothelial dysfunction in diabetic rat and rabbit vasculature metabolically and by scavenging superoxide

Nascimento

Lessa

Kerntopf

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…The existence of such an action of vasoconstrictor prostanoids in the kidney is not supported by our study, inasmuch as cyclooxygenase-inhibition did not restore the blunted relaxations observed in the diabetic animals. Other investigations showed an impaired acetylcholine-induced cyclic GMP generation [7,8] or a restoration of the relaxation with l-arginine [9] or with free radical scavengers [10,11], suggesting a reduced availability or an increased destruction of endotheliumderived NO. Another study specifically found no evidence for an impaired EDHF release in diabetes [34].…”

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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“…It has been suggested that the excessive elevations in plasma glucose, insulin, low density lipoprotein (LDL) cholesterol, endothelin-1 (ET-1), Ang II, and reactive oxygen species that occur in diabetes are involved in the development of this dysfunction in several blood vessels. 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).…”

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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Superoxide dismutase recovers altered endothelium-dependent relaxation in diabetic rat aorta

Cited by 172 publications

References 0 publications

Inositols prevent and reverse endothelial dysfunction in diabetic rat and rabbit vasculature metabolically and by scavenging superoxide

Inositols prevent and reverse endothelial dysfunction in diabetic rat and rabbit vasculature metabolically and by scavenging superoxide

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

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

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