Aminoguanidine treatment increases elasticity and decreases fluid filtration of large arteries from diabetic rats.

Huijberts, M. S. P.; Wolffenbuttel, Bruce H. R.; Boudier, Harry A. Struijker; Crijns, F. R. L.; Kruseman, A. C. Nieuwenhuijzen; Poitevin, Pierre; Lévy, Bernard

doi:10.1172/jci116716

Cited by 132 publications

(84 citation statements)

References 27 publications

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“…However, the stroke volume rise after treatment may result from a reduced aortic as well as ventricular stiffness. In this regard, in a prior study during early treatment of diabetics with aminoguanidine, reduction of aortic stiffness did not result in a greater stroke volume than in untreated diabetic rats (16), suggesting that stroke volume increments are not related invariably to reduction of aortic stiffness.…”

Section: Discussionmentioning

confidence: 80%

An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness

Asif¹,

Egan²,

Vasan³

et al. 2000

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

314

195

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Decreased elasticity of the cardiovascular system is one of the hallmarks of the normal aging process of mammals. A potential explanation for this decreased elasticity is that glucose can react nonenzymatically with long-lived proteins, such as collagen and lens crystallin, and link them together, producing advanced glycation endproducts (AGEs). Previous studies have shown that aminoguanidine, an AGE inhibitor, can prevent glucose cross-linking of proteins and the loss of elasticity associated with aging and diabetes. Recently, an AGE cross-link breaker (ALT-711) has been described, which we have evaluated in aged dogs. After 1 month of administration of ALT-711, a significant reduction (≈40%) in age-related left ventricular stiffness was observed [(57.1 ± 6.8 mmHg⋅m 2 /ml pretreatment and 33.1 ± 4.6 mmHg⋅m 2 /ml posttreatment (1 mmHg = 133 Pa)]. This decrease was accompanied by improvement in cardiac function.

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Section: Discussionmentioning

confidence: 80%

An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness

Asif¹,

Egan²,

Vasan³

et al. 2000

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

314

195

View full text Add to dashboard Cite

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“…AG also inhibits the formation of advanced glycosylation end products (AGEs), which occurs via the non-enzymatic glycosylation of proteins during hyperglycaemia (Brownlee et al, 1986). In doing so AG may increase the elasticity of blood vessels (Huijberts et al, 1993;Hill & Edge, 1994) and possibly prevent an angiopathy of the vasa nervorum. AGEs have also been suggested to interact directly with nitric oxide and result in its deactivation (Bucala et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

Aminoguanidine‐effects on endoneurial vasoactive nitric oxide and on motor nerve conduction velocity in control and streptozotocin‐diabetic rats

Dewhurst

Omawari

Tomlinson

1997

British J Pharmacology

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1 The e ects of aminoguanidine (AG) treatment on reductions in motor nerve conduction velocity (MNCV) and sciatic nerve blood¯ow, indexed by laser Doppler¯ux (LDF), were investigated in rats with experimental diabetes (streptozotocin-induced; 8 ± 10 weeks duration). The contribution of endoneurial vasoactive nitric oxide to the LDF of these animals was also investigated by the direct micro-injection of N G -nitro-L-arginine methyl ester (L-NAME; 1 nmol in 1 ml), followed by L-arginine (100 nmol in 1 ml), into the sciatic nerve endoneurium. 2 The MNCV (m s 71 , mean+1 s.d.) of diabetic rats (38.2+1.5) was lower (P50.01) than that of agematched controls (47.2+4.2). AG treatment (50 mg kg 71 day 71 , i.p.) attenuated the diabetes-induced de®cits in MNCV (43.4+5.9; P50.01), but had no e ect in controls (48.8+3.8) or, if administered via drinking water (1 g l 71 ), diabetics (37.4+4.1). 3 L-NAME markedly reduced the resting LDF (arbitrary units; mean+s.e.mean) of controls (209+13 to 120+18; P50.005), an e ect reversed by subsequent L-arginine (to 206+27). In diabetic rats the LDF reduction following L-NAME was much smaller (111+11 to 84+6; P50.05), but the change with Larginine was signi®cantly increased (to 145+12; P50.001). 4 AG treatment increased the resting LDF of control (265+34) and diabetic rats (133+14 for daily injection and 119+13 for drinking water). The responses to L-NAME and L-arginine were not changed markedly by AG treatment. However, L-arginine appeared to be less e ective. 5 In conclusion, these data suggest that AG treatment may a ect nitric oxide production in the vasa nervorum of peripheral nerves. However, the e ects of AG-treatment are not consistent with the prevention of a diabetes-associated reduction in endoneurial nitric oxide production. The mechanisms by which AG attenuates nerve conduction slowing in streptozotocin-diabetic rats therefore remain unclear.

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“…Several authors found no bene®cial e ect of aminoguanidine on disordered endothelium-dependent vasodilatation in experimental diabetes (Hill & Ege, 1994;Pieper et al, 1996;Crijns et al, 1998). In contrast, aminoguanidine prevented diabetes-induced changes in arteriolar mechanical behaviour, as de®ned by decreased passive compliance and impaired myogenic reactivity of the arteriolar wall (Huijberts, et al, 1993;Hill & Ege, 1994). Taken together, the deleterious e ects of AGE accumulation in vascular tissues are more likely related to alterations in the connective tissue composition of the microvascular wall resulting in increased tissue rigidity, rather than to functional interference with vascular smooth muscle reactivity.…”

Section: Aetiology Of Endothelial Dysfunction In Diabetesmentioning

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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Aminoguanidine treatment increases elasticity and decreases fluid filtration of large arteries from diabetic rats.

Cited by 132 publications

References 27 publications

An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness

An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness

Aminoguanidine‐effects on endoneurial vasoactive nitric oxide and on motor nerve conduction velocity in control and streptozotocin‐diabetic rats

Endothelial dysfunction in diabetes

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