Treatment of Streptozotocin-Induced Diabetic Rats With AVE7688, a Vasopeptidase Inhibitor

Davidson, Eric P.; Kleinschmidt, Travis L.; Oltman, Christine L.; Lund, Donald D.; Yorek, Mark A.

doi:10.2337/db06-1180

Cited by 39 publications

(106 citation statements)

References 53 publications

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“…The vascular relaxation in response to sodium nitroprusside was not affected by diabetes or FP15 treatment. The latter is consistent with previous findings from our group (20,55) suggesting that, in contrast to other pathological conditions, i.e., hypertension (42), short-term diabetes does not affect the function of the smooth muscle layer and endothelium-independent relaxation of large arteries.…”

Section: Discussionsupporting

confidence: 93%

“…Interestingly and surprisingly, nerve blood flow and vascular conductance deficits in diabetic rats were "supranormalized" by FP15 treatment. Similar or more modest supranormalization of endoneurial nutritive blood flow has been caused by treatments with hydroxylethyl starch deferoxamine (19), a superoxide dismutase mimetic (17), or a vasopeptidase inhibitor (21) in our earlier studies in STZ-diabetic rats.…”

Section: Discussionsupporting

confidence: 70%

“…Nitric oxide and endothelium-derived hyperpolarizing factor are the two major factors controlling acetylcholine-and bradykinin-induced relaxation in these vascular beds (20,55). Diabetes-induced superoxide formation in vascular endothelium leads to generation of peroxynitrite (16,18), thus creating tivity of coronary and mesentery arteries (the present study) and corpus cavernosum (46) were corrected by FP15 and another peroxynitrite decomposition catalyst, 5,10,15,20-tetrakis(N-methyl-4Ј-pyridyl) porphyrinato iron III, respectively.…”

Section: Discussionmentioning

confidence: 99%

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Role of nitrosative stress in early neuropathy and vascular dysfunction in streptozotocin-diabetic rats

Obrosova

Drel²,

Oltman³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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106

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Obrosova IG, Drel VR, Oltman CL, Mashtalir N, Tibrewala J, Groves JT, Yorek MA. Role of nitrosative stress in early neuropathy and vascular dysfunction in streptozotocin-diabetic rats. Am J Physiol Endocrinol Metab 293: E1645-E1655, 2007. First published October 2, 2007; doi:10.1152/ajpendo.00479.2007.-Evidence for important roles of the highly reactive oxidant peroxynitrite in diabetic complications is emerging. We evaluated the role of peroxynitrite in early peripheral neuropathy and vascular dysfunction in STZ-diabetic rats. In the first dose-finding study, control and STZ-diabetic rats were maintained with or without the potent peroxynitrite decomposition catalyst Fe(III)tetrakis-2-(N-triethylene glycol monomethyl ether) pyridyl porphyrin (FP15) at 3, 5, or 10 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 in the drinking water for 4 wk after an initial 2 wk without treatment for assessment of early neuropathy. In the second study with similar experimental design, control and STZ-diabetic rats were maintained with or without FP15, 5 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 , for vascular studies. Rats with 6-wk duration of diabetes developed motor and sensory nerve conduction velocity deficits, mechanical hyperalgesia, and tactile allodynia in the absence of small sensory nerve fiber degeneration. They also had increased nitrotyrosine and poly(ADP-ribose) immunofluorescence in the sciatic nerve and dorsal root ganglia. All these variables were dose-dependently corrected by FP15, with minimal differences between the 5 and 10 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 doses. FP15, 5 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 , also corrected endoneurial nutritive blood flow and nitrotyrosine, but not superoxide, fluorescence in aorta and epineurial arterioles. Diabetes-induced decreases in acetylcholine-mediated relaxation by epineurial arterioles and coronary and mesenteric arteries, as well as bradykinin-induced relaxation by coronary and mesenteric arteries, were alleviated by FP15 treatment. The findings reveal the important role of nitrosative stress in early neuropathy and vasculopathy and provide the rationale for further studies of peroxynitrite decomposition catalysts in long-term diabetic models.OXIDATIVE STRESS resulting from increased production of reactive oxygen species (ROS) and downregulation or insufficient upregulation of antioxidant defense is a well-recognized fundamental mechanism in diabetic complications. Superoxide is a primary free radical produced in diabetic and hyperglycemic conditions. Superoxide is rapidly converted to several other ROS, i.e., hydroxyl radicals (Fenton and Haber-Weiss reactions), peroxynitrite (reaction with nitric oxide), and hydrogen peroxide (reaction catalyzed by intrinsic superoxide dismutase) (22). The rate of superoxide reaction with nitric oxide exceeds by at least one order of magnitude the rates of other aforementioned reactions, which makes peroxynitrite the number one oxidant in biological systems (38,57,71). Peroxynitrite causes the following numerous cytotoxic effects (nitrosative stress): 1) protein nitration and nitrosylation, 2) DNA singl...

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Role of nitrosative stress in early neuropathy and vascular dysfunction in streptozotocin-diabetic rats

Obrosova

Drel²,

Oltman³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

Self Cite

106

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“…Superior beneficial effects are observed when VPI is used as treatment in animal models of type 1 diabetes (T1D), type 2 diabetes (T2D) and DN [15,16,17]. Currently, the VPI is tested in phase IIb/III clinical trials for hypertension and phase II trials for DN.…”

Section: Introductionmentioning

confidence: 99%

Genetic and Functional Effects of Membrane Metalloendopeptidase on Diabetic Nephropathy Development

Zhang

Gu²,

Forsberg³

et al. 2011

Am J Nephrol

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Background/Aims: Vasopeptidase as an agent inhibits membrane metalloendopeptidase (MME, also known as neutral endopeptidase). MME is widely distributed in the body and particularly abundant in the kidney. The MME gene is located on chromosome 3q25.1 within a linkage region for diabetic nephropathy (DN). The present study aims to evaluate the genetic and functional effects of MME in the development of DN. Methods: A case-control genetic study of the MME gene in type 1 diabetes (T1D) patients with and without DN (n = 578/599) was performed. All subjects were selected from the Genetics of Kidneys in Diabetes study. Genotyping was performed with TagMan allelic discrimination. Mme mRNA and protein expression levels in kidney tissues of db/db mice at the ages of 5, 12 and 26 weeks were analyzed with TaqMan real-time RT-PCR and Western blot. Results: The haplotype A-C constructed with single nucleotide polymorphisms (SNPs) rs3796268A/G and rs3773885C/T in the MME gene was found to be associated with DN (p = 0.015, OR = 1.33, 95% CI 1.05–1.68) in female T1D patients. Further analyses of renal traits in T1D patients with DN and end-stage renal disease according to the genotypes of SNP rs3773885 indicated that the C allele carriers had higher serum creatinine levels compared to the subjects carrying T allele in both females and males. Mme expression at mRNA and protein levels was upregulated in kidneys of db/db mice at the ages of 12 and 26 weeks (p = 0.017 and <0.001) but not at the age of 5 weeks compared to the controls. Conclusions: The present study provides the first evidence that MME has genetic and biological effects on the development of DN, and suggests that the inhibition of MME expression in the kidney with the agent of vasopeptidase may be a useful therapeutic approach for this disease.

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“…Two pharmacological studies (18,19) revealing beneficial effects of the NAD(P)H oxidase inhibitor apocynin and the xanthine oxidase inhibitor allopurinol on early PDN, suggest that these two superoxidegenerating enzymes contribute to diabetes-associated superoxide production in PNS. Increased superoxide production has been documented in vasa nervorum in rat models of both Type 1 and Type 2 diabetes (16,20,21), and in high glucoseexposed human Schwann cells (22 Anesthesia, euthanasia and tissue sampling. The animals were sedated by CO 2 , and immediately sacrificed by cervical dislocation.…”

Section: Introductionmentioning

confidence: 99%

Peripheral neuropathy in mice with neuronal nitric oxide synthase gene deficiency

Vareniuk

Pacher²,

Pavlov³

et al. 2009

Int J Mol Med

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Abstract. Evidence for the important role of the potent oxidant peroxynitrite in peripheral diabetic neuropathy and neuropathic pain is emerging. This study evaluated the contribution of neuronal nitric oxide synthase (nNOS) to diabetes-induced nitrosative stress in peripheral nerve and dorsal root ganglia, and peripheral nerve dysfunction and degeneration. Control and nNOS -/-mice were made diabetic with streptozotocin, and maintained for 6 weeks. Peroxynitrite injury was assessed by nitrotyrosine and poly(ADP-ribose) immunoreactivities. Peripheral diabetic neuropathy was evaluated by measurements of sciatic motor and hind-limb digital sensory nerve conduction velocities, thermal algesia, tactile allodynia, and intraepidermal nerve fiber density. Control nNOS -/-mice displayed normal motor nerve conduction velocity and thermal response latency, whereas sensory nerve conduction velocity was slightly lower compared with non-diabetic wild-type mice, and tactile response threshold and intraepidermal nerve fiber density were reduced by 47 and 38%, respectively. Both diabetic wild-type and nNOS -/-mice displayed enhanced nitrosative stress in peripheral nerve. In contrast to diabetic wild-type mice, diabetic nNOS -/-mice had near normal nitrotyrosine and poly(ADP-ribose) immunofluorescence in dorsal root ganglia. Both diabetic wild-type and nNOS -/-mice developed motor and sensory nerve conduction velocity deficits and thermal hypoalgesia although nNOS gene deficiency slightly reduced severity of the three disorders. Tactile response thresholds were similarly decreased in control and diabetic nNOS -/-mice compared with non-diabetic wild-type mice. Intraepidermal nerve fiber density was lower by 27% in diabetic nNOS -/-mice compared with the corresponding nondiabetic group, and by 20% in diabetic nNOS -/-mice compared with diabetic wild-type mice. In conclusion, nNOS is required for maintaining the normal peripheral nerve function and small sensory nerve fibre innervation. nNOS gene deficiency does not protect from development of nerve conduction deficit, sensory neuropathy and intraepidermal nerve fiber loss.

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Treatment of Streptozotocin-Induced Diabetic Rats With AVE7688, a Vasopeptidase Inhibitor

Cited by 39 publications

References 53 publications

Role of nitrosative stress in early neuropathy and vascular dysfunction in streptozotocin-diabetic rats

Role of nitrosative stress in early neuropathy and vascular dysfunction in streptozotocin-diabetic rats

Genetic and Functional Effects of Membrane Metalloendopeptidase on Diabetic Nephropathy Development

Peripheral neuropathy in mice with neuronal nitric oxide synthase gene deficiency

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