Selective inhibition of the inducible nitric oxide synthase by aminoguanidine

Misko, Thomas P.; Moore, William M.; Kasten, Tom; Nickols, G. Allen; Corbett, John A.; Tilton, Ronald G.; McDaniel, Michael L.; Williamson, Joseph R.; Currie, Mark G.

doi:10.1016/0014-2999(93)90357-n

Cited by 687 publications

(312 citation statements)

References 19 publications

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“…It remains to be determined if other nonsteroid anti-inflammatory agents also enhance the developmental toxicity or vasoconstrictive actions of Coc. We have recently carried out experiments with the NOS inhibitor L-nitro-arginine-methyl-ester or the selective iNOS inhibitor aminoguanidine (Misko et al, 1993), and have likewise found enhanced effects of Coc upon hatchability and/or vasoconstriction (unpublished observations), supporting the tentative interpretation of our results, as discussed above.…”

Section: Discussionsupporting

confidence: 86%

Vasoconstriction Caused by Cocaine is Enhanced by Sodium Salicylate: Is Inducible Nitric Oxide Synthase mRNA Related?

Mendoza-Baumgart

Pravetoni

Sparber

2004

Neuropsychopharmacol

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We have previously found that sodium salicylate (NaSal), injected into chicken eggs at nontoxic doses used for quantifying hydroxyl free radicals in hearts and brains of embryos, caused or exacerbated hemorrhages and dramatically reduced hatchability when combined with cocaine (Coc). It has also been reported that inducible nitric oxide synthase (iNOS) gene expression is altered in brain in response to vascular damage and inflammation. In this study we measured diameters of membrane-bound blood vessels (BV) before and after pretreatment with saline (NaCl) or NaSal (100 mg/kg egg), followed by infusion of either NaCl or Coc HCl (total of 67.5 mg/kg egg) during 15 min. Brains and hearts of the embryos were then analyzed for iNOS messenger RNA (mRNA) concentrations. Coc caused vasoconstriction that was significant 5 min postinfusion (5 min PI) of the entire dose (ie after 67.5 mg/kg egg). Significant vasoconstriction was evident within 5 min in the group injected with NaSal followed by infusion with Coc (ie after 22.5 mg Coc/kg egg). Expression of iNOS mRNA was significantly increased only in the brains of the group exposed to NaSal plus Coc, and the increase was inversely related to BV diameter. These data are discussed in relation to effects of salicylate upon prostanoid synthesis and/or nitric oxide synthesis via iNOS inhibition and their possible relationship to Coc-associated cerebral vascular and/or cardiovascular events in abusing humans.

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Section: Discussionsupporting

confidence: 86%

Vasoconstriction Caused by Cocaine is Enhanced by Sodium Salicylate: Is Inducible Nitric Oxide Synthase mRNA Related?

Mendoza-Baumgart

Pravetoni

Sparber

2004

Neuropsychopharmacol

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“…However aminoguanidine also inhibits nNOS [42] and iNOS [43]. New compounds which inhibit formation of AGEs, break the AGE-crosslink or inhibit RAGE without affecting NO synthesis [44] need to be evaluated in prevention of nitrergic neuropathy.…”

Section: Discussionmentioning

confidence: 99%

Synergistic action of advanced glycation end products and endogenous nitric oxide leads to neuronal apoptosis in vitro: A new insight into selective nitrergic neuropathy in diabetes

et al. 2004

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Aims/hypothesis. We have previously shown that in diabetes nitrergic neurones innervating the urogenital and gastrointestinal organs undergo a selective degenerative process. This comprises an initial insulin-reversible decrease in neuronal nitric oxide synthase (nNOS) in the axons, followed by apoptosis of the nitrergic neurones, a process that is not reversible by insulin. Since apoptosis was independent of serum glucose concentrations, and advanced glycation endproducts (AGEs) have been implicated in the pathogenesis of diabetic complications, we have now measured AGEs in the serum and penis, pyloric sphincter and pelvic ganglia of diabetic animals at different times after streptozotocin treatment. Furthermore, we have studied their effect in vitro on human neuroblastoma (SH-SY5Y) cells in the presence or absence of nNOS expression. Methods. Serum AGEs were measured using fluorometry and ELISA. Accumulation of AGEs in the tissues was evaluated with immunohistochemistry. The viability, apoptosis and oxidative stress in SH-SY5Y cells were measured upon exposure to AGEs or high concentrations of glucose. Results. AGEs increased gradually in the serum and tissues of streptozotocin-induced diabetic rats; this process was not affected by delayed insulin treatment. In SH-SY5Y cells, AGEs, but not high glucose concentrations, increased the reactive oxygen species and caspase-3-dependent apoptosis in a synergistic fashion with endogenous nitric oxide (NO). Apoptosis was prevented by treatment with a NOS inhibitor, a pan-caspase inhibitor, a soluble receptor of AGEs or an anti-oxidant, but not an inhibitor of soluble guanylate cyclase. Conclusions/interpretation. The synergistic actions of NO and AGEs account for the irreversible nitrergic degeneration in diabetes. [Diabetologia (2004) 47: 331-339]

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“…A possible role of iNOS in this is suggested by studies of aminoguanidine. Aminoguanidine is a relatively selective inhibitor of iNOS [7] and has been found to inhibit the diabetes-induced increase in iNOS levels and nitric oxide production in retina [4]. Importantly, aminoguanidine has also been found to inhibit development of the microvascular lesions of diabetic retinopathy in diabetic dogs [8], rats [9,10] and mice (T. S. Kern, unpublished data).…”

Section: Introductionmentioning

confidence: 95%

Critical role of inducible nitric oxide synthase in degeneration of retinal capillaries in mice with streptozotocin-induced diabetes

et al. 2007

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Aims/hypothesis Diabetes results in the upregulation of the production of several components of the inflammatory response in the retina, including inducible nitric oxide synthase (iNOS). The aim of this study was to investigate the role of iNOS in the pathogenesis of the early stages of diabetic retinopathy using iNOS-deficient mice (iNos −/− ). Materials and methods iNos −/− mice and wild-type (WT; C57BL/6J) mice were made diabetic with streptozotocin or kept as non-diabetic controls. Mice were killed at different time points after the induction of diabetes for assessment of vascular histopathology, cell loss in the ganglion cell layer (GCL), retinal thickness, and biochemical and physiological abnormalities. Results The concentrations of nitric oxide, nitration of proteins, poly(ADP-ribose) (PAR)-modified proteins, endothelial nitric oxide synthase, prostaglandin E 2 , superoxide and leucostasis were significantly (p<0.05) increased in retinas of WT mice diabetic for 2 months compared with nondiabetic WT mice. All of these abnormalities except PARmodified proteins in retinas were inhibited (p<0.05) in diabetic iNos −/− mice. The number of acellular capillaries and pericyte ghosts was significantly increased in retinas from WT mice diabetic for 9 months compared with nondiabetic WT controls, these increases being significantly inhibited in diabetic iNos −/− mice (p<0.05 for all). Retinas from WT diabetic mice were significantly thinner than those from their non-diabetic controls, whereas diabetic iNos −/− mice were protected from this abnormality. We found no evidence of cell loss in the GCL of diabetic WT or iNos −/− mice. Deletion of iNos had no beneficial effect on diabetes-induced abnormalities on the electroretinogram.Conclusions/interpretation We demonstrate that the inflammatory enzyme iNOS plays an important role in the pathogenesis of vascular lesions characteristic of the early stages of diabetic retinopathy in mice.

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Selective inhibition of the inducible nitric oxide synthase by aminoguanidine

Cited by 687 publications

References 19 publications

Vasoconstriction Caused by Cocaine is Enhanced by Sodium Salicylate: Is Inducible Nitric Oxide Synthase mRNA Related?

Vasoconstriction Caused by Cocaine is Enhanced by Sodium Salicylate: Is Inducible Nitric Oxide Synthase mRNA Related?

Synergistic action of advanced glycation end products and endogenous nitric oxide leads to neuronal apoptosis in vitro: A new insight into selective nitrergic neuropathy in diabetes

Critical role of inducible nitric oxide synthase in degeneration of retinal capillaries in mice with streptozotocin-induced diabetes

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