Co-administration Of Aminoguanidine Research Articles

Nicotine reverses the enhanced renal vasodilator capacity in endotoxic rats: Role of α7/α4β2 nAChRs and HSP70.

Nicotine alleviates renal inflammation and injury induced by endotoxemia. This study investigated (i) the nicotine modulation of hemodynamic and renal vasodilatory responses to endotoxemia in rats, and (ii) roles of α7 or α4β2-nAChRs and related HSP70/TNFα/iNOS signaling in the interaction. Endotoxemia was induced by ip lipopolysaccharide (5 mg/kg/day, for 2 days) and changes in systolic blood pressure and vasodilator responsiveness of isolated perfused kidney to acetylcholine or 5'-N-ethylcarboxamidoadenosine (NECA, adenosine receptor agonist) were evaluated. Lipopolysaccharide had no effect on serum creatinine, reduced blood pressure, and increased renal vasodilations induced by acetylcholine or NECA in male and female preparations. Immunohistochemical analyses showed that lipopolysaccharide reduced renal HSP70 expression, but increased α7-nAChRs, α4β2-nAChRs and iNOS expressions. The co-administration of aminoguanidine (iNOS inhibitor), pentoxifylline (TNFα inhibitor), or nicotine attenuated lipopolysaccharide mediation of renal vasodilations and elevations in α7/α4β2-nAChR and iNOS expressions. Nicotine also reversed the downregulating effect of lipopolysaccharide on HSP70 expression. α7-nAChRs (methyllycaconitine citrate, MLA) or α4β2-nAChRs (dihydro-β-erythroidine, DHβE) blockade potentiated the lipopolysaccharide enhancement of renal vasodilations, and abolished the depressant effect of nicotine on lipopolysaccharide responses. A similar abolition of nicotine effects was seen after HSP70 inhibition by quercetin. Alternatively, lipopolysaccharide hypotension was eliminated in rats treated with DHβE/nicotine or quercetin/nicotine regimen in contrast to no effect for nicotine alone or combined with MLA. These findings establish that nicotine offsets lipopolysaccharide facilitation of renal vasodilations possibly through a crosstalk between HSP70 and nAChRs of the α7 and α4β2 types.

Involvement of nitric oxide (NO) signaling pathway in the antidepressant action of the total flavonoids extracted from Xiaobuxin-Tang

Our previous studies have demonstrated that the total flavonoids (XBXT-2) isolated from the extract of Xiaobuxin-Tang (XBXT), a traditional Chinese herbal decoction, exerted antidepressant-like effects. Recently, accumulating studies have suggested that l-arginine-NO is implicated in the regulation of depression. Therefore, the aim of current study attempts to explore the involvement of l-arginine-NO pathway in the antidepressant-like effect of XBXT-2 in the mouse forced swim test (FST). Our results showed that the antidepressant-like action of XBXT-2 (100mg/kg, i.g.) was reversed by pretreatment with l-arginine (a nitric oxide precursor, 750mg/kg, i.p.). While co-administration of aminoguanidine (a specific inducible NOS inhibitor, 40, 80mg/kg, i.p.) and sub-effective dose of XBXT-2 (50mg/kg, i.g.) did not significantly alter the immobility in FST. In contrast, combined administration of 7-nitroindazole (a specific neuronal NOS inhibitor, 50mg/kg, i.p.) potentiated the antidepressant-like effect of non-effective doses of XBXT-2 (50mg/kg, i.g.). Meanwhile, NO modulators were devoid of any locomotor effects on the animals. In conclusion, the antidepressant-like action of XBXT-2 may be involvement of NO signaling pathway.

Vascular dysfunction induced by elevated glucose levels in rats is mediated by vascular endothelial growth factor.

The purpose of these experiments was to investigate a potential role for vascular endothelial growth factor (VEGF) in mediating vascular dysfunction induced by increased glucose flux via the sorbitol pathway. Skin chambers were mounted on the backs of Sprague-Dawley rats and 1 wk later, granulation tissue in the chamber was exposed twice daily for 7 d to 5 mM glucose, 30 mM glucose, or 1 mM sorbitol in the presence and absence of neutralizing VEGF antibodies. Albumin permeation and blood flow were increased two- to three-fold by 30 mM glucose and 1 mM sorbitol; these increases were prevented by coadministration of neutralizing VEGF antibodies. Blood flow and albumin permeation were increased approximately 2.5-fold 1 h after topical application of recombinant human VEGF and these effects were prevented by nitric oxide synthase (NOS) inhibitors (aminoguanidine and N(G)-monomethyl L-arginine). Topical application of a superoxide generating system increased albumin permeation and blood flow and these changes were markedly attenuated by VEGF antibody and NOS inhibitors. Application of sodium nitroprusside for 7 d or the single application of a calcium ionophore, A23187, mimicked effects of glucose, sorbitol, and VEGF on vascular dysfunction and the ionophore effect was prevented by coadministration of aminoguanidine. These observations suggest a potentially important role for VEGF in mediating vascular dysfunction induced by "hypoxia-like" cytosolic metabolic imbalances (reductive stress, increased superoxide, and nitric oxide production) linked to increased flux of glucose via the sorbitol pathway.

Administration of AGEs in vivo induces extracellular matrix gene expression.

The role that advanced glycosylation end-products (AGEs) may play in the development of diabetic nephropathy is still not completely understood. In order to elucidate the nature of their effect, the consequences of exogenously administered AGEs on extracellular matrix gene expression were examined in mice by competitive PCR. Normal adult mice receiving repeated injections of AGEs had an increase in the expression of genes coding for type IV collagen and laminin in the glomeruli. The increase was accompanied by up-regulation of TGF-beta 1 but not PDGF-B expression. The expression of smooth muscle and beta-actin did not change, showing that the increase in gene expression was specific for genes implicated in the early stages of diabetic nephropathy. The co-administration of aminoguanidine, a drug that inhibits AGEs cross-links, prevented the up-regulation of gene expression in AGEs-injected mice. Thus, AGEs can induce extracellular matrix genes in the absence of hyperglycaemia.