endothelin-1 and pimagedine

Hemorrhagic shock-induced changes in vascular reactivity appear organ-specific. In the present study, we examined the hypothesis that vascular reactivity induced by septic shock similarly displays organ-specific differences and is regulated by inducible nitric oxide synthase (iNOS) and endothelin-1 (ET-1).. Endotoxic shock was induced in rabbits by administration of lipopolysaccharide (LPS) (1 mg/kg), and organ specificity of vascular reactivity of superior mesenteric artery (SMA), celiac artery (CA), and left renal artery (LRA) as well as the potential involvement of iNOS and ET-1 examined.. Vascular reactivity of SMA, CA, and LRA was increased at the early stages and decreased at the late stages after LPS administration. Superior mesenteric artery showed the greatest decrease in vascular reactivity in response to norepinephrine (NE) (34.9%) and acetylcholine (Ach; 32.3%), followed by LRA (NE, 33.7%; Ach, 30.5%) and CA (NE, 16.2%), whereas the relaxation reactivity of CA in response to Ach was increased to 159%. The mRNA and protein levels of iNOS and ET-1 in SMA, CA, and LRA were not affected at the early stages of endotoxic shock after LPS administration but significantly increased at the late stages. Expression levels were higher in SMA than CA and LRA and negatively correlated with the decrease in vascular reactivity. The iNOS and ET-1 inhibitors, aminoguanidine (20 mg/kg) and PD-142893 (0.02 mg/kg), respectively, induced significant improvements in vascular reactivity and organ perfusion and stabilized the hemodynamic parameters in rabbits subjected to endotoxic shock.. Changes in vascular reactivity during endotoxic shock are organ-specific. Differential expression patterns of iNOS and ET-1 in different blood vessels contribute to the organ specificity of vascular reactivity.. Therapeutic study, level II.

Topics: Acetylcholine; Animals; Celiac Artery; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Enzyme Inhibitors; Female; Guanidines; Lactic Acid; Lipopolysaccharides; Male; Mesenteric Artery, Superior; Nitric Oxide Synthase Type II; Norepinephrine; Oligopeptides; Rabbits; Renal Artery; RNA, Messenger; Shock, Septic; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

Circulating levels of endothelin (ET)-1 are increased in the diabetic state, as is endogenous ET(A)-receptor-mediated vasoconstriction. However, the responsible mechanisms remain unknown. We hypothesized that ET-1-induced vasoconstriction is augmented in type 2 diabetes with hyperglycemia through an increment in advanced glycation end-products (AGEs). So, we investigated whether treatment with aminoguanidine (AG), an inhibitor of AGEs, would normalize the ET-1-induced contraction induced by ET-1 in strips of thoracic aortas isolated from OLETF rats at the chronic stage of diabetes. In such aortas (vs. those from age-matched genetic control LETO rats): (1) the ET-1-induced contraction was enhanced, (2) the levels of HIF1α/ECE1/plasma ET-1 and plasma CML-AGEs were increased, (3) the ET-1-stimulated ERK phosphorylation mediated by ET(A)-R was increased, (4) the expression level of Jab1-modified ET(A)-R protein was reduced, and (5) the expression level of O-GlcNAcylated ET(A)-R protein was increased. Aortas isolated from such OLETF rats that had been treated with AG (50mg/kg/day for 10 weeks) exhibited reduced ET-1-induced contraction, suppressed ET-1-stimulated ERK phosphorylation accompanied by down-regulation of ET(A)-R, and increased modification of ET(A)-R by Jab1. Such AG-treated rats exhibited normalized plasma ET-1 and CML-AGE levels, and their aortas exhibited decreased HIF1α/ECE1 expression. However, such AG treatment did not alter the elevated levels of plasma glucose or insulin, or systolic blood pressure seen in OLETF rats. These data from the OLETF model suggest that within the timescale studied here, AG normalizes ET-1-induced aortic contraction by suppressing ET(A)-R/ERK activities and/or by normalizing the imbalance between Jab1 and O-GlcNAc in type 2 diabetes.

Topics: Acetylglucosamine; Animals; Aorta, Thoracic; Blood Glucose; Blood Pressure; COP9 Signalosome Complex; Diabetes Mellitus, Type 2; Dinoprostone; Endothelin-1; Endothelins; Extracellular Signal-Regulated MAP Kinases; Glycation End Products, Advanced; Guanidines; In Vitro Techniques; Insulin; Intracellular Signaling Peptides and Proteins; Male; Peptide Fragments; Phenylephrine; Phosphorylation; Proteins; Rats; Rats, Inbred OLETF; Receptor, Endothelin A; Receptor, Endothelin B; Vasoconstriction

Diabetic nephropathy (DN) due to microvascular complication is a serious status characterized by continuously progressive until occurrence of the end stage of renal disease. It is attractive to investigate further mechanisms underlying the entity of DN and new drug discovery. We hypothesized that the entity of DN is inflammatory and is characterized by upregulated inflammatory/pro-inflammatory factors such as peroxisome proliferator-activated receptor alpha, NADPH oxidase, endoplasmic reticulum stress (ER stress), and endothelin receptor A (ET(A)) and downregulated connexin 43 (Cx43) in the kidney. Aminoguanidine is a special blocker to advanced glycation end products and argirein, a new compound contains a molecule of rhein linked to L: -arginine by a hydrogen bond. Rhein possesses anti-inflammatory activity and has been chemically modified to produce a new compound diacerein launched in European market for treating osteoarthritis. Argirein with two active molecules rhein and L: -arginine may be effective in suppressing the inflammatory cytokines contributing to the pathogenesis of DN. With a single injection of streptozotocin 65 mg/kg, ip in rats, early diabetic nephropathy was produced and revealed as an increased microalbuminuria, elevated creatinine and urea in serum, associated with upregulation of mRNA and protein of NADPH oxidase p22phox, p47phox, and p67phox and ET(A), upregulated PKR-like eukaryotic initiation factor 2α kinase (PERK), and downregulated Cx43 in the renal tissue. Upregulation of PERK suggested that there is an ER stress involved in the diabetic kidney, along with an increase in inflammatory/pro-inflammatory factors indicating an entity of chronic inflammation. Abnormalities of biomarkers were blunted by either aminoguanidine or argirein significantly. The new compound argirein is potential in alleviating and retarding microvascular complications of diabetes such as DN in clinical settings.

Topics: Animals; Anthraquinones; Aspartic Acid Endopeptidases; Blood Glucose; Blood Urea Nitrogen; Connexin 43; Creatinine; Diabetes Mellitus, Experimental; Diabetic Nephropathies; eIF-2 Kinase; Endothelin-1; Endothelin-Converting Enzymes; Enzyme Inhibitors; Gene Expression; Guanidines; Kidney; Male; Metalloendopeptidases; NADPH Oxidases; Nitric Oxide Donors; PPAR alpha; Protein Subunits; Proteinuria; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A

Ischemia/reperfusion (I/R) injury, which is commonly seen in the field of renal surgery or transplantation, is a major cause of acute renal failure. Previous studies have shown that ozone oxidative preconditioning (OzoneOP) attenuated renal I/R injury. The objective of this study was to examine the hypothesis that protective effects of OzoneOP in renal I/R injury were associated with endogenous NO.. In a right-nephrectomized rat mode, anesthetized rats underwent 45 min of renal ischemia. OzoneOP (1 mg/kg) was administered before I/R injury. Rats were killed at 24, 48, and 72 h after I/R injury and blood samples and renal tissues were obtained.. OzoneOP prevented the renal dysfunction induced by I/R and increased nitric oxide (NO) release and renal NO synthase (endothelial, eNOS, and inducible, iNOS) expression. In contrast, enhancement of endothelin-1 in the kidney after the reperfusion was markedly suppressed by OzoneOP.. Our findings indicated that the protective effect of OzoneOP was closely related to the NO production following the increase in eNOS and iNOS expression. Ozone treatment may have important clinical implications, particularly in view of the minimizing renal damage before transplantation.

Topics: Acute Kidney Injury; Animals; Blood Urea Nitrogen; Creatinine; Endothelin-1; Glutathione; Glutathione Peroxidase; Guanidines; Ischemic Preconditioning; Kidney; Male; Malondialdehyde; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Ozone; Rats; Rats, Wistar; Reperfusion Injury; Superoxide Dismutase

To investigate the role of advanced glycation end products (AGEs) and their receptors (RAGE) in the pathogenesis of diabetic mellitus erectile dysfunction (DMED) and the effects of AGEs and RAGE on the activity of endothelin-1 (ET-1) in rat cavernosum.. Forty male Sprague-Dawley rats were taken at random to construct 2 groups of diabetes mellitus (DM) models of equal number, one given free access to water and the other administered aminoguanidine hydrochloride (DM + AG) in water at the dose of 1 g/L. Another 20 male SD rats were equally divided into a normal control and an AG control group. After 8 weeks, the cavernosum tissues were harvested from all groups of rats, part of the isolated penile tissues homogenated to detect the content of AGE-peptide (AGE-P) and the activity of ET-1, and the AGEs and RAGE in the rest of the penile tissues analyzed by immunohisto- chemical assay.. Compared with the normal controls, the expressions of AGEs and RAGE, the content of AGE-P and the activity of ET-1 in the cavernosum tissues were significantly high in the DM group (P < 0.05), while the administration of AG to the DM rats reversed the above results. No significant difference was observed between the normal control and AG control groups in any of the data (P > 0.05).. In DM conditions, the joint effect of AGEs and RAGE may elevate the activity of ET-1 in rat cavernosum and thus promote the development of DMED.

Topics: Animals; Diabetes Mellitus, Experimental; Endothelin-1; Enzyme Inhibitors; Glycation End Products, Advanced; Guanidines; Male; Penis; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface

We aimed to investigate the effects of Liuwei Dihuang decoction (LW) on the endothelin-1-reactive oxidative species (ET-ROS) system and matrix metalloproteinases (MMPs) in the early diabetic nephropathy induced by streptozotocin (STZ) in rats. Rats were divided into six groups as follows: the control group, the untreated model group, the treated groups with the LW (5, 10 and 15 g kg(-1), p.o.) and the aminoguanidine-treated group (100 mg kg(-1), orally). The treatment was performed for 4 weeks, beginning on the fifth week after one intraperitoneal injection of STZ (65 mg kg(-1)). In the untreated model group, increased blood glucose, decreased plasma insulin level and an impaired renal function were observed. There was an altered redox system shown by an increased malondialdehyde and decreased activity of glutathione peroxidase and superoxide dismutase in the renal cortex. An enhanced inducible nitric oxide synthetase, total nitric oxide synthase and constitutive nitric oxide synthase and a declined nitric oxide were found. An increased extracellular matrix was indicated by an abnormality of MMP-2 and MMP-9 activities and an increase in hydroxyproline. An up-regulated ET-1 level and increased mRNA expression of endothelin-converting enzyme, preproET-1 and ET( A) receptor were presented in the affected renal cortex, but no change in ET(B) receptor mRNA. The LW was most effective in reversing these changes in diabetic rats and was as effective as aminoguanidine. The benefits of the extracts in relieving the abnormalities in early diabetic nephropathy are likely to be mediated by suppression of the renal ET-ROS system and escalating the activity of MMPs.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Endothelin-1; Enzyme Inhibitors; Female; Gene Expression Regulation; Guanidines; Kidney Cortex; Male; Matrix Metalloproteinases; Phytotherapy; Plant Extracts; Protective Agents; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; RNA, Messenger; Streptozocin

1. The aims of the present study were to examine whether: (i) upregulation of the endothelin (ET) pathway is involved in impairment of vascular relaxation and early retinopathy in diabetic rats; and (ii) vascular and retinal abnormalities respond to the total triterpene acid (TTA) isolated from Fructus Corni compared with responses to the novel endothelin receptor antagonist CPU0213 and aminoguanidine (AMG), a special antagonist for advanced glycation end-products (AGE) and inducible nitric oxide synthase (iNOS). 2. Male Sprague-Dawley rats were randomized into five groups, namely a normal control and four diabetic groups, which included an untreated diabetic group and groups treated with AMG (100 mg/kg, i.g.), CPU0213 (30 mg/kg, s.c.) or TTA (50 mg/kg, i.g.). Diabetes was induced by single injection of streptozotocin (60 mg/kg, i.p.) on the 1st day. The mRNA expression of prepro-endothelin-1 (ppET-1), endothelin-converting enzyme (ECE) and iNOS in the thoracic aorta and mRNA for ET(A) receptors and iNOS in the retina were detected by reverse transcription-polymerase chain reaction. Vasorelaxation to acetylcholine (ACh) and functional assessment of nitric oxide (NO) bioavailability was determined in the thoracic aorta. 3. We observed upregulated mRNA expression of iNOS, ppET-1 and ECE in the thoracic aorta and upregulated mRNA for the ET(A) receptor and iNOS in the retina in the untreated diabetic group. Vasodilatation mediated by ACh and NO bioavailability were markedly reduced in the thoracic aorta compared with the normal control group. These abnormalities were essentially reversed by TTA, CPU0213 or AMG, with the exception with that AMG did not modify vasodilatation to ACh. 4. These data suggest that upregulation of gene transcription of the ET system mediates depressed vasorelaxation, NO bioavailability and changes in iNOS and ET(A) receptors that reflect early retinopathy in diabetic rats. Total triterpene acid, in terms of pharmacological properties resembling the endothelin receptor antagonist CPU0213, is effective in normalizing expression of the ET system and iNOS in early diabetic retinopathy and vasculaopathy.

Topics: Animals; Aorta, Thoracic; Aspartic Acid Endopeptidases; Cornus; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Endothelin A Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Guanidines; Male; Metalloendopeptidases; Nitric Oxide Synthase Type II; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Retina; RNA, Messenger; Thoracic Arteries; Triterpenes; Up-Regulation; Vasodilation

1. The aim of the present study was to evaluate the contribution of disturbance of coronary perfusion to myocardial depression in hearts isolated from lipopolysaccharide (LPS)-treated rats and to investigate the involvement of endothelin (ET)-1 and nitric oxide (NO). 2. Rats were treated with LPS (10 mg/kg, i.p.) and, 4 h later, plasma ET-1 concentrations were measured by radioimmunoassay and hearts were excised for perfusion at a constant perfusion flow. The selective ETA receptor antagonist BQ-123, in the absence or presence of aminoguanidine, a specific inhibitor of inducible NO synthase, was given 15 min before LPS challenge. Coronary perfusion pressure (CPP) and measures of myocardial contractile function were recorded. 3. In hearts isolated from LPS-treated rats, there was a marked increase in CPP that was abolished by pretreatment with BQ-123. In parallel, an increase in plasma ET-1 concentrations was seen in these rats. Lipopolysaccharide also induced decreases in left ventricular developed pressure (LVDP), the product of LVDP and heart rate and maximal rate of rise/fall of left ventricular pressure (+/- dP/dtmax). Single treatment with BQ-123 or aminoguanidine attenuated LPS-induced myocardial depression. However, when these two drugs were given simultaneously, myocardial depression elicited by LPS was blocked significantly. 4. Endothelin-1-mediated coronary vasoconstriction, together with NO, contributes to myocardial depression in hearts isolated from LPS-treated rats.

Topics: Animals; Coronary Vessels; Endothelin A Receptor Antagonists; Endothelin-1; Guanidines; In Vitro Techniques; Lipopolysaccharides; Male; Myocardial Contraction; Nitric Oxide; Nitric Oxide Synthase; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Time Factors; Vasoconstriction

Possible involvement of nitric oxide (NO) in the protective effect of ischemic preconditioning against the ischemia/reperfusion-induced acute renal failure was investigated. Ischemic preconditioning, which consists of three cycles of 2-minute ischemia followed by 5-minute reperfusion, was performed prior to 45-minute ischemia. Ischemic preconditioning significantly improved the renal dysfunction induced by 45-minute ischemia followed by 24-hour reperfusion. Histopathological examination of the kidney of ischemia/reperfusion rats revealed severe renal damage, and suppression of the damage was seen with the ischemic preconditioning treatment. NO metabolites (NOx) production in the kidney after 45-minute ischemia and reperfusion was markedly increased in ischemia/reperfusion rats with ischemic preconditioning, compared with animals not subjected to ischemic preconditioning, and these increases correlated with changes in endothelial NO synthase (eNOS) protein expression in renal tissues. The improvement of renal dysfunction in ischemic preconditioning rats was abolished by the pretreatment with NG-nitro-L-arginine, a nonselective NOS inhibitor, but not with aminoguanidine, an inducible NOS inhibitor. In addition, increment of endothelin-1 (ET-1) content in the kidney after the reperfusion was markedly suppressed by ischemic preconditioning treatment. These findings suggest that the protective effect of ischemic preconditioning on ischemia/reperfusion -induced acute renal failure is closely related to the renal nitric oxide production following the increase in eNOS expression after the reperfusion and that the suppressive effect of ischemic preconditioning on the ischemia/reperfusion -induced renal ET-1 overproduction may be partly involved in the ameliorating effect of ischemic preconditioning.

Topics: Acute Kidney Injury; Animals; Blood Urea Nitrogen; Endothelin-1; Enzyme Inhibitors; Guanidines; Ischemic Preconditioning; Kidney; Male; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Rats; Rats, Sprague-Dawley

Portal hypertension is often accompanied by a hyperdynamic circulation state. Some reports have suggested that nitric oxide (NO) plays an important role in this hyperdynamic state. On the other hand, although endothelin (ET)-1, a powerful vasoconstrictor, was recently identified, little is known about its role in portal hypertension or about the interaction between NO and ET-1. The aim of this study was therefore to investigate whether or not the inhibitor of NO synthase (NOS) might improve portal hypertension, and also to clarify the relationship between NO and ET-1.. Portal hypertensive (PHT) rats, in which hypertension was induced by a two-step ligation of the portal vein (PVL), were used. The mean arterial pressure (MAP), portal pressure (PP), visceral blood flow volume (BFV), and serum levels of NO and ET-1 were determined in PVL rats treated with two NOS inhibitors with different functions: N(G)-nitro-L-arginine methyl ester (L-NAME) and aminoguanidine (AG). Control (CTR) rats. treated by a sham operation (SO), were also studied.. Two-step PVL treatment induced a significant increase in the serum level of NO3-and ET-1 in the portal vein. L-NAME and AG administration significantly decreased PP at doses of 50 mg/kg in PHT rats after 60 min administration, while no inhibitor effected any modification in the CTBR rats. Both NOS inhibitors increased MAP and decreased PP and BFV in the portal vein, gastric mucosa, and spleen, in addition to decreasing the serum levels of NO3- and ET-1 in the PHT rats, while neither blockade modified any parameters in the CTR rats. In PHT rats, L-arginine, a NO substance, reversed the effect of L-NAME, while it did not induce any recovery from the AG effect.. In PHT rats, NO seems to contribute to portal hypertension. PVL increases not only the serum level of NO3-, but also that of ET-1 in the portal vein. Both L-NAME and AG reduce PP and BFV of the portal vein, spleen, gastric mucosa. and liver. In addition, the inhibition of NOS diminishes the serum level not only of NO, but also of ET-1. Use of an appropriate NOS inhibitor may therefore positively affect the hyperdynamic state in portal hypertension.

Topics: Animals; Blood Pressure; Disease Models, Animal; Endothelin-1; Enzyme Inhibitors; Guanidines; Hypertension, Portal; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Portal Vein; Rats; Rats, Sprague-Dawley

In the present study, we examined the pattern of Evan's blue (EB) extravasation over time and we verified the effect of two inhibitors of aldose reductase (sorbinil and ARI 509) as well as aminoguanidine, which modulate nitric oxide (NO) production, on streptozotocin-induced capillary extravasation abnormalities in the upper bronchi, heart, kidney, duodenum, pancreas, skeletal muscle and skin. Albumin extravasation was measured using the EB technique (20 mg/kg). On the third day, a transient decrease in EB leakage was observed in the lung (-49%), heart (-29%) and skeletal muscle (-64%). These early changes in EB were transient, and values returned to normal there after. Later on, EB extravasation was significantly enhanced in the skin (+358, +680, +580, +525 and +365, respectively, at 2, 4, 5, 6 and 7 weeks of diabetes), the duodenum (+101, +160, +92, +124 and +76%), the upper bronchus (+70, +113, +70, +41 and +25%) and the pancreas (+43, +102, +46, +15 and +78%). In the kidney, the increase of EB extravasation was significant at 2 weeks (26%), and from 5 to 7 weeks (+12, +22, +36%). The chronic treatment of diabetic rats with aminoguanidine normalized capillary permeability in most tissues, suggesting that NO is involved in the development of endothelium dysfunction in this streptozotocin-induced diabetic model. Treatment with aldose reductase inhibitors selectively normalized EB extravasation in the kidney.

Topics: Aldehyde Reductase; Animals; Capillary Permeability; Coloring Agents; Diabetes Mellitus, Experimental; Endothelin-1; Endothelium, Vascular; Enzyme Inhibitors; Evans Blue; Female; Guanidines; Imidazoles; Imidazolidines; Nitric Oxide; Rats; Rats, Sprague-Dawley; Serum Albumin; Sorbitol