Effect of Angiotensin 1-7 Peptide Agonist AVE 0991 on Diabetic Endothelial Dysfunction in an Experimental Animal Model: A Possible Tool to Treat Diabetic Erectile Dysfunction.

Background The renin-angiotensin system and its metabolites are crucial in the pathogenesis and progression of complications of diabetes. Aim In this study, we aimed to evaluate the effect of angiotensin 1-7 non-peptide agonist AVE 0991 (576 ug/kg/day i.p.) on diabetic endothelial dysfunction. Materials and methods In this experimental animal study, we investigated the effects of angiotensin 1-7 non-peptide agonist AVE 0991 (576 ug/kg/day i.p.) treatment in male Wistar rats. Diabetes was created via injecting streptozotocin (55 mg/kg/i.p., single dose). Following the cavernous tissue submaximal phenylephrine contraction, relaxation responses were obtained by applying electrical field stimulation (0.5 ms, 40 V) for 15 seconds at 2, 4, 8, 16, 32, and 64 Hz, with two-minute intervals, respectively. To evaluate the effect of nitric oxide, the responses were compared by incubating with 100 mM N(gamma)-nitro-L-arginine methyl ester (L-NAME) for 20 minutes. Additionally, Y-27632 and sodium nitroprusside responses were evaluated in tissues contracted with submaximal doses of phenylephrine. Results Following a submaximal contraction of phenylephrine in the aorta rings, relaxation responses obtained with acetylcholine, sodium nitroprusside, and Y-27632 were impaired in diabetic rats; however, significant results were obtained with treatment. Although there was no significance between the groups in the electrical field stimulation responses, there was a significant dose-dependent difference in the treatment group in this parameter after L-NAME, sodium nitroprusside, and Y-27632 relaxation. Conclusions We determined that treatment with a non-peptide receptor antagonist of angiotensin 1-7, an enzyme detected in the aortic and cavernosum endothelium, may be a promising alternative for treating the complications of diabetes.

Urotensin receptor antagonist palosuran attenuates cyclosporine-a-induced nephrotoxicity in rats.

BACKGROUND: Cyclosporine-A (CsA) is widely used for immunosuppressive therapy in renal transplantation. Nephrotoxicity is the main dose-limiting undesirable consequence of CsA. Urotensin II (U-II), a novel peptide with a powerful influence on vascular biology, has been added to the list of potential renal vascular regulators. Upregulation of the urotensin receptors and elevation of plasma U-II levels are thought to possibly play a role in the etiology of renal failure. OBJECTIVES: The present study examines this hypothesis by evaluating renal function and histology with regard to the potential role of U-II and its antagonist, palosuran, in the pathogenesis of CsA-induced nephrotoxicity in rats. MATERIAL AND METHODS: Male Sprague-Dawley rats were treated with CsA (15 mg/kg, for 21 days, intraperitoneally) or CsA + palosuran (300 mg/kg, for 21 days). Renal function was measured and histopathology, U-II immunostaining and protein detection with western blotting of the kidneys were performed. RESULTS: Cyclosporine-A administration caused a marked decline in creatinine clearance (Ccr). Fractional sodium excretion (FENa) tended to increase in the CsA-treated rats. Plasma U-II levels decreased in the CsA-treated rats. Cyclosporine-A treatment resulted in a marked deterioration in renal histology and an increase in the expression of U-II protein in the kidneys. Palosuran's improvement of renal function manifested as a significant decrease in serum creatinine levels and a significant increase in urine creatinine levels, resulting in a marked increase in Ccr. Palosuran produced a significant normalization of kidney histology and prevented an increase in U-II expression. CONCLUSIONS: Cyclosporine-A-induced renal impairment was accompanied by an increase in U-II expression in kidneys and a contrary decrease in systemic U-II levels. Palosuran improved the condition of rats suffering from renal dysfunction by preventing the decrease in renal U-II expression without affecting the systemic levels of U-II. The protective effect of palosuran in CsA nephrotoxicity is possibly independent of its U-II receptor antagonism.

Effect of Ceftiofur on Hyperalgesia and Allodynia in a Rat Neuropathic Pain Model: The Role of Immune Processes.

OBJECTIVE: Inflammatory and immune mechanisms play important roles in the pathogenesis of neuropathic pain. Ceftiofur, a third-generation cephalosporin, has anti-inflammatory effects by inhibiting tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, nuclear factor (NF)-κB, and mitogen-activated protein kinase (MAPK) signaling. This study aimed to investigate the effect of ceftiofur on hyperalgesia and allodynia in neuropathic rats and to define the possible contribution of immune mechanisms to this effect. METHODS: A neuropathic pain model was performed by ligating the right sciatic nerve. Mechanic hyperalgesia and allodynia were measured using an analgesia meter and dynamic plantar esthesiometer, respectively. Following sciatic nerve ligation, ceftiofur was administered intraperitoneally (10 and 20 mg/kg/day) for 14 days. The control group received saline. Pain thresholds were recorded pre- and postoperatively on days 3, 7, 10, and 14. Protein was extracted from lumbar spinal cord tissue on day 14, and TNF-α, IL-1ß, p65 NF-κB, p38 MAPK, and inducible nitric oxide synthase (iNOS) were evaluated by Western blotting. RESULTS: Neuropathic rats showed decreased pain thresholds in analgesia meter and esthesiometer measurements. Ceftiofur 20 mg/kg/day significantly alleviated hyperalgesia, but not allodynia, and the increased iNOS and IL-1ß expression was attenuated in neuropathic rats at both doses while decreasing p38 MAPK expression only at 20 mg/kg/day. TNF-α and p65 NF-κB expression remained unchanged 14 days after surgery. CONCLUSIONS: Ceftiofur has anti-inflammatory effects by decreasing iNOS, IL-1ß, and p38 MAPK expression in lumbar spinal cord, and treatment of neuropathic rats with repeated doses of ceftiofur for 14 days results in antihyperalgesic effects.

Esophageal Epithelial Resistance and Lower Esophageal Sphincter Muscle Contraction Increase in a Chronic Diabetic Rabbit Model.

BACKGROUND: Esophageal motility disorders and possibly gastroesophageal reflux disease are common in patients with diabetes mellitus. AIMS: We aimed to investigate both the electrophysiological characteristics of the esophageal epithelium and the contractility of the lower esophageal sphincter (LES) muscle in alloxane-induced diabetic rabbits. METHODS: Electrophysiological properties were measured using an Ussing chamber method. An acid-pepsin model was employed with pH 1.7 or weakly acidic (pH 4) Ringer and/or pepsin. Smooth muscle strips of the LES were mounted in an isolated organ bath. Contractile responses to an electrical field stimulation and cumulative concentrations of acetylcholine were recorded. Contractility of the muscle strips were tested in the presence of Rho-kinase inhibitor (Y-27632) and nonspecific nitric oxide inhibitor (L-NAME). RESULTS: The resistance of diabetic tissue perfused in the pH 1.7 Ringer decreased 17 %; pepsin addition decreased it by 49 %. The same concentrations caused a more distinct loss of resistance in the control tissues (22 and 76 %, p < 0.05). The perfusion of tissues in increased concentrations of luminal and serosal glucose did not change the tissue resistance and voltage. Diabetes significantly increased both the electrical field stimulation and acetylcholine-induced contractions in the LES muscle strips (p < 0.01). Incubation with Y-27632 significantly decreased the acetylcholine-induced contractions in a concentration-dependent manner (p < 0.01). CONCLUSIONS: The acid-pepsin model in the diabetic rabbit esophageal tissue had less injury compared with the control. The diabetic rabbit LES muscle had higher contractility, possibly because of the activation of the Rho-Rhokinase pathway. Our results show that in a chronic diabetic rabbit model the esophagus resists reflux by activating mechanisms of mucosal defense and increasing the contractility of the LES.