Kinin B1 Receptor Enhances the Oxidative Stress in a Rat Model of Insulin Resistance: Outcome in Hypertension, Allodynia and Metabolic Complications

BACKGROUND: Kinin B(1) receptor (B(1)R) is induced by the oxidative stress in models of diabetes mellitus. This study aims at determining whether B(1)R activation could perpetuate the oxidative stress which leads to diabetic complications. METHODS AND FINDINGS: Young Sprague-Dawley rats were fed with 10% D-Glucose or tap water (controls) for 8-12 weeks. A selective B(1)R antagonist (SSR240612) was administered acutely (3-30 mg/kg) or daily for a period of 7 days (10 mg/kg) and the impact was measured on systolic blood pressure, allodynia, protein and/or mRNA B(1)R expression, aortic superoxide anion (O(2)(*-)) production and expression of superoxide dismutase (MnSOD) and catalase. SSR240612 reduced dose-dependently (3-30 mg/kg) high blood pressure in 12-week glucose-fed rats, but had no effect in controls. Eight-week glucose-fed rats exhibited insulin resistance (HOMA index), hypertension, tactile and cold allodynia and significant increases of plasma levels of glucose and insulin. This was associated with higher aortic levels of O(2)(*-), NADPH oxidase activity, MnSOD and catalase expression. All these abnormalities including B(1)R overexpression (spinal cord, aorta, liver and gastrocnemius muscle) were normalized by the prolonged treatment with SSR240612. The production of O(2)(*-) in the aorta of glucose-fed rats was also measured in the presence and absence of inhibitors (10-100 microM) of NADPH oxidase (apocynin), xanthine oxidase (allopurinol) or nitric oxide synthase (L-NAME) with and without Sar[D-Phe(8)]des-Arg(9)-BK (20 microM; B(1)R agonist). Data show that the greater aortic O(2)(*-) production induced by the B(1)R agonist was blocked only by apocynin. CONCLUSIONS: Activation of kinin B(1)R increased O(2)(*-) through the activation of NADPH oxidase in the vasculature. Prolonged blockade of B(1)R restored cardiovascular, sensory and metabolic abnormalities by reducing oxidative stress and B(1)R gene expression in this model

Activation of TRPV1 by capsaicin induces functional Kinin B₁receptor in rat spinal cord microglia

<p>Abstract</p> <p>Background</p> <p>The kinin B₁receptor (B₁R) is upregulated by pro-inflammatory cytokines and oxydative stress, which are enhanced by transient receptor potential vanilloid subtype 1 (TRPV1) activation. To examine the link between TRPV1 and B₁R in inflammatory pain, this study aimed to determine the ability of TRPV1 to regulate microglial B₁R expression in the spinal cord dorsal horn, and the underlying mechanism.</p> <p>Methods</p> <p>B₁R expression (mRNA, protein and binding sites) was measured in cervical, thoracic and lumbar spinal cord in response to TRPV1 activation by systemic capsaicin (1-50 mg/kg, s.c) in rats pre-treated with TRPV1 antagonists (capsazepine or SB-366791), the antioxidant N-acetyl-L-cysteine (NAC), or vehicle. B₁R function was assessed using a tail-flick test after intrathecal (i.t.) injection of a selective B₁R agonist (des-Arg⁹-BK), and its microglial localization was investigated by confocal microscopy with the selective fluorescent B₁R agonist, [N^α-bodipy]-des-Arg⁹-BK. The effect of i.t. capsaicin (1 μg/site) was also investigated.</p> <p>Results</p> <p>Capsaicin (10 to 50 mg/kg, s.c.) enhanced time-dependently (0-24h) B₁R mRNA levels in the lumbar spinal cord; this effect was prevented by capsazepine (10 mg/kg, i.p.; 10 μg/site, i.t.) and SB-366791 (1 mg/kg, i.p.; 30 μg/site, i.t.). Increases of B₁R mRNA were correlated with IL-1β mRNA levels, and they were significantly less in cervical and thoracic spinal cord. Intrathecal capsaicin (1 μg/site) also enhanced B₁R mRNA in lumbar spinal cord. NAC (1 g/kg/d × 7 days) prevented B₁R up-regulation, superoxide anion production and NF-kB activation induced by capsaicin (15 mg/kg). Des-Arg⁹-BK (9.6 nmol/site, i.t.) decreased by 25-30% the nociceptive threshold at 1 min post-injection in capsaicin-treated rats (10-50 mg/kg) while it was without effect in control rats. Des-Arg⁹-BK-induced thermal hyperalgesia was blocked by capsazepine, SB-366791 and by antagonists/inhibitors of B₁R (SSR240612, 10 mg/kg, p.o.), glutamate NMDA receptor (DL-AP5, 10 μg/site, i.t.), substance P NK-1 receptor (RP-67580, 10 μg/site, i.t.) and nitric oxide synthase (L-NNA, 10 μg/site, i.t.). The B₁R fluorescent agonist was co-localized with an immunomarker of microglia (Iba-1) in spinal cord dorsal horn of capsaicin-treated rats.</p> <p>Conclusion</p> <p>This study highlights a new mechanism for B₁R induction via TRPV1 activation and establishes a link between these two pro-nociceptive receptors in inflammatory pain.</p

Surgical management of gynecomastia - a 10-year analysis

BACKGROUND: Gynecomastia is defined as the benign enlargement of the male breast. Most studies on surgical treatment of gynecomastia show only small series and lack histopathology results. The aim of this study was to analyze the surgical approach in the treatment of gynecomastia and the related outcome over a 10-year period. PATIENTS AND METHODS: All patients undergoing surgical gynecomastia corrections in our department between 1996 and 2006 were included for retrospective evaluation. The data were analyzed for etiology, stage of gynecomastia, surgical technique, complications, risk factors, and histological results. RESULTS: A total of 100 patients with 160 operations were included. Techniques included subcutaneous mastectomy alone or with additional hand-assisted liposuction, isolated liposuction, and formal breast reduction. Atypical histological findings were found in 3% of the patients (spindle-cell hemangioendothelioma, papilloma). The surgical revision rate among all patients was 7%. Body mass index and a weight of the resected specimen higher than 40 g were identified as significant risk factors for complications (p < 0.05). CONCLUSIONS: The treatment of gynecomastia requires an individualized approach. Caution must be taken in performing large resections, which are associated with increased complication rates. Histological tissue analysis should be routinely performed in all true gynecomastia corrections, because histological results may reveal atypical cellular pathology

Contribution of adenylyl cyclase modulation of pre- and postsynaptic GABA neurotransmission to morphine antinociception and tolerance

Opioid inhibition of presynaptic GABA release in the ventrolateral periaqueductal gray (vlPAG) activates the descending antinociception pathway. Tolerance to repeated opioid administration is associated with upregulation of adenylyl cyclase activity. The objective of these studies was to test the hypothesis that adenylyl cyclase contributes to opioid tolerance by modulating GABA neurotransmission. Repeated microinjections of morphine or the adenylyl cyclase activator NKH477 into the vlPAG decreased morphine antinociception as would be expected with the development of tolerance. Conversely, microinjection of the adenylyl cyclase inhibitor SQ22536 reversed both the development and expression of morphine tolerance. These behavioral results indicate that morphine tolerance is dependent on adenylyl cyclase activation. Electrophysiological experiments revealed that acute activation of adenylyl cyclase with forskolin increased the frequency of presynaptic GABA release. However, recordings from rats treated with repeated morphine administration did not exhibit increased basal miniature inhibitory postsynaptic current (mIPSC) frequency but showed a decrease in mean amplitude of mIPSCs indicating that repeated morphine administration modulates postsynaptic GABAA receptors without affecting the probability of presynaptic GABA release. SQ22536 reversed this change in mIPSC amplitude and inhibited mIPSC frequency selectively in morphine tolerant rats. Repeated morphine or NKH477 administration also decreased antinociception induced by microinjection of the GABAA receptor antagonist bicuculline, further demonstrating changes in GABA neurotransmission with morphine tolerance. These results show that the upregulation of adenylyl cyclase caused by repeated vlPAG morphine administration produces antinociceptive tolerance by modulating both pre- and postsynaptic GABA neurotransmission