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Sunsang Wang - One of the best experts on this subject based on the ideXlab platform.

  • splanchnic Hyposensitivity to glypressin in a hemorrhage transfused common bile duct ligated rat model of portal hypertension role of nitric oxide and bradykinin
    Hepato-gastroenterology, 2009
    Co-Authors: Chienting Chen, Fullyoung Chang, Sunsang Wang, Shwuling Wu, Chechang Chan, Huichun Huang
    Abstract:

    BACKGROUND/AIMS: The portal hypotensive effect of vasopressin during hemorrhage is less effective than that during stable condition in cirrhotic patients or experimental portal hypertension (the so-called Hyposensitivity phenomenon). Recent studies have demonstrated that constitutive nitric oxide activities and bradykinin in hemorrhage-transfused partially portal vein-ligated rats are responsible, at least partly, for the splanchnic Hyposensitivity to glypressin (a long acting vasopressin analogue). This study investigated the relative contribution of nitric oxide synthase isoforms and the role of bradykinin in the pathogenesis of splanchnic Hyposensitivity in rats with cirrhosis induced by common bile duct-ligation (BDL). METHODOLOGY: Five weeks after BDL, systemic and portal hemodynamics were measured in stable or bleeding BDL rats receiving intravenous infusion of glypressin (0.2 mg/kg). In the treatment groups, N(G)-nitro-L-arginine methyl ester (L-NAME, a non-selective nitric oxide synthase inhibitor), L-canavanine (a specific inducible nitric oxide synthase inhibitor) or HOE 140 (a bradykinin B2 receptor antagonist) was administered 45 minutes before the infusion of glypressin. In rats with a hypotensive hemorrhage, 4.5 ml of blood was withdrawn and 50% of the withdrawn blood was reinfused before the administration of glypressin or various inhibitors. RESULTS: Splanchnic Hyposensitivity to glypressin was demonstrated in the hemorrhage-transfused BDL rats. The infusion of L-NAME elevated the mean arterial pressure in the bleeding BDL rats without the modulation of portal pressure. The addition of L-NAME or HOE 140, but not L-canavanine, significantly and similarly potentiated the portal-hypotensive effects of glypressin. CONCLUSIONS: Constitutive nitric oxide synthase and bradykinin play major roles in the development of splanchnic Hyposensitivity to glypressin observed in hemorrhage-transfused rats with biliary cirrhosis.

  • splanchnic Hyposensitivity to glypressin in a hemorrhage transfused rat model of portal hypertension the role of tumor necrosis factor α
    臺灣消化醫學雜誌, 2007
    Co-Authors: Huichun Huang, Sunsang Wang, Fullyoung Chang
    Abstract:

    Introduction: Vasopressin and its long-acting analogue, glypressin given during hemorrhage are less effective than when given during a stable state in portal hypertensive or cirrhotic conditions, that is, the so-called Hyposensitivity phenomenon. According to the previous studies, nitric oxide has been ascribed to participate in the Hyposensitivity. Tumor necrosis factor-α stimulates nitric oxide synthesis and is enhanced during acute hemorrhage. However, its role in portal hypertension with acute hemorrhage and vascular hyporesponsiveness remains unclear. Materials and Methods: Portal hypertension was induced by partial portal vein ligation (PVL) on male Spraque-Dawley rats. Fourteen days after PVL, portal and systemic hemodynamic parameters were evaluated then rats were divided into without-bleeding and with-bleeding groups. In rats with a hypotensive hemorrhage, 4.5ml of blood was withdrawn with an infusion/withdrawal pump, of which 50% was re-infused. The without-bleeding groups received no manipulation during the same period of time. Forty-five minutes later, the second hemodynamic measurement was performed, followed by glypressin (0.07mg/kg) infusion. Ten minutes after glypressin administration, the third hemodynamic study was done, followed by heparinized blood sampling for TNF-α measurements. Results: splanchnic Hyposensitivity to glypressin was noted in portal hypetensive rats during acute hemorrhage. The level of tumor necrosis factor tended to be higher in rats with bleeding but not statistically significant (P=0.087). Conclusion: Tumor necrosis factor did not seem to play a significant role in splanchnic Hyposensitivity to glypressin in portal hypertensive rats during acute hemorrhage. The influences of other endogenous vasoactive substances should also be considered.

  • nitric oxide synthase expression in the splanchnic Hyposensitivity to glypressin of a hemorrhage transfused rat model with portal hypertension
    Journal of The Chinese Medical Association, 2004
    Co-Authors: Huichun Huang, Fullyoung Chang, Sunsang Wang, Chechang Chan, Yichou Chen, Reihwa Lu, Shwuling Wu
    Abstract:

    BACKGROUND: Nitric oxide (NO) has been proposed to participate in the vascular hyporesponsiveness to vasopressin and its long-acting analogue glypressin during hemorrhage in portal hypertensive states. This study surveyed the role of NO regarding splanchnic hyporeactivity to glypressin and NO synthases (NOS) expression in different vascular beds in bleeding portal-hypertensive rats. METHODS: Under general anesthesia with ketamine, partially portal vein-ligated male Sprague-Dawley rats without or with bleeding were used to investigate the hemodynamic effects of glypressin (0.07 mg/kg intravenously) and constitutive (cNOS) and inducible NOS (iNOS) mRNA expression over the abdominal aorta and superior mesenteric artery. RESULTS: Splanchnic Hyposensitivity to glypressin was noted in the hemorrhage-transfused rats with enhanced cNOS expression of superior mesenteric artery. No significant differences of cNOS and iNOS expression in abdominal aorta and iNOS in superior mesenteric artery were found between the with-bleeding and without-bleeding groups. CONCLUSIONS: In rats with portal hypertension and acute hemorrhage, cNOS over-expression in superior mesenteric artery may take a part in the splanchnic Hyposensitivity to glypressin.

  • cyclooxygenase expression in splanchnic Hyposensitivity to glypressin of bleeding portal hypertensive rats
    European Journal of Clinical Investigation, 2003
    Co-Authors: Fullyoung Chang, Sunsang Wang, Huichun Huang, Choyu Chan, Yungtai Chen, Chengyen Chen
    Abstract:

    Background Prostacyclin mediates, at least partly, the splanchnic vascular hyporesponsiveness to glypressin in bleeding portal hypertensive rats. This study investigated the relative contribution of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in the splanchnic Hyposensitivity to glypressin in rats with portal hypertension induced by partial portal vein ligation (PVL). Methods Fourteen days after the operation, the rats were divided into without- and with-bleeding groups. Three series of PVL rats were used to investigate (i) the haemodynamic effects of glypressin (0·07 mg kg−1 intravenously), (ii) COX-1/COX-2 mRNA expression over abdominal aorta and superior mesenteric artery and (iii) plasma levels of 6-keto-prostaglandin-F1α. In rats with a hypotensive haemorrhage, 4·5 mL of blood was withdrawn and 50% of the withdrawn blood was re-infused before blood and vessel sampling or the administration of glypressin. Results Splanchnic Hyposensitivity to glypressin was demonstrated in the haemorrhage-transfused PVL rats with enhanced COX-1 expression of superior mesenteric artery and increased plasma levels of 6-keto-prostaglandin-F1α. There were no differences in the COX-2 expression of superior mesenteric artery and COX-1 and COX-2 expressions of abdominal aorta between without- and with-bleeding groups. Conclusion In portal hypertensive rats with acute haemorrhage, COX-1 over-expression in the superior mesenteric artery plays a role in mediating the splanchnic Hyposensitivity to glypressin.

  • inhibition of prostacyclin by indomethacin ameliorates the splanchnic Hyposensitivity to glypressin in haemorrhage transfused common bile duct ligated rats
    European Journal of Clinical Investigation, 2001
    Co-Authors: Sunsang Wang, Fullyoung Chang, Choyu Chan, Szuhsien Wu, Chengyen Chen, Huichun Huang
    Abstract:

    Background Prostacyclin (PGI 2 ) is an important contributor to the mediation of hyporeactivity to vasoconstrictors and the development of hyperdynamic circulation in portal hypertensive states. Inhibition of PGI 2 synthesis in haemorrhage-transfused partially portal vein-ligated rats could ameliorate the splanchnic Hyposensitivity to glypressin, a long-acting vasopressin analogue. This study investigated whether the Hyposensitivity to glypressin also exists in rats with common bile duct ligation (BDL) and whether the inhibition of PGI 2 synthesis by indomethacin could potentiate the portal-hypotensive effect of glypressin in bleeding BDL rats. Methods Two series of BDL rats were used. Series 1 investigated the haemodynamic effects of low dose glypressin (0.07 mg kg -1 ) in BDL rats with or without bleeding by catheterization. In series 2, haemodynamic parameters were measured in stable or bleeding BDL rats that were receiving intravenously high dose glypressin (0.2 mg kg -1 ) or indomethacin (5 mg kg -1 ) followed by high dose glypressin. In rats with a hypotensive haemorrhage, 4.5 mL of blood was withdrawn and 50% of the withdrawn blood was reinfused before the administration of glypressin or indomethacin. Results Splanchnic Hyposensitivity to glypressin was demonstrated in haemorrhage-transfused BDL rats receiving high, but not low, doses of glypressin. Indomethacin infusion did not cause significant systemic and portal haemodynamic changes in bleeding BDL rats (P > 0.05). The addition of indomethacin significantly enhanced the portal-hypotensive effects of glypressin (P < 0.05) and potentiated the increases in mean arterial pressure induced by glypressin infusion (P < 0.001) in bleeding BDL rats. Conclusion Splanchnic Hyposensitivity to glypressin observed in haemorrhage-transfused BDL rats could be ameliorated by the addition of indomethacin, suggesting a role of endogenous PGI 2 in its pathophysiology.

Peter James Lunniss - One of the best experts on this subject based on the ideXlab platform.

  • assessment of rectal afferent neuronal function and brain activity in patients with constipation and rectal Hyposensitivity
    Neurogastroenterology and Motility, 2013
    Co-Authors: Rebecca E. Burgell, Peter James Lunniss, Asbjørn Mohr Drewes, Dina Lelic, Emma V Carrington, Soren Schou Olesen, Susan Surguy, S M Scott
    Abstract:

    Background  Blunted rectal sensation (rectal Hyposensitivity: RH) is present in almost one-quarter of patients with chronic constipation. The mechanisms of its development are not fully understood, but in a proportion, afferent dysfunction is likely. To determine if, in patients with RH, alteration of rectal sensory pathways exists, rectal evoked potentials (EPs) and inverse modeling of cortical dipoles were examined. Methods  Rectal EPs (64 channels) were recorded in 13 patients with constipation and RH (elevated thresholds to balloon distension) and 11 healthy controls, in response to electrical stimulation of the rectum at 10 cm from the anal verge using a bipolar stimulating electrode. Stimuli were delivered at pain threshold. Evoked potential peak latencies and amplitudes were analyzed, and inverse modeling was performed on traces obtained to determine the location of cortical generators. Key Results  Pain threshold was higher in patients than controls [median 59 (range 23–80) mA vs 24 (10–55) mA; P = 0.007]. Median latency to the first negative peak was 142 (±24) ms in subjects compared with 116 (±15) ms in controls (P = 0.004). There was no difference in topographic analysis of EPs or location of cortical activity demonstrated by inverse modeling between groups. Conclusions & Inferences  This study is the first showing objective evidence of alteration in the rectal afferent pathway of individuals with RH and constipation. Prolonged latencies suggest a primary defect in sensory neuronal function, while cerebral processing of visceral sensory information appears normal.

  • prospective randomized double blind study of temporary sacral nerve stimulation in patients with rectal evacuatory dysfunction and rectal Hyposensitivity
    Annals of Surgery, 2012
    Co-Authors: Charles H Knowles, Peter James Lunniss, Norman S. Williams, Chetan Bhan, Noel N Thin, Katherine Gill, Karyn Grimmer, Stephen Scott
    Abstract:

    OBJECTIVE: Prospective randomized double-blind placebo-controlled crossover trial of 14 female patients (median age 52 [30-69] years) with proctographically defined evacuatory dysfunction (ED) and demonstrable rectal Hyposensitivity (elevated thresholds to balloon distension in comparison with age- and sex-matched controls). BACKGROUND: Sacral nerve stimulation (SNS) is an evolving treatment for constipation. However, variable outcomes might be improved by better patient selection. Evidence that the effect of SNS may be mediated by modulation of afferent signaling promotes a role in patients with ED associated with rectal hyposensation. METHODS: SNS was performed by the standard 2-stage technique (temporary then permanent implantation). During a 4-week period of temporary stimulation, patients were randomized ON-OFF/OFF-ON for two 2-week periods. Before insertion (PRE), and during each crossover period, primary (rectal sensory thresholds) and secondary (bowel diaries, constipation, and GIQoL [gastrointestinal quality of life] scores) outcome variables were blindly assessed. RESULTS: Thirteen patients completed the trial. Following stimulation, defecatory desire volumes to rectal balloon distension were normalized in 10 of 13 patients (PRE: mean 277 mL [234-320] vs ON: 163 mL [133-193] vs OFF: 220 mL [183-257 mL]; P = 0.006) and maximum tolerable volume in 9 of 13 (PRE: mean 350 mL [323-377] vs ON: 262 mL [219-305] vs OFF: 298 mL [256-340 mL]; P = 0.012). There was a significant increase in the percentage of successful bowel movements (PRE: median 43% [0-100] vs ON: 89% [11-100] vs OFF: 83% [11-100]; P = 0.007) and Wexner constipation scores improved (PRE: median 19 [9-26] vs ON: 10 [6-27] vs OFF: 13 [5-29]; P = 0.01). There were no significant changes in disease-specific or generic quality of life measures. Eleven patients progressed to permanent stimulation (9/11 success at 19 months). CONCLUSIONS: Most patients with chronic constipation secondary to ED with rectal Hyposensitivity responded to temporary SNS. The physiological results presented support a mechanistic role for rectal afferent modulation.

  • rectal Hyposensitivity pathophysiological mechanisms
    Neurogastroenterology and Motility, 2009
    Co-Authors: Marc A. Gladman, Norman S. Williams, S M Scott, Qasim Aziz, Peter James Lunniss
    Abstract:

    Rectal Hyposensitivity (RH) relates to a diminished perception of rectal distension. It may occur due to afferent nerve dysfunction and/or sec- ondary to abnormal structural or biomechanical properties of the rectum. The aim of this study was to determine the contribution of these underlying pathophysiological mechanisms by systematically evaluating rectal diameter, compliance and afferent nerve sensitivity in patients with RH, using method- ology employed in clinical practice. The study popu- lation comprised 45 (33 women; median age 48, range 25-72 years) constipated patients (Rome II criteria) with RH and 20 with normal rectal sensitivity on balloon distension and 20 healthy volunteers. Rectal diameter was measured at minimum distending pressure during isobaric distension under fluoroscopic screening. Rectal compliance was assessed during phasic isobaric distension by measuring the slope of the pressure-volume curve. Electrical stimulation of the rectal mucosa was employed to determine afferent nerve function. Values were compared to normal ran- ges established in healthy volunteers. The upper limits of normal for rectal diameter, compliance and elec- trosensitivity were 6.3 cm, 17.9 mL mmHg )1 and 21.3 mA respectively. Among patients with RH, rectal diameter, but not compliance, was increased above the normal range (megarectum) in seven patients (16%), two of whom had elevated electrosensitivity thresholds. Rectal diameter and compliance were elevated in 23 patients (51%), nine of whom had elevated electrosensitivity thresholds. The remaining 15 patients (33%) with RH had normal rectal compli- ance and diameter, all of whom had elevated electro- sensitivity thresholds. Two-third of the patients with RH on simple balloon distension have elevated rectal compliance and/or diameter, suggesting that impaired perception of rectal distension is due to inadequate stimulation of the rectal afferent pathway. However, a proportion of such patients also appear to have impaired nerve function. In the remaining one-third of the patients, rectal diameter and compliance are nor- mal, while electrosensitivity thresholds are elevated, suggestive of true impaired afferent nerve function. Identification of these subgroups of patients with RH may have implications regarding their management.

  • rectal Hyposensitivity evaluation of anal sensation in female patients with refractory constipation with and without faecal incontinence
    Neurogastroenterology and Motility, 2007
    Co-Authors: Subash Vasudevan, Marc A. Gladman, S M Scott, Peter James Lunniss
    Abstract:

    Abstract  Rectal Hyposensitivity (RH) is commonly found in patients with intractable constipation, faecal incontinence or both. Anal sensation may also be blunted in these conditions. We aimed to determine whether RH is associated with anal Hyposensitivity, which may reflect a combined viscero-somatic neuropathy. One hundred and fifty-eight female patients with chronic constipation underwent physiological investigation including rectal sensation to volumetric balloon distension, and distal anal mucosal sensation to electrostimulation. Data were also obtained from 32 healthy female volunteers. Anal mucosal electrosensory thresholds were significantly higher in patients compared with volunteers (median: 2.4 mA, range: 0.4–19.6 vs 1.1 mA, range: 0.1–4.2, respectively), although the patient group was older (P < 0.0001), but there was no difference (P = 0.572) in the incidence of blunted anal sensation between those with normal rectal sensation (n = 113, 20% abnormal) and RH (n = 45, 24% abnormal). Irrespective of rectal sensory function, there was a strong association between symptom duration (P = 0.012) and anal Hyposensitivity. One-fifth of constipated female patients had evidence of diminished anal sensation. However, the presence of RH was not associated with an increased frequency of anal Hyposensitivity, thereby suggesting that different aetiopathogenic mechanisms underlie the development of anal and rectal hyosensitivity. Further studies in carefully selected, homogenous patient populations are necessary to elucidate these mechanisms.

  • Rectal Hyposensitivity: evaluation of anal sensation in female patients with refractory constipation with and without faecal incontinence*
    Neurogastroenterology and Motility, 2007
    Co-Authors: Subash P. Vasudevan, Marc A. Gladman, S M Scott, Peter James Lunniss
    Abstract:

    Abstract  Rectal Hyposensitivity (RH) is commonly found in patients with intractable constipation, faecal incontinence or both. Anal sensation may also be blunted in these conditions. We aimed to determine whether RH is associated with anal Hyposensitivity, which may reflect a combined viscero-somatic neuropathy. One hundred and fifty-eight female patients with chronic constipation underwent physiological investigation including rectal sensation to volumetric balloon distension, and distal anal mucosal sensation to electrostimulation. Data were also obtained from 32 healthy female volunteers. Anal mucosal electrosensory thresholds were significantly higher in patients compared with volunteers (median: 2.4 mA, range: 0.4–19.6 vs 1.1 mA, range: 0.1–4.2, respectively), although the patient group was older (P 

Maree T. Smith - One of the best experts on this subject based on the ideXlab platform.

  • morphine Hyposensitivity in streptozotocin diabetic rats reversal by dietary l arginine treatment
    Clinical and Experimental Pharmacology and Physiology, 2018
    Co-Authors: Shahrdad Lotfipour, Maree T. Smith
    Abstract:

    Painful diabetic neuropathy (PDN) is a long-term complication of diabetes. Defining symptoms include mechanical allodynia (pain due to light pressure or touch) and morphine Hyposensitivity. In our previous work using the streptozotocin (STZ)-diabetic rat model of PDN, morphine Hyposensitivity developed in a temporal manner with efficacy abolished at 3-months post-STZ and maintained for 6-months post-STZ. As this time course mimicked that for the temporal development of Hyposensitivity to the pain-relieving effects of the furoxan nitric oxide (NO) donor, PRG150 (3-methylfuroxan-4-carbaldehyde) in STZ-diabetic rats, we hypothesized that progressive depletion of endogenous NO bioactivity may underpin the temporal loss of morphine sensitivity in STZ-diabetic rats. Furthermore, we hypothesized that replenishment of NO bioactivity may restore morphine sensitivity in these animals. Diabetes was induced in male Dark Agouti rats by intravenous injection of STZ (85 mg/kg). Diabetes was confirmed on day 7 if blood glucose concentrations were ≥15 mM. Mechanical allodynia was fully developed in the bilateral hindpaws by 3-weeks of STZ-diabetes in rats and this was maintained for the study duration. Morphine Hyposensitivity developed in a temporal manner with efficacy abolished by 3-months post-STZ. Administration of dietary L-arginine (NO precursor) at 1 g/day to STZ-diabetic rats according to a 15-week prevention protocol initiated at 9-weeks post-STZ prevented abolition of morphine efficacy. When given as an 8-week intervention protocol in rats where morphine efficacy was abolished, dietary L-arginine at 1 g/day progressively rescued morphine efficacy and potency. Our findings implicate NO depletion in the development of morphine Hyposensitivity in STZ-diabetic rats. This article is protected by copyright. All rights reserved.

  • Morphine Hyposensitivity in streptozotocin-diabetic rats: Reversal by dietary l-arginine treatment.
    Clinical and Experimental Pharmacology and Physiology, 2017
    Co-Authors: Shahrdad Lotfipour, Maree T. Smith
    Abstract:

    Painful diabetic neuropathy (PDN) is a long-term complication of diabetes. Defining symptoms include mechanical allodynia (pain due to light pressure or touch) and morphine Hyposensitivity. In our previous work using the streptozotocin (STZ)-diabetic rat model of PDN, morphine Hyposensitivity developed in a temporal manner with efficacy abolished at 3 months post-STZ and maintained for 6 months post-STZ. As this time course mimicked that for the temporal development of Hyposensitivity to the pain-relieving effects of the furoxan nitric oxide (NO) donor, PRG150 (3-methylfuroxan-4-carbaldehyde) in STZ-diabetic rats, we hypothesized that progressive depletion of endogenous NO bioactivity may underpin the temporal loss of morphine sensitivity in STZ-diabetic rats. Furthermore, we hypothesized that replenishment of NO bioactivity may restore morphine sensitivity in these animals. Diabetes was induced in male Dark Agouti rats by intravenous injection of STZ (85 mg/kg). Diabetes was confirmed on day 7 if blood glucose concentrations were ≥15 mmol/L. Mechanical allodynia was fully developed in the bilateral hindpaws by 3 weeks of STZ-diabetes in rats and this was maintained for the study duration. Morphine Hyposensitivity developed in a temporal manner with efficacy abolished by 3 months post-STZ. Administration of dietary l-arginine (NO precursor) at 1 g/d to STZ-diabetic rats according to a 15-week prevention protocol initiated at 9 weeks post-STZ prevented abolition of morphine efficacy. When given as an 8-week intervention protocol in rats where morphine efficacy was abolished, dietary l-arginine at 1 g/d progressively rescued morphine efficacy and potency. Our findings implicate NO depletion in the development of morphine Hyposensitivity in STZ-diabetic rats.

  • translational research section original research article insulin implants prevent the temporal development of mechanical allodynia and opioid Hyposensitivity for 24 wks in streptozotocin stz diabetic wistar rats
    2016
    Co-Authors: Kathleen J Otto, Maree T. Smith, Bruce D Wyse, Peter J Cabot, Brisbane Queensland, Maree Smith
    Abstract:

    Objective. As the Diabetes Control and Complica- tions Trial showed that intensive glycemic control in patients with Type 1 diabetes decreased the risk of development of long-term microvascular complica- tions including painful diabetic neuropathy by ~60%, hyperglycemia was implicated as a causal factor in the etiology of this condition. Hence, the present study was designed as a 24-week longitudinal inves- tigation of the extent to which the level of glycemic control in the streptozotocin (STZ)-diabetic rat model of Type 1 diabetes affects the development of mechanical allodynia and opioid Hyposensitivity in these animals. Results. Diabetes was fully developed (blood glucose levels 15 mM) in adult male Wistar rats by 7 days after intravenous STZ (75 mg/kg) admin- istration. Mechanical allodynia developed in a tem- poral manner in the rat hindpaws, such that it was fully developed by 6 weeks and persisted for at least 24 weeks post-STZ administration. Morphine Hyposensitivity also developed in a temporal manner in the same animals. By contrast, restora- tion and maintenance of euglycemia using insulin implants commencing at diabetes diagnosis on Day 7 post-streptozotocin administration, prevented development of both mechanical allodynia and opioid Hyposensitivity in STZ-diabetic rats for the 24-week study duration. Conclusions. This study shows that long-term res- toration of euglycemia over a 6-month period in STZ- diabetic rats prevents the hallmark symptoms of PDN including morphine Hyposensitivity. Clinical Relevance. Our findings are consistent with epidemiological data showing that tight glycemic control in patients with Type 1 diabetes markedly reduces the prevalence of PDN, further implicating persistent hyperglycemia as a pathogenic factor.

  • insulin implants prevent the temporal development of mechanical allodynia and opioid Hyposensitivity for 24 wks in streptozotocin stz diabetic wistar rats
    Pain Medicine, 2011
    Co-Authors: Kathleen J Otto, Bruce D Wyse, Peter J Cabot, Maree T. Smith
    Abstract:

    Objective. As the Diabetes Control and Complications Trial showed that intensive glycemic control in patients with Type 1 diabetes decreased the risk of development of long-term microvascular complications including painful diabetic neuropathy by ∼60%, hyperglycemia was implicated as a causal factor in the etiology of this condition. Hence, the present study was designed as a 24-week longitudinal investigation of the extent to which the level of glycemic control in the streptozotocin (STZ)-diabetic rat model of Type 1 diabetes affects the development of mechanical allodynia and opioid Hyposensitivity in these animals. Results. Diabetes was fully developed (blood glucose levels ≥ 15 mM) in adult male Wistar rats by 7 days after intravenous STZ (75 mg/kg) administration. Mechanical allodynia developed in a temporal manner in the rat hindpaws, such that it was fully developed by 6 weeks and persisted for at least 24 weeks post-STZ administration. Morphine Hyposensitivity also developed in a temporal manner in the same animals. By contrast, restoration and maintenance of euglycemia using insulin implants commencing at diabetes diagnosis on Day 7 post-streptozotocin administration, prevented development of both mechanical allodynia and opioid Hyposensitivity in STZ-diabetic rats for the 24-week study duration. Conclusions. This study shows that long-term restoration of euglycemia over a 6-month period in STZ-diabetic rats prevents the hallmark symptoms of PDN including morphine Hyposensitivity. Clinical Relevance. Our findings are consistent with epidemiological data showing that tight glycemic control in patients with Type 1 diabetes markedly reduces the prevalence of PDN, further implicating persistent hyperglycemia as a pathogenic factor.

  • longitudinal study of painful diabetic neuropathy in the zucker diabetic fatty rat model of type 2 diabetes impaired basal g protein activity appears to underpin marked morphine Hyposensitivity at 6 months
    Pain Medicine, 2011
    Co-Authors: Kathleen J Otto, Bruce D Wyse, Peter J Cabot, Maree T. Smith
    Abstract:

    Objectives. Epidemiological studies in patients with type 1 and type 2 diabetes show that hyperglycemia is associated with the development of long-term microvascular complications, including painful diabetic neuropathy (PDN). However, as the prevalence of type 2 diabetes in humans far exceeds that of type 1, the present study was undertaken as a 22-week longitudinal investigation commencing at 7 weeks of age, to assess the utility of the Zucker diabetic fatty (ZDF) rat model of type 2 diabetes for the study of PDN. Design. Behavioral methods were used to characterize temporal changes in hindpaw sensitivity as well as morphine potency in these animals. The effect of long-term diabetes on µ-opioid receptor function and mRNA expression levels in the spinal cord was also assessed. Results. Diabetes developed spontaneously in ZDF rats with marked hyperglycemia (blood glucose levels ≥ 15 mM) evident by 11 weeks of age, which was maintained until study completion at 29 weeks. In ZDF rats, there was progressive development of mechanical allodynia in the hindpaws such that it was fully developed by 6 months of age. Concurrently, there was temporal loss of opioid sensitivity in these animals such that marked morphine Hyposensitivity was evident at 6 months. In the spinal cord, basal G-protein function was significantly impaired at 29 weeks of age, resulting in apparently reduced agonist-stimulated µ-opioid receptor function compared with the prediabetic state. Conclusions. Together, our findings suggest that impaired basal G-protein activity underpins morphine Hyposensitivity in PDN. Clinical Relevance. Clinical management of diabetic neuropathic pain has been challenging. This study provides a mechanistic explanation regarding the effectiveness, or lack thereof, of opioid analgesia in the treatment of diabetic neuropathic pain.

Huichun Huang - One of the best experts on this subject based on the ideXlab platform.

  • splanchnic Hyposensitivity to glypressin in a hemorrhage transfused common bile duct ligated rat model of portal hypertension role of nitric oxide and bradykinin
    Hepato-gastroenterology, 2009
    Co-Authors: Chienting Chen, Fullyoung Chang, Sunsang Wang, Shwuling Wu, Chechang Chan, Huichun Huang
    Abstract:

    BACKGROUND/AIMS: The portal hypotensive effect of vasopressin during hemorrhage is less effective than that during stable condition in cirrhotic patients or experimental portal hypertension (the so-called Hyposensitivity phenomenon). Recent studies have demonstrated that constitutive nitric oxide activities and bradykinin in hemorrhage-transfused partially portal vein-ligated rats are responsible, at least partly, for the splanchnic Hyposensitivity to glypressin (a long acting vasopressin analogue). This study investigated the relative contribution of nitric oxide synthase isoforms and the role of bradykinin in the pathogenesis of splanchnic Hyposensitivity in rats with cirrhosis induced by common bile duct-ligation (BDL). METHODOLOGY: Five weeks after BDL, systemic and portal hemodynamics were measured in stable or bleeding BDL rats receiving intravenous infusion of glypressin (0.2 mg/kg). In the treatment groups, N(G)-nitro-L-arginine methyl ester (L-NAME, a non-selective nitric oxide synthase inhibitor), L-canavanine (a specific inducible nitric oxide synthase inhibitor) or HOE 140 (a bradykinin B2 receptor antagonist) was administered 45 minutes before the infusion of glypressin. In rats with a hypotensive hemorrhage, 4.5 ml of blood was withdrawn and 50% of the withdrawn blood was reinfused before the administration of glypressin or various inhibitors. RESULTS: Splanchnic Hyposensitivity to glypressin was demonstrated in the hemorrhage-transfused BDL rats. The infusion of L-NAME elevated the mean arterial pressure in the bleeding BDL rats without the modulation of portal pressure. The addition of L-NAME or HOE 140, but not L-canavanine, significantly and similarly potentiated the portal-hypotensive effects of glypressin. CONCLUSIONS: Constitutive nitric oxide synthase and bradykinin play major roles in the development of splanchnic Hyposensitivity to glypressin observed in hemorrhage-transfused rats with biliary cirrhosis.

  • splanchnic Hyposensitivity to glypressin in a hemorrhage transfused rat model of portal hypertension the role of tumor necrosis factor α
    臺灣消化醫學雜誌, 2007
    Co-Authors: Huichun Huang, Sunsang Wang, Fullyoung Chang
    Abstract:

    Introduction: Vasopressin and its long-acting analogue, glypressin given during hemorrhage are less effective than when given during a stable state in portal hypertensive or cirrhotic conditions, that is, the so-called Hyposensitivity phenomenon. According to the previous studies, nitric oxide has been ascribed to participate in the Hyposensitivity. Tumor necrosis factor-α stimulates nitric oxide synthesis and is enhanced during acute hemorrhage. However, its role in portal hypertension with acute hemorrhage and vascular hyporesponsiveness remains unclear. Materials and Methods: Portal hypertension was induced by partial portal vein ligation (PVL) on male Spraque-Dawley rats. Fourteen days after PVL, portal and systemic hemodynamic parameters were evaluated then rats were divided into without-bleeding and with-bleeding groups. In rats with a hypotensive hemorrhage, 4.5ml of blood was withdrawn with an infusion/withdrawal pump, of which 50% was re-infused. The without-bleeding groups received no manipulation during the same period of time. Forty-five minutes later, the second hemodynamic measurement was performed, followed by glypressin (0.07mg/kg) infusion. Ten minutes after glypressin administration, the third hemodynamic study was done, followed by heparinized blood sampling for TNF-α measurements. Results: splanchnic Hyposensitivity to glypressin was noted in portal hypetensive rats during acute hemorrhage. The level of tumor necrosis factor tended to be higher in rats with bleeding but not statistically significant (P=0.087). Conclusion: Tumor necrosis factor did not seem to play a significant role in splanchnic Hyposensitivity to glypressin in portal hypertensive rats during acute hemorrhage. The influences of other endogenous vasoactive substances should also be considered.

  • nitric oxide synthase expression in the splanchnic Hyposensitivity to glypressin of a hemorrhage transfused rat model with portal hypertension
    Journal of The Chinese Medical Association, 2004
    Co-Authors: Huichun Huang, Fullyoung Chang, Sunsang Wang, Chechang Chan, Yichou Chen, Reihwa Lu, Shwuling Wu
    Abstract:

    BACKGROUND: Nitric oxide (NO) has been proposed to participate in the vascular hyporesponsiveness to vasopressin and its long-acting analogue glypressin during hemorrhage in portal hypertensive states. This study surveyed the role of NO regarding splanchnic hyporeactivity to glypressin and NO synthases (NOS) expression in different vascular beds in bleeding portal-hypertensive rats. METHODS: Under general anesthesia with ketamine, partially portal vein-ligated male Sprague-Dawley rats without or with bleeding were used to investigate the hemodynamic effects of glypressin (0.07 mg/kg intravenously) and constitutive (cNOS) and inducible NOS (iNOS) mRNA expression over the abdominal aorta and superior mesenteric artery. RESULTS: Splanchnic Hyposensitivity to glypressin was noted in the hemorrhage-transfused rats with enhanced cNOS expression of superior mesenteric artery. No significant differences of cNOS and iNOS expression in abdominal aorta and iNOS in superior mesenteric artery were found between the with-bleeding and without-bleeding groups. CONCLUSIONS: In rats with portal hypertension and acute hemorrhage, cNOS over-expression in superior mesenteric artery may take a part in the splanchnic Hyposensitivity to glypressin.

  • cyclooxygenase expression in splanchnic Hyposensitivity to glypressin of bleeding portal hypertensive rats
    European Journal of Clinical Investigation, 2003
    Co-Authors: Fullyoung Chang, Sunsang Wang, Huichun Huang, Choyu Chan, Yungtai Chen, Chengyen Chen
    Abstract:

    Background Prostacyclin mediates, at least partly, the splanchnic vascular hyporesponsiveness to glypressin in bleeding portal hypertensive rats. This study investigated the relative contribution of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in the splanchnic Hyposensitivity to glypressin in rats with portal hypertension induced by partial portal vein ligation (PVL). Methods Fourteen days after the operation, the rats were divided into without- and with-bleeding groups. Three series of PVL rats were used to investigate (i) the haemodynamic effects of glypressin (0·07 mg kg−1 intravenously), (ii) COX-1/COX-2 mRNA expression over abdominal aorta and superior mesenteric artery and (iii) plasma levels of 6-keto-prostaglandin-F1α. In rats with a hypotensive haemorrhage, 4·5 mL of blood was withdrawn and 50% of the withdrawn blood was re-infused before blood and vessel sampling or the administration of glypressin. Results Splanchnic Hyposensitivity to glypressin was demonstrated in the haemorrhage-transfused PVL rats with enhanced COX-1 expression of superior mesenteric artery and increased plasma levels of 6-keto-prostaglandin-F1α. There were no differences in the COX-2 expression of superior mesenteric artery and COX-1 and COX-2 expressions of abdominal aorta between without- and with-bleeding groups. Conclusion In portal hypertensive rats with acute haemorrhage, COX-1 over-expression in the superior mesenteric artery plays a role in mediating the splanchnic Hyposensitivity to glypressin.

  • inhibition of prostacyclin by indomethacin ameliorates the splanchnic Hyposensitivity to glypressin in haemorrhage transfused common bile duct ligated rats
    European Journal of Clinical Investigation, 2001
    Co-Authors: Sunsang Wang, Fullyoung Chang, Choyu Chan, Szuhsien Wu, Chengyen Chen, Huichun Huang
    Abstract:

    Background Prostacyclin (PGI 2 ) is an important contributor to the mediation of hyporeactivity to vasoconstrictors and the development of hyperdynamic circulation in portal hypertensive states. Inhibition of PGI 2 synthesis in haemorrhage-transfused partially portal vein-ligated rats could ameliorate the splanchnic Hyposensitivity to glypressin, a long-acting vasopressin analogue. This study investigated whether the Hyposensitivity to glypressin also exists in rats with common bile duct ligation (BDL) and whether the inhibition of PGI 2 synthesis by indomethacin could potentiate the portal-hypotensive effect of glypressin in bleeding BDL rats. Methods Two series of BDL rats were used. Series 1 investigated the haemodynamic effects of low dose glypressin (0.07 mg kg -1 ) in BDL rats with or without bleeding by catheterization. In series 2, haemodynamic parameters were measured in stable or bleeding BDL rats that were receiving intravenously high dose glypressin (0.2 mg kg -1 ) or indomethacin (5 mg kg -1 ) followed by high dose glypressin. In rats with a hypotensive haemorrhage, 4.5 mL of blood was withdrawn and 50% of the withdrawn blood was reinfused before the administration of glypressin or indomethacin. Results Splanchnic Hyposensitivity to glypressin was demonstrated in haemorrhage-transfused BDL rats receiving high, but not low, doses of glypressin. Indomethacin infusion did not cause significant systemic and portal haemodynamic changes in bleeding BDL rats (P > 0.05). The addition of indomethacin significantly enhanced the portal-hypotensive effects of glypressin (P < 0.05) and potentiated the increases in mean arterial pressure induced by glypressin infusion (P < 0.001) in bleeding BDL rats. Conclusion Splanchnic Hyposensitivity to glypressin observed in haemorrhage-transfused BDL rats could be ameliorated by the addition of indomethacin, suggesting a role of endogenous PGI 2 in its pathophysiology.

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  • splanchnic Hyposensitivity to glypressin in a hemorrhage transfused common bile duct ligated rat model of portal hypertension role of nitric oxide and bradykinin
    Hepato-gastroenterology, 2009
    Co-Authors: Chienting Chen, Fullyoung Chang, Sunsang Wang, Shwuling Wu, Chechang Chan, Huichun Huang
    Abstract:

    BACKGROUND/AIMS: The portal hypotensive effect of vasopressin during hemorrhage is less effective than that during stable condition in cirrhotic patients or experimental portal hypertension (the so-called Hyposensitivity phenomenon). Recent studies have demonstrated that constitutive nitric oxide activities and bradykinin in hemorrhage-transfused partially portal vein-ligated rats are responsible, at least partly, for the splanchnic Hyposensitivity to glypressin (a long acting vasopressin analogue). This study investigated the relative contribution of nitric oxide synthase isoforms and the role of bradykinin in the pathogenesis of splanchnic Hyposensitivity in rats with cirrhosis induced by common bile duct-ligation (BDL). METHODOLOGY: Five weeks after BDL, systemic and portal hemodynamics were measured in stable or bleeding BDL rats receiving intravenous infusion of glypressin (0.2 mg/kg). In the treatment groups, N(G)-nitro-L-arginine methyl ester (L-NAME, a non-selective nitric oxide synthase inhibitor), L-canavanine (a specific inducible nitric oxide synthase inhibitor) or HOE 140 (a bradykinin B2 receptor antagonist) was administered 45 minutes before the infusion of glypressin. In rats with a hypotensive hemorrhage, 4.5 ml of blood was withdrawn and 50% of the withdrawn blood was reinfused before the administration of glypressin or various inhibitors. RESULTS: Splanchnic Hyposensitivity to glypressin was demonstrated in the hemorrhage-transfused BDL rats. The infusion of L-NAME elevated the mean arterial pressure in the bleeding BDL rats without the modulation of portal pressure. The addition of L-NAME or HOE 140, but not L-canavanine, significantly and similarly potentiated the portal-hypotensive effects of glypressin. CONCLUSIONS: Constitutive nitric oxide synthase and bradykinin play major roles in the development of splanchnic Hyposensitivity to glypressin observed in hemorrhage-transfused rats with biliary cirrhosis.

  • splanchnic Hyposensitivity to glypressin in a hemorrhage transfused rat model of portal hypertension the role of tumor necrosis factor α
    臺灣消化醫學雜誌, 2007
    Co-Authors: Huichun Huang, Sunsang Wang, Fullyoung Chang
    Abstract:

    Introduction: Vasopressin and its long-acting analogue, glypressin given during hemorrhage are less effective than when given during a stable state in portal hypertensive or cirrhotic conditions, that is, the so-called Hyposensitivity phenomenon. According to the previous studies, nitric oxide has been ascribed to participate in the Hyposensitivity. Tumor necrosis factor-α stimulates nitric oxide synthesis and is enhanced during acute hemorrhage. However, its role in portal hypertension with acute hemorrhage and vascular hyporesponsiveness remains unclear. Materials and Methods: Portal hypertension was induced by partial portal vein ligation (PVL) on male Spraque-Dawley rats. Fourteen days after PVL, portal and systemic hemodynamic parameters were evaluated then rats were divided into without-bleeding and with-bleeding groups. In rats with a hypotensive hemorrhage, 4.5ml of blood was withdrawn with an infusion/withdrawal pump, of which 50% was re-infused. The without-bleeding groups received no manipulation during the same period of time. Forty-five minutes later, the second hemodynamic measurement was performed, followed by glypressin (0.07mg/kg) infusion. Ten minutes after glypressin administration, the third hemodynamic study was done, followed by heparinized blood sampling for TNF-α measurements. Results: splanchnic Hyposensitivity to glypressin was noted in portal hypetensive rats during acute hemorrhage. The level of tumor necrosis factor tended to be higher in rats with bleeding but not statistically significant (P=0.087). Conclusion: Tumor necrosis factor did not seem to play a significant role in splanchnic Hyposensitivity to glypressin in portal hypertensive rats during acute hemorrhage. The influences of other endogenous vasoactive substances should also be considered.

  • nitric oxide synthase expression in the splanchnic Hyposensitivity to glypressin of a hemorrhage transfused rat model with portal hypertension
    Journal of The Chinese Medical Association, 2004
    Co-Authors: Huichun Huang, Fullyoung Chang, Sunsang Wang, Chechang Chan, Yichou Chen, Reihwa Lu, Shwuling Wu
    Abstract:

    BACKGROUND: Nitric oxide (NO) has been proposed to participate in the vascular hyporesponsiveness to vasopressin and its long-acting analogue glypressin during hemorrhage in portal hypertensive states. This study surveyed the role of NO regarding splanchnic hyporeactivity to glypressin and NO synthases (NOS) expression in different vascular beds in bleeding portal-hypertensive rats. METHODS: Under general anesthesia with ketamine, partially portal vein-ligated male Sprague-Dawley rats without or with bleeding were used to investigate the hemodynamic effects of glypressin (0.07 mg/kg intravenously) and constitutive (cNOS) and inducible NOS (iNOS) mRNA expression over the abdominal aorta and superior mesenteric artery. RESULTS: Splanchnic Hyposensitivity to glypressin was noted in the hemorrhage-transfused rats with enhanced cNOS expression of superior mesenteric artery. No significant differences of cNOS and iNOS expression in abdominal aorta and iNOS in superior mesenteric artery were found between the with-bleeding and without-bleeding groups. CONCLUSIONS: In rats with portal hypertension and acute hemorrhage, cNOS over-expression in superior mesenteric artery may take a part in the splanchnic Hyposensitivity to glypressin.

  • cyclooxygenase expression in splanchnic Hyposensitivity to glypressin of bleeding portal hypertensive rats
    European Journal of Clinical Investigation, 2003
    Co-Authors: Fullyoung Chang, Sunsang Wang, Huichun Huang, Choyu Chan, Yungtai Chen, Chengyen Chen
    Abstract:

    Background Prostacyclin mediates, at least partly, the splanchnic vascular hyporesponsiveness to glypressin in bleeding portal hypertensive rats. This study investigated the relative contribution of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in the splanchnic Hyposensitivity to glypressin in rats with portal hypertension induced by partial portal vein ligation (PVL). Methods Fourteen days after the operation, the rats were divided into without- and with-bleeding groups. Three series of PVL rats were used to investigate (i) the haemodynamic effects of glypressin (0·07 mg kg−1 intravenously), (ii) COX-1/COX-2 mRNA expression over abdominal aorta and superior mesenteric artery and (iii) plasma levels of 6-keto-prostaglandin-F1α. In rats with a hypotensive haemorrhage, 4·5 mL of blood was withdrawn and 50% of the withdrawn blood was re-infused before blood and vessel sampling or the administration of glypressin. Results Splanchnic Hyposensitivity to glypressin was demonstrated in the haemorrhage-transfused PVL rats with enhanced COX-1 expression of superior mesenteric artery and increased plasma levels of 6-keto-prostaglandin-F1α. There were no differences in the COX-2 expression of superior mesenteric artery and COX-1 and COX-2 expressions of abdominal aorta between without- and with-bleeding groups. Conclusion In portal hypertensive rats with acute haemorrhage, COX-1 over-expression in the superior mesenteric artery plays a role in mediating the splanchnic Hyposensitivity to glypressin.

  • inhibition of prostacyclin by indomethacin ameliorates the splanchnic Hyposensitivity to glypressin in haemorrhage transfused common bile duct ligated rats
    European Journal of Clinical Investigation, 2001
    Co-Authors: Sunsang Wang, Fullyoung Chang, Choyu Chan, Szuhsien Wu, Chengyen Chen, Huichun Huang
    Abstract:

    Background Prostacyclin (PGI 2 ) is an important contributor to the mediation of hyporeactivity to vasoconstrictors and the development of hyperdynamic circulation in portal hypertensive states. Inhibition of PGI 2 synthesis in haemorrhage-transfused partially portal vein-ligated rats could ameliorate the splanchnic Hyposensitivity to glypressin, a long-acting vasopressin analogue. This study investigated whether the Hyposensitivity to glypressin also exists in rats with common bile duct ligation (BDL) and whether the inhibition of PGI 2 synthesis by indomethacin could potentiate the portal-hypotensive effect of glypressin in bleeding BDL rats. Methods Two series of BDL rats were used. Series 1 investigated the haemodynamic effects of low dose glypressin (0.07 mg kg -1 ) in BDL rats with or without bleeding by catheterization. In series 2, haemodynamic parameters were measured in stable or bleeding BDL rats that were receiving intravenously high dose glypressin (0.2 mg kg -1 ) or indomethacin (5 mg kg -1 ) followed by high dose glypressin. In rats with a hypotensive haemorrhage, 4.5 mL of blood was withdrawn and 50% of the withdrawn blood was reinfused before the administration of glypressin or indomethacin. Results Splanchnic Hyposensitivity to glypressin was demonstrated in haemorrhage-transfused BDL rats receiving high, but not low, doses of glypressin. Indomethacin infusion did not cause significant systemic and portal haemodynamic changes in bleeding BDL rats (P > 0.05). The addition of indomethacin significantly enhanced the portal-hypotensive effects of glypressin (P < 0.05) and potentiated the increases in mean arterial pressure induced by glypressin infusion (P < 0.001) in bleeding BDL rats. Conclusion Splanchnic Hyposensitivity to glypressin observed in haemorrhage-transfused BDL rats could be ameliorated by the addition of indomethacin, suggesting a role of endogenous PGI 2 in its pathophysiology.