Porter H. Glover

Hypertension in Response to Autoantibodies to the Angiotensin II Type I Receptor (AT1-AA) in Pregnant Rats: Role of Endothelin-1

Agonistic autoantibodies to the angiotensin II type I receptor (AT1-AA) and endothelin -1 (ET-1) are suggested to be important links between placental ischemia and hypertension during preeclampsia. Activation of the angiotensin II type 1 receptor (AT1R) increases endothelial cell production of ET-1; however, the importance of ET-1 in response to AT1-AA–mediated AT1 R activation during preeclampsia is unknown. Furthermore, the role of AT1-AA–mediated increases in blood pressure during pregnancy remains unclear. The objective of this study was to test the hypothesis that AT1-AA, increased to levels observed in preeclamptic women and placental ischemic rats, increases mean arterial pressure (MAP) by activation of the ET-1 system. Chronic infusion of purified rat AT1-AA into normal pregnant (NP) rats for 7 days increased AT1-AA from 0.68±0.5 to 10.88±1.1 chronotropic units (P<0.001). The increased AT1-AA increased MAP from 99±1 to 119±2 mm Hg (P<0.001). The hypertension was associated with significant increases in renal cortices (11-fold) and placental (4-fold) ET-1. To determine whether ET-1 mediates AT1-AA–induced hypertension, pregnant rats infused with AT1-AA and NP rats were treated with an ETA receptor antagonist. MAP was 100±1 mm Hg in AT1-AA+ETA antagonist-treated rats versus 98±2 mm Hg in ETA antagonist-treated rats. Collectively, these data support the hypothesis that one potential pathway whereby AT1-AAs increase blood pressure during pregnancy is by an ET-1–dependent mechanism.

Angiotensin II type 1 autoantibody induced hypertension during pregnancy is associated with renal endothelial dysfunction.

BACKGROUND Previous investigations suggested that agonistic autoantibodies to the angiotensin II type I receptor (AT1-AA) might mediate a hypertensive response through dysregulation of the endothelin-1 system. AT1-AA induced hypertension was attenuated by the AT1 receptor and/or endothelin-1 type A receptor antagonists. OBJECTIVES This study was undertaken to determine if AT1-AA induced hypertension was associated with renal endothelial dysfunction. METHODS We compared the vascular reactivity of renal interlobar arteries from normal pregnant control rats and AT1-AA long-term infused pregnant rats in the presence and absence of endothelin type A (ET(A)) receptor antagonism. Renal endothelial function was tested using isolated renal interlobar arteries in a pressure myograph, which were exposed to acetylcholine or sodium nitroprusside. RESULTS Vasodilatory responses to the endothelial-dependent agonist acetylcholine were impaired in AT1-AA rats (74 [10]%) compared with normal pregnant controls (95 [5]%, P < 0.05). In the presence of ET(A) receptor antagonism, no differences were observed between controls or the AT1-AA treated group with regard to endothelial-dependent (acetylcholine) relaxation. CONCLUSION AT1-AA induced hypertension during pregnancy was associated with disparate renal endothelial responses to acetylcholine. The difference in renal vascular responses between AT1-AA and normal pregnant rats was abolished by ET(A) receptor blockade.

Blood pressure and renal hemodynamic responses to acute angiotensin II infusion are enhanced in a female mouse model of systemic lupus erythematosus

Inflammation and immune system dysfunction contributes to the development of cardiovascular and renal disease. Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disorder that carries a high risk for both renal and cardiovascular disease. While hemodynamic changes that may contribute to increased cardiovascular risk have been reported in humans and animal models of SLE, renal hemodynamics have not been widely studied. The renin-angiotensin system (RAS) plays a central role in renal hemodynamic control, and although RAS blockade is a common therapeutic strategy, the role of RAS in hemodynamic function during SLE is not clear. This study tested whether mean arterial pressure (MAP) and renal hemodynamic responses to acute infusions of ANG II in anesthetized animals were enhanced in an established female mouse model of SLE (NZBWF1). Baseline MAP was not different between anesthetized SLE and control (NZWLacJ) mice, while renal blood flow (RBF) was significantly lower in mice with SLE. SLE mice exhibited an enhanced pressor response and greater reduction in RBF after ANG II infusion. An acute infusion of the ANG II receptor blocker losartan increased RBF in control mice but not in mice with SLE. Renin and ANG II type 1 receptor expression was significantly lower, and ANG II type 2 receptor expression was increased in the renal cortex from SLE mice compared with controls. These data suggest that there are fewer ANG II receptors in the kidneys from mice with SLE but that the existing receptors exhibit an enhanced sensitivity to ANG II.

Sexual Dimorphism in the Blood Pressure Response to Angiotensin II in Mice After Angiotensin-converting Enzyme Blockade

BACKGROUND The incidence of hypertension and progression of renal disease are greater in men than in women. Data suggest that there is a dimorphic response to angiotensin II (Ang II) in rats, with male rats exhibiting a greater increase in mean arterial pressure (MAP) than females. However, during endogenous renin-angiotensin system (RAS) blockade with angiotensin-converting enzyme (ACE) inhibition, female rats have a greater MAP response to Ang II. We tested whether female mice exhibit a greater MAP response to chronic Ang II during ACE inhibition. METHODS Twenty-week-old male and female C57BL/6J mice (n > or = 6/group), treated with enalapril (40 mg/kg/day in drinking water), were assigned to groups receiving either Ang II (800 ng/kg/min) or saline for 2 weeks. Enalapril treatment began 4 days before and continued throughout the experiment. RESULTS MAP was higher in male mice than female mice treated with enalapril and Ang II (male: 144 +/- 3 vs. female: 121 +/- 6 mm Hg, P < 0.05) and was not different between mice treated with enalapril alone (male: 99 +/- 3 vs. female: 100 +/- 3 mm Hg). F2-isoprostanes were not increased by Ang II; however, female mice had significantly higher levels than males. Renal cortical expression of catalase and Cu/Zn-superoxide dismutase (SOD) was not different between experimental groups. Urinary protein was higher in male mice when compared to females, but was not changed after treatment with Ang II in either group. CONCLUSIONS These data suggest that there are species and sex-specific differences in the mechanism of the blood pressure response to Ang II, even during ACE inhibition.

Placental Ischemia Impairs Middle Cerebral Artery Myogenic Responses in the Pregnant Rat

One potential mechanism contributing to the increased risk for encephalopathies in women with preeclampsia is altered cerebral vascular autoregulation resulting from impaired myogenic tone. Whether placental ischemia, a commonly proposed initiator of preeclampsia, alters cerebral vascular function is unknown. This study tested the hypothesis that placental ischemia in pregnant rats (caused by reduced uterine perfusion pressure [RUPP]) leads to impaired myogenic responses in middle cerebral arteries. Mean arterial pressure was increased by RUPP (135±3 mm Hg) compared with normal pregnant rats (103±2 mm Hg) and nonpregnant controls (116±1 mm Hg). Middle cerebral arteries from rats euthanized on gestation day 19 were assessed in a pressure arteriograph under active (+Ca2+) and passive (0 Ca2+) conditions, whereas luminal pressure was varied between 25 and 150 mm Hg. The slope of the relationship between tone and pressure in the middle cerebral artery was 0.08±0.01 in control rats and was similar in normal pregnant rats (0.05±0.01). In the RUPP model of placental ischemia, this relationship was markedly reduced (slope=0.01±0.00; P<0.05). Endothelial dependent and independent dilation was not different between groups, nor was there evidence of vascular remodeling assessed by the wall:lumen ratio and calculated wall stress. The impaired myogenic response was associated with brain edema measured by percentage of water content (RUPP P<0.05 versus control and normal pregnant rats). This study demonstrates that placental ischemia in pregnant rats leads to impaired myogenic tone in the middle cerebral arteries and that the RUPP model is a potentially important tool to examine mechanisms leading to encephalopathy during preeclamptic pregnancies.

High-dose circumferential chemodenervation of the internal anal sphincter: A new treatment modality for uncomplicated chronic anal fissure: A retrospective cohort study (with video)

BACKGROUND Botulinum toxin injection into the internal anal sphincter is gaining popularity as a second line therapy for chronic anal fissures if medical therapy fails. The dosage of botulinum toxin reported ranged from 20 to 50 IU with no more than 3 injection sites and results in a healing rate of 41%-88% at 3 months. We propose a new injection method of high-dose circumferential chemodenervation of 100 IU in treating chronic anal fissure. METHODS This was a retrospective review at a single academic center. 75 patients (50 women and 25 men) with uncomplicated chronic anal fissures underwent high-dose circumferential chemodenervation-internal anal sphincter (100 IU). We measured fissure healing, complication, and recurrence rates at 3 and 6 months post injection. RESULTS Of the 75 patients, healing rate was 90.7% at 3 months follow up with the first injection and 81.3% with the second injection. The recurrence rates were 20.6% and 12.5% at 6 months after the 1st and 2nd injections respectively. Excluding 5 patients who lost follow up, the total healing rate of the study cohort was 100%. At 2 weeks and 3 months, there were no major complications including hematoma, infection, flatus, fecal, and urinary incontinence. CONCLUSIONS High-dose circumferential chemodenervation-internal anal sphincter (100 IU) is a safe and effective method for uncomplicated chronic anal fissure.

Management of complicated chronic anal fissures with high-dose circumferential chemodenervation (HDCC) of the internal anal sphincter

BACKGROUND Botulinum toxin injection into the internal anal sphincter (IAS) is gaining popularity as a second line therapy for chronic anal fissures after patients fail medical therapy. The dosage of Botulinum toxin reported in the literature ranged from 20 to 50 IU. Complicated chronic anal fissure is defined as persistent fissure concurrent with other perianal pathology. We report a new approach involving high-dose circumferential chemodenervation (HDCC) of 100 IU in treating these complicated chronic anal fissures. AIM The aim of this study was to evaluate the fissure healing, complication, and recurrence rates with HDCC. METHODS Complicated anal fissure was defined as fissure with other perianal pathologies including skin tag, hypertrophied papilla, fistula, symptomatic hemorrhoids, anal condylomata, and abscess. Between 2008 and 2012, 62 consecutive patients (28 Blacks, 33 Whites, 1 Hispanic) with complete follow-up data were included in this single arm study. These patients underwent HDCC-IAS with addition interventions by a single colorectal surgeon. Follow up data were obtained by chart review and office follow up. RESULTS Of the 62 patients, the overall success rate was greater than 70% at 3 months follow-up. A few patients developed transient flatus or fecal incontinence, but shortly resolved. There was no major complication following HDCC-IAS. CONCLUSIONS Combination therapy involving HDCC-IAS and local anorectal surgery for associated condition is both safe and effective for fissure healing.

Esophageal diverticulum arising from a prolonged retained esophageal foreign body.

Esophageal foreign body impaction (EFBI) is a rare condition in childhood which needs urgent removal. However, if left untreated, its chronic impaction may lead to serious secondary complications. Symptoms associated with chronic EFBI are attributed to airway disease or gastroesophageal reflux, which further delays definitive diagnosis and management. We present a girl with ingestion of a bottle cap diaphragm that was embedded in her esophagus resulting in esophageal narrowing and a secondary diverticulum formation. As the disk was unable to be removed using standard grasping forceps, the authors used an injector needle to impale the disk and successfully removed it without any complications.

Impact of social media on Gastroenterologists in the United States

Ibrahim Kalouche Patrick Merlin of American Gastrointestinal and Endoscopic Surgeons (SAGES). In addition, their affiliated official publications host active FaceVerdun Hospital, Verdun, France Laurent Peyrin-Biroulet ∗ Inserm U954 and Department of Hepato-Gastroenterology, Lorraine University, book pages and regularly release the “latest news,” blogs, and other content each month. In this study, we were interested in assessing if Gastroenterologists in the United States (US) are currently utilizing social media for healthcare-related activities and what attitudes they had toward social media in healthcare. Vandoeuvre-lès-Nancy, France

Su1609 High-Dose Circumferential Chemodenervation (HDCC) of the Internal Anal Sphincter: A New Treatment Modality for Uncomplicated Chronic Anal Fissure

S A T A b st ra ct s surgery, patients underwent a regular follow up (range 12-26 months) for assessing recurrence. Results: Two patients were lost during the follow up. RNA transcripts for MMP-7 were detected in 31/57 samples (54%). Recurrence was diagnosed in 6 out of 55 patients (11%); 4 patients eventually died because of metastases or peritoneal dissemination. All the 6 patients who had relapsed were positive for MMP-7. Sensitivity and specificity of the test were 100% and 49% respectively. Conclusions: Positivity of MMP-7 in peritoneal cavity samples could be a novel biomarker for predicting disease recurrence in patients with CRC.