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.

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.

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.

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 (+Ca(2+)) and passive (0 Ca(2+)) 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.

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.

Tumor necrosis factor-alpha antagonist etanercept decreases blood pressure and protects the kidney in a mouse model of systemic lupus erythematosus.

Chronic inflammation has been implicated in the pathology of hypertension; however, the role for specific cytokines remains unclear. We tested whether tumor necrosis factor-α blockade with etanercept (Etan) reduces mean arterial pressure in a female mouse model of systemic lupus erythematosus (SLE). SLE is a chronic inflammatory disorder with prevalent hypertension. Thirty-week-old SLE (NZBWF1) and control mice (NZW/LacJ) received Etan (0.8 mg/kg SC weekly) for 4 weeks or vehicle. Mean arterial pressure (in millimeters of mercury) was increased in SLE mice (150±5 versus 113±5 in controls; P<0.05) and was lower in Etan-treated SLE mice (132±3) but not controls (117±5). Albuminuria (in micrograms per milligram of creatinine) was elevated in SLE mice (28 742±9032 versus 1075±883; P<0.05) and was lower in Etan-treated SLE mice (8154±3899) but not control animals (783±226). Glomerulosclerosis (in percentage of glomeruli) was evident in SLE mice (2.5±1.6 versus 0.0±0.0 in controls; P<0.05) and was ameliorated in Etan-treated SLE mice (0.1±0.1). Renal cortex CD68(+) cell staining (in percentage of area) was elevated in SLE mice (4.75±0.80 versus 0.79±0.12 in controls; P<0.05) and was lower in Etan-treated SLE mice (2.28±0.32) but not controls (1.43±0.25). Renal cortex NADPH oxidase activity (relative light units per milligram of protein) was higher in SLE mice compared with controls (10 718±1276 versus 7584±229; P<0.05) and lowered in Etan-treated SLE mice (6645±490). Renal cortex nuclear factor κB (phosphorylated and nonphosphorylated) was increased in SLE mice compared with controls and lower in Etan-treated SLE mice. These data suggest that TNF-α mechanistically contributes to the development of hypertension in a chronic inflammatory disease through increased renal nuclear factor κB, oxidative stress, and inflammation.

Rosiglitazone decreases blood pressure and renal injury in a female mouse model of systemic lupus erythematosus.

Women with systemic lupus erythematosus (SLE) exhibit a high prevalence of hypertension and renal injury. Rosiglitazone (Rosi), a peroxisome proliferator activator receptor gamma (PPARgamma) agonist, has renal protective and antihypertensive effects. We tested whether Rosi ameliorates hypertension and renal injury in a female mouse model of SLE (NZBWF1). Thirty-week-old SLE and control (NZW/LacJ) mice (n > or = 6/group) were fed Rosi (5 mg.kg(-1).day(-1) in standard chow) or standard chow for 4 wk. SLE mice had increased blood pressure (BP in mmHg) compared with controls (139 +/- 4 vs. 111 +/- 4, P < 0.05). Rosi treatment lowered BP in SLE mice (127 +/- 4, P < 0.05) but not in controls (111 +/- 4). Urinary albumin (mug/mg creatinine) was increased in SLE mice compared with controls (12,396 +/- 6,525 vs. 50 +/- 6) and reduced with Rosi treatment (148 +/- 117). Glomerulosclerosis (% of glomeruli with sclerosis) was reduced in Rosi-treated SLE mice (4.2 +/- 1.6 vs. 0.4 +/- 0.3, P < 0.05). Renal monocyte/macrophage numbers (cell number/1,320 points counted) were reduced in SLE mice treated with Rosi (32.6 +/- 11.0 vs. 10.6 +/- 3.6, P < 0.05) but unchanged in controls (3.7 +/- 1.6 vs. 3.7 +/- 2.0). Renal osteopontin expression, a cytokine-regulating macrophage recruitment, was reduced in Rosi-treated SLE mice. Urinary endothelin (in pg/mg creatinine) was increased in SLE mice compared with controls (1.9 +/- 0.59 vs. 0.6 +/- 0.04, P < 0.05) and reduced in SLE mice treated with Rosi (0.8 +/- 0.11, P < 0.05). PPARgamma protein expression in the renal cortex was significantly lower in SLE mice compared with controls and was unaffected by Rosi. These data suggest that Rosi may be an important therapeutic option for the treatment of SLE hypertension and renal injury.