Hypertension is one of the most important, preventable causes of premature morbidity and mortality in the developed world. Aldosterone is a major mineralocorticoid hormone that plays a key role in the regulation of blood pressure and is implicated in the pathogenesis of hypertension and heart failure. Aldosterone synthase (AS, cytochrome P450 11B2, cyp11B2) is the sole enzyme responsible for the production of aldosterone in humans. To determine the effects of increased expression of human aldosterone synthase (hAS) on blood pressure (BP), we established transgenic mice carrying the hAS gene (cyp11B2). We showed that hAS overexpression increased levels of aldosterone in hAS+/− mice. On high salt diet (HS), BPs of hAS+/− mice were significantly increased compared with WT mice. Fadrozole (an inhibitor of aldosterone synthase) treatment significantly reduced BPs of hAS+/− mice on HS. This is the first time overexpression of AS in a transgenic mouse line has shown an ability to induce HP. Specifically inhibiting AS activity in these mice is a promising therapy for reducing hypertension. This hAS transgenic mouse model is therefore an ideal animal model for hypertension therapy studies.
Minocycline and doxycycline, two semisynthetic second-generation tetracyclines, are reported to provide neuroprotection against brain injury and glutamate-induced neurotoxicity in neuronal cultures. Doxycycline has been postulated as the potential ideal candidate for further therapeutic development as it has fewer adverse effects than minocycline. In this study, we determined whether minocycline and doxycycline could similarly protect neurons against excitotoxic insults. We treated cultured rat cortical neurons and cerebellar granule neurons (CGN) with excitotoxic concentrations of NMDA or glutamate in the presence or absence of minocycline or doxycycline. Intracellular Ca2+ concentration ([Ca2+]i) was also measured using a Fluorescent Light Imaging Plate Reader (FLIPR; Molecular Devices) with the calcium sensitive dye Fluo-3 AM. We found that minocycline and tetracycline markedly protected neurons against NMDA- and glutamate-induced neuronal death. In contrast, the structurally related tetracycline, doxycycline, was ineffective at concentrations up to 100 μM. Furthermore, minocycline, but not doxycycline, also significantly attenuated NMDA- or glutamate-induced [Ca2+]i in both cortical neurons and CGN. Our results suggest that minocycline but not doxycycline is able to directly block NMDA- or glutamate-induced excitotoxicity in neurons most likely by inhibiting NMDA- and glutamate-induced [Ca2+]i. This finding may contribute to our understanding of the molecular mechanisms underlying doxycycline- and minocycline-induced neuroprotection.
Background: Successful pregnancy in intestinal failure (IF) is possible but requires careful surveillance to optimize nutrition and to minimize complications. Teduglutide during pregnancy might improve life quality and decrease risk of complications, but experiences are lacking. Potential risks and benefits for the mother and fetus are thus unknown. Teduglutide induces intestinal hyperplasia, increases intestinal blood flow and delays gastric emptying thereby improving absorption in IF. By decreasing the rate of gastric emptying and the intestinal motility pregnancy itself might thus exert some of the positive effect that teduglutide may achieve. During breast-feeding after delivery the water, electrolyte and nutrition needs are increased but other aspects less complicated. Here we describe a patient who successfully used teduglutide during breastfeeding. Method: The patient was at the age of 33 operated due to intestinal ischemia caused by strangulation related to congenital malrotation of the small intestine during pregnancy in week 16. The child was lost. During a period with a high jejunostomy (40 cm jejunum left), ascendostomy and gastrostomy stomal flow and intravenous needs were large. Liver tests became pathological after 5 months. After 10 months anastomosis of jejunum to colon ascendens, stricturoplasty and closure of gastrostomy. Liver tests normalized and PN could be decreased. The patient wanted to become pregnant and was early informed that this was possible. Results: Pregnant 11 months after the reanastomosis. Normal course of pregnancy during careful surveillance and PN adaptation. Delivered by Cesarian section. One month after termination of breast-feeding, teduglutide treatment was started and had good effect. After one year teduglutide was withdrawn due to desire to become pregnant, which succeeds 1.5 years later. Normal course of the pregnancy. Delivery by Cesarian section. Started teduglutide treatment one month after delivery. Continued breast-feeding for another four months during the treatment. PN gradually decreased to intermittent use, but long-term weight stability without PN has not been achieved. Effects of GLP-2 are highly specific for the intestine. Pig studies show abscence of GLP-2 in fetal blood until the very late phase of pregnancy, and exogenous GLP-2 had no effect on the fetus. In line with earlier findings our patient exhibited no liver pathology during the pregnancy. Conclusions: Teduglutide could be used with good effect and without side effects during breast-feeding. Experiences from use during pregnancy are lacking but knowledge about biological effects of GLP-2 biology give no reasons to expect harmful effects on the fetus.
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