Here we reveal a novel requirement for Wnt/planar cell polarity signaling in the anterior-posterior organization of the monoaminergic system. We find that 5-HT and mdDA axons express the core planar cell polarity components Frizzled3, Celsr3, and Vangl2. In addition, monoaminergic projections show anterior-posterior guidance defects in Frizzled3, BAY 73-4506 mouse Celsr3, and Vangl2 mutant mice. The only known ligands for planar cell polarity signaling are Wnt proteins. In culture, Wnt5a attracts 5-HT but repels mdDA axons, and Wnt7b attracts mdDA axons. However, mdDA axons from Frizzled3 mutant mice are unresponsive to Wnt5a and Wnt7b. Both Wnts are expressed in gradients
along the anterior-posterior axis, consistent with their role as directional cues. Finally, Wnt5a mutants show transient anterior-posterior guidance defects in mdDA projections. Furthermore, we observe during development that the cell bodies of migrating descending 5-HT neurons eventually reorient along the direction of their axons. In Frizzled3 mutants, many 5-HT and mdDA neuron cell bodies are oriented abnormally along the direction of their aberrant axon projections. Overall, our data find more suggest that Wnt/planar cell
polarity signaling may be a global anterior-posterior guidance mechanism that controls axonal and cellular organization beyond the spinal cord.”
“Background It is controversial whether the combination of very low dose hydrochlorothiazide (HCTZ) and an angiotensin receptor blocker (ARB) is effective in lowering blood pressure (BP).\n\nObjectives The aim of this study was to evaluate the antihypertensive effect and the safety of an ARB and a very low dose of HCTZ in hypertensive patients.\n\nMethods This is an observational study. We HIF inhibitor examined 41 hypertensive patients who were treated with candesartan or another ARB at a standard dose but whose home BP was still greater than or equal to 135/85 mmHg. No patients were taking diuretics at baseline. Clinic and ambulatory
BP (ABP) measurement and blood/urine analyses were performed at baseline and in the 2nd to 3rd month after treatment. All patients were either maintained at or switched to 8 mg candesartan, and then 6.25 mg HCTZ was added. Other concomitant drugs were not changed throughout the study period.\n\nResults A total of 41 individuals (age 62.7 +/- 12.7 years, 61% male) completed the protocol. The add-on treatment of HCTZ significantly lowered clinic and ABPs for both systolic and diastolic BP. The BP reduction was particularly pronounced in sleep BP. In addition, the rate of nondippers decreased from 48.8 to 36.6%, but the rates of dippers (39.0-43.9%) and extreme-dippers (12.2-19.5%) increased. Serum uric acid increased significantly, but the other metabolic measures were not changed by the combination therapy.\n\nConclusion Adding a very low dose of HCTZ (6.25 mg) to an ARB was very effective in lowering clinic and ABP, particularly for night-time BP.