LCZ696, an Angiotensin Receptor-Neprilysin Inhibitor, Ameliorates Endothelial Dysfunction in Diabetic C57BL/6 Mice.

AIMS: LCZ696 (sacubitril/valsartan) exerts cardioprotective effects. Recent studies have suggested that it improves the endothelial function; however, the underlying mechanisms have not been thoroughly investigated. We investigated whether LCZ696 ameliorates diabetes-induced endothelial dysfunction. METHODS: Diabetes was induced using streptozotocin in 8-week-old male C57BL/6 mice. Diabetic mice were randomly assigned to receive LCZ696 (100 mg/kg/day), valsartan (50 mg/kg/day), or a vehicle for three weeks. The endothelium-dependent and endothelium-independent vascular responses of the aortic segments were determined based on the response to acetylcholine and sodium nitroprusside, respectively. Human umbilical vein endothelial cells (HUVEC) and aortic segments obtained from C57BL/6 mice were used to perform in vitro and ex vivo experiments, respectively. RESULTS: LCZ696 and valsartan reduced the blood pressure in diabetic mice (P＜0.05). The administration of LCZ696 (P＜0.001) and valsartan (P＜0.01) ameliorated endothelium-dependent vascular relaxation, but not endothelium-independent vascular relaxation, under diabetic conditions. LCZ696, but not valsartan, increased eNOSSer1177 (P=0.06) and Akt (P＜0.05) phosphorylation in the aorta. In HUVEC, methylglyoxal (MGO), a major precursor of advanced glycation end products, decreased eNOSSer1177 phosphorylation (P＜0.05) and increased eNOSThr495 phosphorylation (P＜0.001). However, atrial natriuretic peptide (ANP) reversed these effects. ANP also ameliorated the MGO-induced impairment of endothelium-dependent vascular relaxation in the aortic segments (P＜0.05), although L-NAME completely blocked this effect (P＜0.001). CONCLUSION: LCZ696 ameliorated diabetes-induced endothelial dysfunction by increasing the bioavailability of ANP. Our findings suggest that LCZ696 has a vascular protective effect in a diabetic model and highlight that it may be more effective than valsartan.

Enhancing semiconductor device performance using ordered dopant arrays.

As the size of semiconductor devices continues to shrink, the normally random distribution of the individual dopant atoms within the semiconductor becomes a critical factor in determining device performance--homogeneity can no longer be assumed. Here we report the fabrication of semiconductor devices in which both the number and position of the dopant atoms are precisely controlled. To achieve this, we make use of a recently developed single-ion implantation technique, which enables us to implant dopant ions one-by-one into a fine semiconductor region until the desired number is reached. Electrical measurements of the resulting transistors reveal that device-to-device fluctuations in the threshold voltage (Vth; the turn-on voltage of the device) are less for those structures with ordered dopant arrays than for those with conventional random doping. We also find that the devices with ordered dopant arrays exhibit a shift in Vth, relative to the undoped semiconductor, that is twice that for a random dopant distribution (- 0.4 V versus -0.2 V); we attribute this to the uniformity of electrostatic potential in the conducting channel region due to the ordered distribution of dopant atoms. Our results therefore serve to highlight the improvements in device performance that can be achieved through atomic-scale control of the doping process. Furthermore, ordered dopant arrays of this type may enhance the prospects for realizing silicon-based solid-state quantum computers.