AimsAngiotensin receptor-neprilysin inhibitors (ARNis) acts an ARB and neprilysin inhibitor. Diabetes mellitus significantly increases the risk of cardiovascular disease and heart failure (HF). Therefore, we evaluated the effects and mechanisms of ARNi in HF with reduced ejection fraction (HFrEF) Methods and resultsMale C57BL/6J mice were injected with streptozotocin to produce diabetic mice. After myocardial reperfusion injury, diabetic mice were randomized to treatment for 4 weeks with LCZ696 (60 mg/kg), valsartan (30 mg/kg), or no treatment (n = 26-28 in each group). Cardiac function was assessed by a pressure-volume Millar catheter. The ratios of heart weight to body weight in the valsartan (P = 0.02) and LCZ696 (P = 0.005) groups were significantly less than that in the control group. Treatment with LCZ696 improved LVEF (43 ± 3.4%) with a significantly reduction of atrial natriuretic peptide mRNA in the left ventricle compared with that in the control group (29 ± 3.2%) (P = 0.006). The fibrotic area in the LCZ696 group was significantly suppressed compared with those in the control (P = 0.003) and valsartan (P = 0.04) groups. Moreover, the mRNA level of transforming growth factor-(TGF-) in the left ventricle was suppressed in the LCZ696 group compared with that in the control (P = 0.002) group.
We examined whether protein and carbohydrate (CHO) supplementation during 5-day training enhanced plasma volume (PV) expansion and thermoregulatory and cardiovascular adaptations in young men. Eighteen men [age 23 ± 4 (SD) yr] were divided into two groups according to supplements: placebo (CNT: 0.93 kcal/kg, 0.00 g protein/kg, n = 9) and protein and CHO (Pro-CHO: 3.6 kcal/kg, 0.36 protein/kg, n = 9). Subjects in both groups performed a cycling exercise at 70% peak oxygen consumption rate (VO2peak), 30 min/day, for 5 consecutive days at 30°C ambient temperature and 50% relative humidity and took either a placebo or Pro-CHO within 10 min after exercise for each day. Before and after training, PV at rest, heart rate (HR), and esophageal temperature (T(es)) during 30-min exercise at 65% of pretraining VO2peak in the same condition as training were determined. Also, the sensitivity of the chest sweat rate (ΔSR/ΔT(es)) and forearm vascular conductance (ΔFVC/ΔT(es)) in response to increased T(es) were determined. After training, PV and cardiac stroke volume (SV) at rest increased in both groups (P < 0.001) but the increases were twofold higher in Pro-CHO than CNT (P = 0.007 and P = 0.078, respectively). The increases in HR from 5 to 30 min and T(es) from 0 to 30 min of exercise were attenuated after training in both groups with greater attenuation in Pro-CHO than CNT (P = 0.002 and P = 0.072, respectively). ΔSR/ΔT(es) increased in CNT (P = 0.052) and Pro-CHO (P < 0.001) and the increases were higher in Pro-CHO than CNT (P = 0.018). ΔFVC/ΔT(es) increased in Pro-CHO (P < 0.001), whereas not in CNT (P = 0.16). Thus protein-CHO supplementation during 5-day training enhanced PV expansion and thermoregulatory adaptation and, thereby, the reduction in heat and cardiovascular strain in young men.
The goal of this study is to identify a novel inhibitor with antiinflammatory and antiproliferative properties for the treatment of psoriasis. Compound f152A1 [(3S,5Z,8S,11E)-8,9,16-trihydroxy-14-methoxy-3-methyl-3,4,9,10-tetrahydro-1H-benzo[c][1] oxacyclotetradecine1,7(8H)-dione] was identified as the main active metabolite with strong inhibitory activity against tumor necrosis factor-␣ (TNF␣) transcription in a fraction originated from the fermentation broth of the fungus Curvularia verruculosa. Although active in cell-based assays, f152A1 was unstable in plasma and liver microsome preparations, thus limiting its pharmaceutical utilization. To improve the metabolic properties of f152A1, a medicinal chemistry program was undertaken, resulting in the generation of over 400 analogs of f152A1. Eventually, E6201 [(3S,4R,5Z,8S,9S,11E)-14-(ethylamino)-8, 9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione] was identified as a promising analog in this series. In the present study, we characterized the in vitro activities of E6201 and discovered that the compound inhibits lipopolysaccharide-activated TNF␣ reporter activity in THP-1-33 cells with an IC 50 value of 50 nM and selectively inhibits mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)-1 and MEK kinase-1 in cell-free biochemical assays. In addition, E6201 showed inhibitory activity in several other cell-based systems: 1) phosphorylation of c-jun N-terminal kinase and p38 MAPKs; 2) nuclear factor-B and activated protein-1 activation in various cell types; 3) interleukin (IL)-2 production from human lymphocytes; 4) hyperproliferation of human keratinocytes; 5) IL-8 production from human keratinocytes; and 6) proinflammatory cytokine production from human peripheral blood mononuclear cells. Based on the data presented here, E6201 may be beneficial for treatment of inflammatory and hyperproliferative diseases such as psoriasis through its anti-inflammatory activities on immune cells and antihyperproliferative activities on keratinocytes.This work was supported by Eisai Co., Ltd. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
Non-technical summary Thermoregulatory responses during exercise are reduced following thermal dehydration. If individuals do not rehydrate adequately, it could lead to heat exhaustion or stroke with the worst case scenario being death. Plasma volume loss during dehydration has been suggested to suppress cutaneous vasodilatation in response to hyperthermia via a baroreflex-mediated reduction in active vasodilator activity rather than enhanced active vasoconstrictor activity. However, no changes in the electrical signals of the efferent neural pathway have ever been identified. In the present study, we found a component of efferent skin sympathetic nerve activity that was synchronized with the cardiac cycle in thermally stressed individuals. This nerve activity increased with an increase in oesophageal temperature and the increase was significantly suppressed by hypovolaemia. Thus, this component of skin sympathetic nerve activity might represent the active vasodilator signals that regulate skin blood flow during hyperthermia in humans.Abstract Although cutaneous vasodilatation in hyperthermia was suppressed during hypovolaemia, the efferent neural pathway mediating this suppression has not been identified. To determine the electrical nerve signals which account for the suppression of cutaneous vasodilatation during hypovolaemia, skin sympathetic nerve activity (SSNA; microneurography) from the peroneal nerve, laser-Doppler blood flow (LDF) on the ipsilateral dorsal foot, mean arterial pressure (MAP; sonometry) and oesophageal temperature (T oes ) were measured before and during 45 min of passive warming in 20 healthy subjects during normovolaemia (n = 10) or hypovolaemia (n = 10) conditions. Hypovolaemia was achieved by diuretic administration. Cutaneous vascular conductance (CVC = LDF/MAP), SSNA burst frequency and total SSNA obtained from rectified and filtered SSNA signal increased as T oes increased by ∼0.5 • C by the end of warming in both groups. The increase in CVC was significantly lower in hypovolaemia than normovolaemia (P < 0.0001), but with no significant difference in the increase in burst frequency and total SSNA between groups (P > 0.32). However, using an alternative analysis that constructed spike incidence histograms from the original signal using 0.05 s bins during the 5 s following a given R-wave, we found a SSNA component synchronized with the cardiac cycle with a 1.1-1.3 s latency. This component increased with an increase in T oes and the increase was significantly suppressed by hypovolaemia (P < 0.0001). In conclusion, hypovolaemic suppression of cutaneous vasodilatation during hyperthermia might be caused by a reduction in the SSNA component synchronized with cardiac cycle. , plasma noradrenaline concentration; P osmol , plasma osmolality; PP, pulse pressure; PV, plasma volume; RH, relative humidity; RR, respiratory rate; SBP, systolic blood pressure; SkBF, skin blood flow; SR, sweat rate; SSNA, skin sympathetic nerve activity; T a , ambient temperature; T oes , oesophageal temperature;...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.