Impaired flow-induced arterial remodeling in DOCA-salt hypertensive rats

Arteries from young healthy animals respond to chronic changes in blood flow and blood pressure by structural remodeling. We tested whether the ability to respond to decreased (-90%) or increased (+100%) blood flow is impaired during the development of deoxycorticosterone acetate (DOCA)-salt hypertension in rats, a model for an upregulated endothelin-1 system. Mesenteric small arteries (MrA) were exposed to low blood flow (LF) or high blood flow (HF) for 4 or 7 weeks. The bioavailability of vasoactive peptides was modified by chronic treatment of the rats with the dual neutral endopeptidase (NEP)/endothelin-converting enzyme (ECE) inhibitor SOL1. After 3 or 6 weeks of hypertension, the MrA showed hypertrophic arterial remodeling (3 weeks: media cross-sectional area (mCSA): 10 +/- 1 x 10(3) to 17 +/- 2 x 10(3) mu m(2); 6 weeks: 13 +/- 2 x 10(3) to 24 +/- 3 x 10(3) mu m(2)). After 3, but not 6, weeks of hypertension, the arterial diameter was increased (empty set: 385 +/- 13 to 463 +/- 14 mu m). SOL1 reduced hypertrophy after 3 weeks of hypertension (mCSA: 6 x 10(3) +/- 1 x 10(3) mu m(2)). The diameter of the HF arteries of normotensive rats increased (empty set: 463 +/- 22 mu m) but no expansion occurred in the HF arteries of hypertensive rats (empty set: 471 +/- 16 mu m). MrA from SOL1-treated hypertensive rats did show a significant diameter increase (empty set: 419 +/- 13 to 475 +/- 16 mu m). Arteries exposed to LF showed inward remodeling in normotensive and hypertensive rats (mean empty set between 235 and 290 mu m), and infiltration of monocyte/ macrophages. SOL1 treatment did not affect the arterial diameter of LF arteries but reduced the infiltration of monocyte/ macrophages. We show for the first time that flow-induced remodeling is impaired during the development of DOCA-salt hypertension and that this can be prevented by chronic NEP/ECE inhibition. Hypertension Research (2012) 35, 1093-1101; doi:10.1038/hr.2012.94; published online 12 July 201

A Genetic Basis for Mechanosensory Traits in Humans

Hearing and touch are genetically related, and people with excellent hearing are more likely to have a fine sense of touch and vice versa

Occupational Noise, Smoking, and a High Body Mass Index are Risk Factors for Age-related Hearing Impairment and Moderate Alcohol Consumption is Protective: A European Population-based Multicenter Study

A multicenter study was set up to elucidate the environmental and medical risk factors contributing to age-related hearing impairment (ARHI). Nine subsamples, collected by nine audiological centers across Europe, added up to a total of 4,083 subjects between 53 and 67 years. Audiometric data (pure-tone average [PTA]) were collected and the participants filled out a questionnaire on environmental risk factors and medical history. People with a history of disease that could affect hearing were excluded. PTAs were adjusted for age and sex and tested for association with exposure to risk factors. Noise exposure was associated with a significant loss of hearing at high sound frequencies (>1 kHz). Smoking significantly increased high-frequency hearing loss, and the effect was dose-dependent. The effect of smoking remained significant when accounting for cardiovascular disease events. Taller people had better hearing on average with a more pronounced effect at low sound frequencies (<2 kHz). A high body mass index (BMI) correlated with hearing loss across the frequency range tested. Moderate alcohol consumption was inversely correlated with hearing loss. Significant associations were found in the high as well as in the low frequencies. The results suggest that a healthy lifestyle can protect against age-related hearing impairment

Thrombospondin-1 in Early Flow-Related Remodeling of Mesenteric Arteries from Young Normotensive and Spontaneously Hypertensive Rats

We tested the hypotheses that TSP-1 participates in the initiation of remodeling of small muscular arteries in response to altered blood flow and that the N-terminal domain of TSP-1 (hepI) can reverse the pathological inward remodeling of resistance arteries from SHR

Clinical aspects of chronic ENT inflammation in children.

In children, all ENT cavities are particularly prone to the development of chronic inflammation. This is due to many predisposing factors, of which the most common are unfavourable anatomy, absence of nasal blowing, day care attendance, allergy, immature immunity, gastro-oesophageal reflux and tobacco smoke exposure. The aim of this paper is to outline the most specific paediatric clinical aspects of chronic pharyngo-tonsillitis, rhinosinusitis, otitis media, adenoiditis and laryngotracheitis and the important influence that some of these pathologies exert on the others.Journal ArticleReviewSCOPUS: re.jinfo:eu-repo/semantics/publishe

Pharmacokinetic and pharmacodynamic properties of SOL1:a novel dual inhibitor of neutral endopeptidase and endothelin converting enzyme

AbstractAimsThe pharmacological profile of the novel putative neutral endopeptidase (NEP) and endothelin converting enzyme (ECE) inhibitor SOL1 was examined.Main methodsThe enzyme inhibitory profile of SOL1 was established in vitro. The pharmacokinetic and pharmacodynamic profile was determined in rodents in vivo.Key findingsIn vitro, at neutral pH, 10μM SOL1 inhibited NEP-1, NEP-2, and ECE-1 by 99%, 94% and 75%, respectively. The IC50s were 25, 25 and 3200nmol/L, respectively. In anesthetized rats, SOL1 inhibited blood pressure (BP) responses to big-ET-1 and ET-1(1–31) with ED50s of 1.9 and 0.03mg/kg, corresponding to plasma EC50s of 4.6 and 0.1μmol/L, respectively. Pharmacokinetics of SOL1 were examined after single injections in mice and rats. In these species, the estimated clearance of SOL1 varied between 5 and 9ml/kg.min and T1/2 between 20 and 60min. Steady state kinetics of SOL1 were examined after continuous s.c. infusions of SOL1 for 3weeks at 50mg/kg.day in DOCA-salt hypertensive rats. This treatment lowered BP by 22mmHg. Steady state concentrations of SOL1 in plasma were 3.9μmol/L. In heart, lung, and kidney the concentrations of SOL1 were 0.4, 1.8, and 20.5μmol/kg, respectively. About 63% of the daily dose was retrieved unaltered in the urine.SignificanceThese data indicate that SOL1 is primarily a NEP inhibitor in vitro as well as in vivo. Given the preferential renal accumulation and renal clearance of SOL1 additional ECE-1 inhibition in the kidney may have contributed to its chronic BP lowering effects in the DOCA-salt hypertensive rat model