Apelin, a (neuro)vasoactive peptide, plays a prominent role in controlling cardiovascular functions and water balance. Because the in vivo apelin half‐life is in the minute range, we aimed to identify metabolically stable apelin‐17 (K17F) analogs. We generated P92 by classic chemical substitutions and LIT01–196 by original addition of a fluorocarbon chain to the N terminus of K17F. Both analogs were much more stable in plasma (half‐life >24 h for LIT01–196) than K17F (4.6 min). Analogs displayed a subnanomolar affinity for the apelin receptor and behaved as full agonists with regard to cAMP production, ERK phosphorylation, and apelin receptor internalization. Ex vivo, these compounds induced vasorelaxation of rat aortas and glomerular arterioles, respectively, precontracted with norepinephrine and angiotensin II, and increased cardiac contractility. In vivo, after intracerebroventricular administration in water‐deprived mice, P92 and LIT01–196 were 6 and 160 times, respectively, more efficient at inhibiting systemic vasopressin release than K17F. Administered intravenously (nmol/kg range) in normotensive rats, these analogs potently increased urine output and induced a profound and sustained decrease in arterial blood pressure. In summary, these new compounds, which favor diuresis and improve cardiac contractility while reducing vascular resistances, represent promising candidates for the treatment of heart failure and water retention/ hyponatremic disorders.—Gerbier, R., Alvear‐Perez, R., Margathe, J.‐F., Flahault, A., Couvineau, P., Gao, J., De Mota, N., Dabire, H., Li, B., Ceraudo, E., Hus‐Citharel, A., Esteoulle, L., Bisoo, C., Hibert, M., Berdeaux, A., Iturrioz, X., Bonnet, D., Llorens‐Cortes, C. Development of original metabolically stable apelin‐17 analogs with diuretic and cardiovascular effects. FASEB J. 31, 687–700 (2017). http://www.fasebj.org

Preterm birth incurs an increased risk of early cardiovascular events and death. In the general population, cardiovascular risk factors cluster in the context of inflammation and oxidative stress. Whether this also occurs in young adults born preterm is unknown. We analyzed 101 healthy young adults (ages 18–29) born preterm (≤29 weeks of gestation) and 105 full-term controls, predominantly (90%) white. They underwent a comprehensive clinical and biological evaluation, including measurement of blood pressure, lung function (spirometry), glucose metabolism (fasting glucose, glycated hemoglobin, and oral glucose tolerance test), as well as biomarkers of inflammation and oxidative stress. Individuals born preterm were at higher risk than those born full-term of stage ≥1 hypertension (adjusted odds ratio, 2.91 [95% CI, 1.51–5.75]), glucose intolerance (adjusted odds ratio, 2.22 [95% CI, 1.13–4.48]), and airflow limitation (adjusted odds ratio, 3.47 [95% CI, 1.76–7.12]). Hypertension was strongly associated with adiposity and with glucose intolerance in participants born full-term but not in those born preterm. We did not find any group difference in levels of biomarkers of inflammation and oxidative stress. In individuals born preterm, inflammation, and oxidative stress were not related to hypertension or glucose intolerance but were associated with adiposity. In those born preterm, cardiovascular risk factors were not related to each other suggesting different pathophysiological pathways leading to the development of cardiovascular risk following preterm birth. Clinicians should consider screening for these abnormalities irrespectively of other risk factors in this at-risk population. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT03261609.

Extracorporeal membrane oxygenation support is indicated in severe and refractory respiratory or circulatory failures. Neurological complications are typically represented by acute ischemic or hemorrhagic lesions, which induce higher morbidity and mortality. The primary goal of this study was to assess the prognostic value of cerebral tissue oxygen saturation (StcO₂) on mortality in neonates and young infants treated with ECMO. A secondary objective was to evaluate the association between StcO₂ and the occurrence of cerebral lesions. This was a prospective study in infants < 3 months of age admitted to a pediatric intensive care unit and requiring ECMO support. The assessment of cerebral perfusion was made by continuous StcO₂ monitoring using near-infrared spectroscopy (NIRS) sensors placed on the two temporo-parietal regions. Neurological lesions were identified by MRI or transfontanellar echography. Thirty-four infants <3 months of age were included in the study over a period of 18 months. The ECMO duration was 10±7 days. The survival rate was 50% (17/34 patients), and the proportion of brain injuries was 20% (7/34 patients). The mean StcO₂ during ECMO in the non-survivors was reduced in both hemispheres (p = 0.0008 right, p = 0.03 left) compared to the survivors. StcO₂ was also reduced in deceased or brain-injured patients compared to the survivors without brain injury (p = 0.002). StcO₂ appears to be a strong prognostic factor of survival and of the presence of cerebral lesions in young infants during ECMO.

Apelin, a (neuro)vasoactive peptide, plays a prominent role in controlling body fluid homeostasis and cardiovascular functions. In animal models, experimental data demonstrate that intracerebroventricular injection of apelin into lactating rats inhibits the phasic electrical activity of AVP neurons, reduces plasma AVP levels, and increases aqueous diuresis. In the kidney, apelin increases diuresis by increasing the renal microcirculation and by counteracting the antidiuretic effect of AVP at the tubular level. Moreover, after water deprivation or salt loading, in humans and in rodents, AVP and apelin are conversely regulated to facilitate systemic AVP release and to avoid additional water loss from the kidney. Furthermore, apelin and vasopressin secretion are significantly altered in various water metabolism disorders including hyponatremia and polyuria-polydipsia syndrome. Since the in vivo half-life of apelin is in the minute range, metabolically stable apelin analogs were developed. The efficacy of these lead compounds for decreasing AVP release and increasing both renal blood flow and diuresis, make them promising candidates for the treatment of water retention and/or hyponatremic disorders.

Hyperactivity of the brain renin–angiotensin (Ang) system has been implicated in the development and maintenance of hypertension. AngIII, one of the main effector peptides of the brain renin–Ang system, exerts a tonic stimulatory control over blood pressure (BP) in hypertensive rats. Aminopeptidase A (APA), the enzyme generating brain AngIII, represents a new therapeutic target for the treatment of hypertension. We developed RB150, a prodrug of the specific and selective APA inhibitor, EC33. When given orally in acute treatment in hypertensive rats, RB150 crosses the gastrointestinal and blood–brain barriers, enters the brain, inhibits brain APA activity and decreases BP. We investigate, here, the antihypertensive effects of chronic oral RB150 (50 mg/kg per day) treatment over 24 days in alert hypertensive deoxycorticosterone acetate-salt rats. We measured variations in APA enzymatic activity, SBP, plasma arginine vasopressin levels and metabolic parameters after RB150 chronic administration. This resulted in a significant decrease in SBP over the 24-day treatment period showing that no tolerance to the antihypertensive RB150 effect was observed throughout the treatment period. Chronic RB150 treatment also significantly decreased plasma arginine vasopressin levels and increased diuresis, which participate to BP decrease by reducing the size of fluid compartment. Interestingly, we observed an increased natriuresis without modifying both plasma sodium and potassium levels. Our results strengthen the interest of developing RB150 as a novel central-acting antihypertensive agent and evaluating its efficacy in salt-sensitive hypertension.