Hypertension Research https://doi.org/10.1038/s41440-019-0253-3 ARTICLE Endothelin-1/nitric oxide balance and HOMA index in children with excess weight and hypertension: a pathophysiological model of hypertension Antonina Orlando 1 ● Francesca Viazzi 2 ● Marco Giussani 3 ● Elisa Nava 1 ● Emanuela Cazzaniga 1 ● Barbara Bonino 2 ● Paola Palestini 1 ● Gianfranco Parati 1,4 ● Simonetta Genovesi 1,4 Received: 20 January 2019 / Revised: 5 March 2019 / Accepted: 5 March 2019 © The Japanese Society of Hypertension 2019 Abstract The aim of this study was to investigate the relationship between endothelin-1, nitric oxide, insulin resistance, and blood pressure in young subjects with a high prevalence of excess weight and/or elevated blood pressure. In a cohort of 238 children (mean age = 11.1 years), height, weight, waist circumference, and blood pressure were assessed. Body mass index, waist-to-height ratio, and blood pressure percentiles were calculated, and the children were classified as having excess weight and elevated blood pressure according to the International Obesity Task Force and the US blood pressure nomograms specific for gender, age and height, respectively. Endothelin-1 and nitric oxide production were assessed, and the homeostatic model assessment index was calculated. Forty-three percent of children were male, 71% had excess weight, and 37% had systolic and/or diastolic values above the ninetieth percentile. Plasma endothelin-1 and nitric oxide production were independently correlated (p < 0.05). In multivariate analyses, the HOMA index was associated with systolic and diastolic blood pressure (p = 0.01), and nitric oxide was independently related to diastolic blood pressure (p = 0.04), even after adjustment for measures of body composition. By using the waist-to-height ratio instead of BMI in the statistical model, the association between the homeostatic model assessment index and blood pressure was attenuated, while the results remained similar for nitric oxide. No correlation was found between endothelin-1 and blood pressure. In our study population, the correlation between nitric oxide and blood pressure and the lack of a relationship between endothelin-1 and blood pressure could be explained by an increase in the vasodilator effect of local and systemic nitric oxide, which counteracts the possible hypertensive effect of endothelin-1. Keywords: Blood pressure ● Children ● Endothelin ● Excess weight ● Nitric oxide Introduction Among the three separately encoded isoforms constituting the endothelin superfamily, endothelin-1 (ET-1) is the dominant isoform in the cardiovascular system and is therefore the most often studied. ET-1 is synthesized pre- dominantly in vascular endothelial cells, but it is also synthesized in vascular smooth muscle cells (VSMC) as well as in extravascular tissues such as the spleen, pancreas, lung, and nervous system, as well as in the glomerular and epithelial cells within the kidney [1–4]. In humans, the physiological action of ET-1 is mediated by ET-A and ET-B receptors. ET-1 contributes to a basal vasoconstrictor tone [5] that seems to be largely mediated by ET-A receptors [6]. In fact, the binding of ET-1 to ET-A and ET-B receptors in VSMCs results in vasoconstriction, whereas the predominant effect of ET-1 binding to ET-B receptors in the endothelium is an increase in nitric oxide (NO) and prostacyclin synthesis [7, 8]. The administration of ET-1 results in a biphasic response characterized by a * Simonetta Genovesi simonetta.genovesi@unimib.it 1 School of Medicine and Surgery, University Milano, Bicocca, Milan, Italy 2 Università degli Studi and IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Genova, Italy 3 Family Pediatrician, ATS Milan, Milan, Italy 4 Department of Cardiovascular, Neural, and Metabolic Sciences, S. Luca Hospital, IRCCS, Istituto Auxologico Italiano, Milan, Italy 1234567890();,: 1234567890();,: