Protection of endothelial-derived vasorelaxation with cariporide, a sodium-proton exchanger inhibitor, after prolonged hypoxia and hypoxia–reoxygenation: Effect of age Sophie Besse a,b,c, ⁎ , Stéphane Tanguy b , François Boucher b , Catherine Huraux c , Bruno Riou c , Bernard Swynghedauw d , Joël de Leiris b a Laboratoire Croissance cellulaire, Réparation et Régénération Tissulaires, UMR CNRS 7149, Université Paris 12-Val de Marne, Créteil, France b Laboratoire Nutrition, Vieillissement et Maladies Cardiovasculaires: prévention et biomarqueurs, IFRT Ingénierie pour le Vivant, Université Joseph Fourier, La Tronche, France c Laboratoire d'Anesthésiologie, EA 3975, Université Pierre et Marie Curie, Paris, France d INSERM U572, Université Denis Diderot, Paris, France Received 28 July 2005; received in revised form 21 November 2005; accepted 28 November 2005 Available online 24 January 2006 Abstract Calcium overload during hypoxia and reoxygenation exerts deleterious effects in endothelial and smooth muscle cells but potential effects of sodium-proton exchanger (NHE) inhibitors have never been investigated in both adult and senescent vessels. Isolated aortic rings from adult and senescent rats were submitted to hypoxia (50 min) or to hypoxia/reoxygenation (20/30 min) without or with cariporide (10 - 6 M) and aortic vasoreactivity was recorded. After hypoxia, relaxation to acetylcholine was preserved in adult rings treated with cariporide (- 22.3% vs. - 9.3% of baseline value in control and treated groups respectively, P b 0.05) but not in senescents. Cariporide treatment restored relaxation to acetylcholine after hypoxia–reoxygenation in adult rings (- 32.04% vs. - 0.03% of baseline value in control and treated groups respectively, P b 0.01) and to a lesser extent, in senescent rings (- 30.8% vs. - 24.4% of baseline value in control and treated groups respectively, P b 0.01). These results suggested that hypoxia induced lower acidosis and/or involved other mechanisms of proton extrusion than NHE in senescent aorta. Improvement of endothelial function with cariporide after reoxygenation in senescent aorta, but in a lesser extent than in adult aorta, suggests a lower role of NHE in pH regulation and subsequent calcium overload during aging. © 2005 Elsevier B.V. All rights reserved. Keywords: Aging; Hypoxia; Reoxygenation; Cariporide; Endothelium; Vasorelaxation 1. Introduction Vascular endothelium plays an important role in modulation of vascular tone by releasing vasoactive factors, such as nitric oxide or endothelin (Marin, 1995). Endothelial cells, located at the blood–organ interface, are exposed to decreases in O 2 tension, cytotoxic stimuli in the blood and/or metabolic changes after an ischemic insult, initiating series of events such neutrophil adhesion, oxidant production, alterations in the membrane permeability and disturbances of intracellular ionic homeostasis (Ten and Pinsky, 2002; Weir et al., 2002). Different investigators have demonstrated that hypoxia mostly induced intracellular proton accumulation in both endothelial (Foy et al., 1997; Cutaia et al., 2000; Hattori et al., 2001) and smooth muscle (Madden et al., 2001) cells, resulting from the switch from aerobic to anaerobic metabolism. The Na + –H + exchanger (NHE) restrains this intracellular acidosis by elevating the intracellular Na + concentration in muscle and endothelial cells, which stimulates the Na + –Ca 2+ exchanger in reverse mode and leads to cytosolic Ca 2+ overload (Ladilov et al., 2000; Hattori et al., 2001). In endothelial cells, this Ca 2+ overload after hypoxia and reoxygenation has been suspected to be an important mechanism contributing to vascular dysfunction. European Journal of Pharmacology 531 (2006) 187 – 193 www.elsevier.com/locate/ejphar ⁎ Corresponding author. Laboratoire CRRET, UMR CNRS 7149, Faculté des Sciences, Bat. P1, 61 Avenue du Général de Gaulle, 94010 Créteil, France. Tel.: +33 1 45 17 18 15; fax: +33 1 45 17 18 16. E-mail address: Sophie.Besse@univ-paris5.fr (S. Besse). 0014-2999/$ - see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2005.11.059