The Nebivolol action on vascular tone is dependent on actin cytoskeleton polymerization and Rho-A activity into ECs and SMCs

Article type: Research Article

Authors: Kadi, A.^; | de Isla, N.^; | Moby, V.^; | Lacolley, P.^; | Labrude, P.^; | Stoltz, J.F.^{; ;} | Menu, P.^;

Affiliations: Faculté de Médecine, Université de Lorraine, Vandoeuvre, lès-Nancy, France | CNRS UMR 7561- Groupe de Mécanique et Ingénierie Cellulaire et Tissulaire, Vandoeuvre, lès-Nancy, France | INSERM UMR 961-Laboratoire de Pharmacologie Cardiovasculaire, Vandoeuvre, lès-Nancy, France | CHU –Cell and Tissue Therapy Unit, Vandoeuvre les Nancy, France

Note: [] Corresponding author: Pr. P. Menu, Groupe Mécanique et Ingénierie Cellulaire et Tissulaire –UMR CNRS 7561, Faculté de Médecine, Bat E, 9, avenue de la forêt de Haye, 54505 Vandoeuvre-lès-Nancy, France. Tel.: +33 3 83 68 34 74; E-mails: [email protected], [email protected]

Abstract: Nitric oxide is implicated in the target action of Nebivolol, a selective β1 adrenoceptor blocker used in hypertension treatment. As the Nitric Oxide (NO) production and the actin cytoskeleton are linked, the aim of this work was to study the involvement of actin cytoskeleton on mechanism of action of Nebivolol in cultured endothelial cells. We studied the effect of Nebivolol (200μM) on actin filaments remodeling and its impact on NO production and eNOS activation. Results showed that Nebivolol perturbs actin filaments polymerization, increases NO production and eNOS activity between 30 minutes and 1 h. Stabilization of actin filaments with phalloïdine (50μM) abolishes Nebivolol effects on eNOS activation and NO production. Furthermore, Rho-kinase activity decreased during the first hour of Nebivolol treatment, then increased after 3 h, while actin filaments repolymerized, eNOS activation and NO production decreased. In SMCs, Nebivolol induced a decrease in the Rho-kinase activity from 1 h until 24 h of incubation. In conclusion, we suggest that Nebivolol induced NO production in Endothelial Cells (ECs) via complementary actions between actin cytoskeleton remodeling inducing eNOS activation and Rho-kinase implication. The effect of Nebivolol on ECs occurs during the first hour, this effect on SMCs seems to be maintained until 24 h, explaining persisted action of Nebivolol observed in vivo.

Keywords: Nebivolol, β blocker, actin cytoskeleton, eNOS, nitric oxide, Rho-kinase, endothelial cell

DOI: 10.3233/CH-131718

Journal: Clinical Hemorheology and Microcirculation, vol. 56, no. 3, pp. 231-246, 2014