Time-dependent modulation of cardiomyocyte contractility by alamandine is impaired by chronic treatment with isoproterenol

Time-dependent modulation of cardiomyocyte contractility by alamandine is impaired by chronic treatment with isoproterenol

• Autor
• André Luis Lima Monteiro
• Co-autores
• Anderson Kenedy Santos , Silvia Guatimosim
• Resumo

• INTRODUCTION: Alamandine (ALA) is an heptapeptide that takes part in the cardioprotective arm of the Renin-Angiotensin System. Recently, our group demonstrated that ALA modulates cardiomyocyte contractility via NO-dependent pathways in a rat model of hypertension. Despite this knowledge, there is no information of any time-dependent variation of ALA contractility effects in cardiomyocytes (CMs). Therefore, our goal is to determine whether ALA effects on contractility are affected by the light-dark cycle in control and in a model of adrenergic overstimulation. METHODS: CMs from 10-14 weeks male mice (CEUA:236-2019) were isolated at ZT2 (light phase) and ZT14 (dark phase) and used to evaluate NO production and contractility. Isoproterenol injection (25 mg/Kg/day) for 7 days was used to induce cardiac hypertrophy in mice. RESULTS: CMs isolated at ZT2 and incubated for 15 minutes with ALA 100nM showed an increase in NO production (~30%), and enhanced fractional shortening (FS) (~20%) compared to control. These effects were abolished by eNOS inhibitor, L-NIO (1µM), as well as by a MrgD receptor antagonist, D-Pro7 (1µM). Remarkably, ZT14 CMs did not respond to ALA-induced NO production. Furthermore, ALA diminished FS (~20%), in ZT14 CMs, an effect abolished by D-Pro7 (1µM). CMs from ISO-treated mice lost their light/dark difference in FS intensity compared to saline group. In addition, ZT2 ISO cells showed a smaller increase in NO production in response to ALA, as well as an impairment of the contractile modulation of FS, which had no significant change at both light and dark phases. CONCLUSION: ALA presents time dependent opposite effects on CM contractility which occurs via MrgD-eNOS-NO signaling. This time-dependence of ALA effects in CMs was lost in a model of CM hypertrophy induced by adrenergic hyperstimulation. Our data highlights the importance of understanding the chrono-related effects of ALA in the heart and their consequences during disease development.

• Palavras-chave
• Cardiomyocytes, alamandine, NO, adrenergic, time-dependent
• Área Temática
• Vídeo-pôster / Sala 5 - Farmacologia do Sist. Cardiovascular

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