An Imidazoline 2 Receptor Ligand Relaxes Mouse Aorta via Off-Target Mechanisms Resistant to Aging
Jiménez Altayó, Francesc (Universitat Autònoma de Barcelona. Departament de Farmacologia, de Terapèutica i de Toxicologia)
Cabrera, Anna (Universitat Autònoma de Barcelona. Departament de Farmacologia, de Terapèutica i de Toxicologia)
Bagán, Andrea (Universitat de Barcelona. Departament de Farmacologia, Toxicologia i Química Terapèutica)
Gimenez-Llort, Lydia (Universitat Autònoma de Barcelona. Institut de Neurociències)
D'Ocon, Pilar (Universitat de València)
Pérez, Belén (Universitat Autònoma de Barcelona. Departament de Farmacologia, de Terapèutica i de Toxicologia)
Pallàs, Mercè (Universitat de Barcelona. Institut de Neurociències)
Escolano, Carmen (Universitat de Barcelona. Departament de Farmacologia, Toxicologia i Química Terapèutica)

Data:	2022
Resum:	Imidazoline receptors (IR) are classified into three receptor subtypes (IR, IR, and IR) and previous studies showed that regulation of IR signaling has neuroprotective potential. In order to know if IR has a role in modulating vascular tone in health and disease, we evaluated the putative vasoactive effects of two recently synthesized IR ligands, diethyl (1RS,3aSR,6aSR)-5-(3-chloro-4-fluorophenyl)-4,6-dioxo-1-phenyl-1,3a,4,5,6,6a-hexahydropyrrolo[3,4-c]pyrrole -1-phosphonate (B06) and diethyl [(1-(3-chloro-4-fluorobenzyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-1H-imidazol-4-yl]phosphonate] (MCR5). Thoracic aortas from Oncins France 1 (3- to 4-months-old) and C57BL/6 (3- to 4- and 16- to 17-months-old mice) were mounted in tissue baths to measure isometric tension. In young mice of both strains, MCR5 induced greater relaxations than either B06 or the high-affinity IR selective ligand 2-(2-benzofuranyl)-2-imidazoline (2-BFI), which evoked marginal responses. MCR5 relaxations were independent of IR, as IR ligands did not significantly affect them, involved activation of smooth muscle K channels and inhibition of L-type voltage-gated Ca 2+ channels, and were only slightly modulated by endothelium-derived nitric oxide (negatively) and prostacyclin (positively). Notably, despite the presence of endothelial dysfunction in old mice, MCR5 relaxations were preserved. In conclusion, the present study provides evidence against a functional contribution of IR in the modulation of vascular tone in the mouse aorta. Moreover, the IR ligand MCR5 is an endothelium-independent vasodilator that acts largely via IR-independent pathways and is resistant to aging. We propose MCR5 as a candidate drug for the management of vascular disease in the elderly.
Ajuts:	Agencia Estatal de Investigación PID2020-113634RB-C22 Agencia Estatal de Investigación PID2019-107991RB-I00 Generalitat de Catalunya 2017-SGR-645
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Imidazoline receptor 2 ligands ; Mouse aorta ; Endothelium-independent vasodilatation ; Vascular aging ; Endothelial dysfunction ; Potassium and calcium ion channels ; L-type voltage-gated Ca 2+ channels ; K channels
Publicat a:	Frontiers in Pharmacology, Vol. 13 (may 2022) , ISSN 1663-9812

DOI: 10.3389/fphar.2022.826837
PMID: 35645795

11 p, 1.3 MB

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