An Imidazoline 2 Receptor Ligand Relaxes Mouse Aorta via Off-Target Mechanisms Resistant to Aging

Imidazoline receptors (IR) are classified into three receptor subtypes (I(1)R, I(2)R, and I(3)R) and previous studies showed that regulation of I(2)R signaling has neuroprotective potential. In order to know if I(2)R has a role in modulating vascular tone in health and disease, we evaluated the putative vasoactive effects of two recently synthesized I(2)R 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 I(2)R selective ligand 2-(2-benzofuranyl)-2-imidazoline (2-BFI), which evoked marginal responses. MCR5 relaxations were independent of I(2)R, as IR ligands did not significantly affect them, involved activation of smooth muscle K(ATP) 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 I(2)R in the modulation of vascular tone in the mouse aorta. Moreover, the I(2)R ligand MCR5 is an endothelium-independent vasodilator that acts largely via I(2)R-independent pathways and is resistant to aging. We propose MCR5 as a candidate drug for the management of vascular disease in the elderly.