The vasorelaxant properties of novel benzodiazepine-like ligands on isolated rat thoracic aorta

Background/Aim: In addition to well-established central effects, benzodiazepines, but also some other allosteric modulators of gamma-amino-butyric acid (GABA) receptor exhibit significant vascular effects. However, there are currently no elucidated mechanisms for manifested vasodilatory properties and very little is known about GABA gamma-amino-butyric acid function and GABAA receptor expression within peripheral blood vessels. Methods: In the present study, we demonstrated the vasorelaxant properties of Diazepam, GABA and novel imidazobenzodiazepine amide ligands GL-II-73 and GLII-74, which are characterized as positive allosteric modulators of a5-containing GABAA receptor. Using isometric organ bath system, we examined the vascular responses to phenylephrine, in the presence and absence of various ligands, in the rat thoracic aorta. Results: The observed significant and strong attenuation of the maximal contractile response of phenylephrine indicates a non-competitive antagonism of Diazepam, GL-II-73 and GL-II-74 (p < 0.001), whereas GABA does not affect phenylephrine contraction. Since the strongest inhibitory effect was observed with compound GL-II-74, that, compared to other tested ligands, exhibited a higher potentiation at a5 GABAARs, it could be assumed that the a5 subunit plays a significant role in the structure of putatively present "vascular" GABAARs. Conclusion: This work emphasizes the importance of GABAARs research in the periphery and also points to the possibility of using a5 selective GABAAR modulators as potential therapeutic targets for novel vasodilators.