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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 α5containing 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 α5 GABAARs, it could be assumed that the α5 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 α5 selective GABAAR modulators as potential therapeutic targets for novel vasodilators.

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