Kynurenine causes vasodilation and hypotension induced by activation of KCNQ-encoded voltage-dependent K+ channels

Abstract

Kynurenine is a potential contributor to hypotension in animal and human sepsis. The present study was designed to examine whether the voltage-dependent K+ channels encoded by the KCNQ gene family (Kv7 channels) mediate vasodilator effects of kynurenine and whether modulation of these channels ameliorates hypotension caused by this compound. Rat aortas and mesenteric arteries or human omental arteries without endothelium were used. Some rings were incubated with the selective Kv7 channel inhibitor linopirdine (10 μM). l-Kynurenine (10 μM–1 mM) induced concentration-dependent relaxation in rat aortas and mesenteric arteries as well as human omental arteries, whereas linopirdine abolished the relaxation. l-Kynurenine (1 mM) produced hyperpolarization of vascular smooth muscle, which was reversed by linopirdine (10 μM). Wistar rats received l-kynurenine (1 mM) iv and subsequent linopirdine (10 μM) iv under 3% sevoflurane inhalation. l-Kynurenine iv caused hypotension, whereas linopirdine iv partially reversed it. In conclusion, kynurenine dilates arteries from rats as well as humans via Kv7 channels in the vascular smooth muscle. In rats, this tryptophan metabolite causes hypotension, which is partly counteracted by Kv7 channel inhibition. These results suggest that modulation of Kv7 channels may be a novel strategy to treat hypotension induced by the kynurenine.