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.

Kv7 voltage-activated potassium channel inhibitors reduce fluid resuscitation requirements after hemorrhagic shock in rats

“…Despite only modest effects of acute linopirdine treatment on blood pressure in normotensive rats, we observed that retigabine-induced hypotension was instantaneously reverted with intravenous linopirdine. This finding is in agreement with urodynamic effects of retigabine and linopirdine [24] and with the effects of linopirdine on hypotension induced by kynurenine, a natural tryptophan metabolite that is thought to activate Kv7 channels and which has been implicated in the pathophysiology of sepsis [25]. As such, Kv7 channel modulators may provide an alternative pharmacological approach for the management of hypertensive emergencies, in which drugs that permit rapid, titratable and reversible reduction of blood pressure are highly desirable.…”

Kv7 potassium channels as signal transduction intermediates in the control of microvascular tone

“…In aortae and MAs, the effects of L‐kynurenine (± linopirdine) were mimicked by flupirtine, a Kv7 channel activator. Furthermore, the antagonistic effect of linopirdine on either L‐kynurenine‐ or flupirtine‐induced vasorelaxation was not mimicked by 1 mmol L −1 4‐aminopyridine, a blocker of other classes of Kv channels, suggesting that Kv7 channels are specifically required for the L‐kynurenine effect . Impalement recoding of membrane voltage in smooth muscle cells within the MA wall revealed that L‐kynurenine induced an approximately 12 mV membrane hyperpolarization, which was completely reversed by addition of linopirdine, further supporting Kv7 channels as a specific mediator of L‐kynurenine's vasodilator effect .…”

“…Furthermore, the antagonistic effect of linopirdine on either L‐kynurenine‐ or flupirtine‐induced vasorelaxation was not mimicked by 1 mmol L −1 4‐aminopyridine, a blocker of other classes of Kv channels, suggesting that Kv7 channels are specifically required for the L‐kynurenine effect . Impalement recoding of membrane voltage in smooth muscle cells within the MA wall revealed that L‐kynurenine induced an approximately 12 mV membrane hyperpolarization, which was completely reversed by addition of linopirdine, further supporting Kv7 channels as a specific mediator of L‐kynurenine's vasodilator effect . Finally, intravenous administration of L‐kynurenine (1 mmol L −1 ) to anesthetized male Wistar rats induced about a 35% drop in mean arterial pressure, which was partially reversed following administration of linopirdine (10 μmol L −1 ), providing evidence that these signaling mechanisms may be evident at the systemic level, and that pharmacological targeting of microvascular Kv7 channels may have therapeutic benefit in the treatment of septic shock …”

“…Although the signaling mechanisms underlying its vasodilatory actions remain poorly characterized, both cAMP and cGMP pathways have been invoked . More recently, Kv7 channels have been implicated as mediators of kynurenine's vasodilatory actions . Sakakibara et al found that relaxation of rat aorta, rat mesenteric artery (MA), and human omental artery rings by L‐kynurenine was inhibited by the Kv7 channel blocker linopirdine.…”

Vasorelaxing Action of the Kynurenine Metabolite, Xanthurenic Acid: The Missing Link in Endotoxin-Induced Hypotension?

“…Because the vasorelaxing action of XA was not entirely blocked by apamin and Ctx, it cannot be excluded that additional types of potassium channels are involved. Of note, the vasorelaxing action of L -kynurenine appears to be mediated by activation of Kv7 voltage-sensitive potassium channels (Sakakibara et al, 2015), although, as opposed to XA, the action of L -kynurenine on blood vessels does not require the integrity of the endothelium (Wang et al, 2010; Sakakibara et al, 2015). It is possible that XA and KYN cause arterial relaxation acting on different types of vessels and via different mechanisms.…”