Inhibition of KV7 Channels Protects the Rat Heart against Myocardial Ischemia and Reperfusion Injury

Abstract

The voltage-gated K V 7 (KCNQ) potassium channels are activated by ischemia and involved in hypoxic vasodilatation. We investigated the effect of K V 7 channel modulation on cardiac ischemia and reperfusion injury and its interaction with cardioprotection by ischemic preconditioning (IPC). Reverse-transcription polymerase chain reaction revealed expression of K V 7.1, K V 7.4, and K V 7.5 in the left anterior descending rat coronary artery and all K V 7 subtypes (K V 7.1-K V 7.5) in the left and right ventricles of the heart. Isolated hearts were subjected to no-flow global ischemia and reperfusion with and without IPC. Infarct size was quantified by 2,3,5-triphenyltetrazolium chloride staining. Two blockers of K V 7 channels, XE991 [10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone] (10 mM) and linopirdine (10 mM), reduced infarct size and exerted additive infarct reduction to IPC. An opener of K V 7 channels, flupirtine (10 mM) abolished infarct size reduction by IPC. Hemodynamics were measured using a catheter inserted in the left ventricle and postischemic left ventricular recovery improved in accordance with reduction of infarct size and deteriorated with increased infarct size. XE991 (10 mM) reduced coronary flow in the reperfusion phase and inhibited vasodilatation in isolated small branches of the left anterior descending coronary artery during both simulated ischemia and reoxygenation. K V 7 channels are expressed in rat coronary arteries and myocardium. Inhibition of K V 7 channels exerts cardioprotection and opening of K V 7 channels abrogates cardioprotection by IPC. Although safety issues should be further addressed, our findings suggest a potential role for K V 7 blockers in the treatment of ischemiareperfusion injury.

Perivascular adipose tissue and the dynamic regulation of Kv7 and Kir channels: Implications for resistant hypertension

“…K v 7 channels (in particular K v 7.1 and K v 7.5) are highly expressed in left coronary arteries of rats, and their down‐regulation by diabetes critically determines the sensitivity (forskolin and hypoxia) to key regulators of coronary tone . Conversely, inhibition of K V 7 channels (K v 7.1, K v 7.4 and/or K v 7.5) has been found to exert cardioprotection and opening of K V 7 channels to abrogate cardioprotection by ischemic preconditioning . Down‐regulation of K v 7.4 has been implicated in primary and angiotensin II infusion‐induced hypertension .…”

Effects of the Kv7 voltage‐activated potassium channel inhibitor linopirdine in rat models of haemorrhagic shock

“…Taken together, the findings of the present study support the concept that linopirdine‐supplementation of resuscitation fluids is a safe and effective approach to reduce fluid requirements and tissue oedema formation during resuscitation from haemorrhagic shock. Linopirdine has previously been described to antagonize kynurenine induced hypotension, a natural tryptophan metabolite implicated in the pathophysiology of sepsis, and to protect against myocardial ischaemia‐reperfusion injury . Thus, it might be speculated that the efficacy profile of linopirdine extends beyond haemorrhagic hypovolemic shock.…”

“…Linopirdine has previously been described to antagonize kynurenine induced hypotension, a natural tryptophan metabolite implicated in the pathophysiology of sepsis, 39 and to protect against myocardial ischaemia-reperfusion injury. 40 Thus, it might be speculated that the efficacy profile of linopirdine extends beyond haemorrhagic hypovolemic shock. Considering that linopirdine has a short systemic half-life after intravenous injection and its fluid-sparing effects wear off within three plasma half-lives, linopirdine appears to be a drug that is easily controllable if adverse effects would occur.…”

<p>Impact of Administration Time and Kv7 Subchannels on the Cardioprotective Efficacy of Kv7 Channel Inhibition</p>

“…Recently, we discovered that pharmacological inhibition of Kv7.1-5 by XE991 and linopirdine protects the heart from IR injury. 14 Flupirtine, an activator of Kv7.2-5, has also been reported to protect against cardiac IR injury when administered prior to the onset of ischemia. 15 Both studies implicate that Kv7 channels are involved in IR injury.…”

“…The protective effects of Kv7 channel inhibition is additive to protection by IPC suggesting that Kv7 channel inhibition may act independently of the interactive pathways of protection by IPC. 14 We therefore investigated whether the RISK and SAFE pathways are involved in cardioprotection by Kv7 channel inhibition.…”