Activation of IK1 by Zacopride

In the present issue of Journal of Cardiovascular Pharmacology, Liu et al1 describe the effects of zacopride, an IK1 activator, on ventricular remodeling after myocardial infarction (MI) caused by coronary ligation in a rat preparation. The drug, administered for 28 days starting 1 day after induction of MI, reduced adverse remodeling and improved ejection fraction. The effects were partially surmounted by chloroquine. Zacopride, additionally, downregulated the expression of phosphorylated p70S6 kinase (p-p70S6K) and mTOR. It was concluded that “activation of IK1 channels by zacopride attenuates post-MI cardiac remodeling by suppressing mTOR-p70S6 kinase signaling.” There are 3 issues that arise. First, how safe is the conclusion? This depends on the selectivity of zacopride. Its specificity has been characterized,2 but it can never be assumed that the characterized action accounts for the effect unless other possibilities have been excluded, or if there is ancillary supporting evidence. Here, the authors attempted to prevent the benefit using an IK1 blocker, chloroquine. They were partially successful. However, once again, the outcome does not prove IK1 involvement in the effects. Chloroquine is not selective for IK1, having agonist actions on bitter taste receptors, and smooth muscle relaxant activity, among other properties.3 Thus, it may not be the case that the tools used in this study are sufficiently selective to make the conclusion secure. Moreover, chloroquine may itself possess antiarrhythmic activity.4 This leads on to the second issue, that of the risk of possible proarrhythmia with an IK1 agonist. Although this seems to be unlikely in the setting of evolving infarction and remodeling, the nature of the setting determines the effect of drugs on arrhythmia occurrence. For example, drugs that suppress arrhythmias during evolution of MI may facilitate the initiation of arrhythmias such as ventricular fibrillation (VF) during acute (<1 hour) ischemia, or vice versa.5–8 If a drug is given during the wrong setting (eg, acute ischemia as opposed to the MI resolution and remodeling phase), its benefit may be overshadowed by unanticipated adverse actions such as proarrhythmia. Zacopride is an IK1 agonist. In acute myocardial ischemia (the necessary prelude to coronary obstruction-induced MI), there is some evidence from animal studies that IK1 blockade is antiarrhythmic. Drugs that inhibit IK1 have been reported to inhibit ischemia-induced VF primate, rabbit and rat.11,12 The rat data are particularly important with respect to mechanistic interpretation. Rat ventricles lacks functional IKr and IKs so protection against VF by nonselective K channel-targeting drugs (and most are) cannot be attributed to IKr or IKs block in this species.9–12 This, together with an inability of IKATP block (or activation) or Ito inhibition to reduce the incidence of ischemia-induced VF in this species13,14 means that when a specific IK1 blocker inhibits ischemia-induced VF in this species, and the effects relate to QT widening, then IK1 blockade is the likely mechanism.11,15 Why does this matter in the present context? If IK1 block inhibits VF during early ischemia, then IK1 activation (eg, by zacopride) may run the risk of facilitating the occurrence of VF if the drug is given in this setting. Although a rat coronary ligation model is likely to be “clean” with new episodes of regional ischemia unlikely to occur spontaneously, one may anticipate a high likelihood of new episodes of ischemia in a human with MI caused by longstanding coronary atherosclerosis and sudden thrombosis—because these patients are at risk. When ischemia is “suboptimal” (eg, because the risk zone is smaller than optimal—in rat under around 30% of left ventricular volume), then proarrhythmic bioactive substances including drugs may interact with the ischemic electrophysiological milieu to facilitate the initiation of VF.16,17 If this were to happen with an IK1 agonist like zacopride, which is likely to have the opposite effects of protective IK1 blockers on VF caused by acute ischemia, the outcome could be very concerning. This is easily tested. In conclusion, this interesting study will benefit from further safety pharmacology follow-up to ensure that no adverse rhythm effects occur in the sort of pathological setting (acute ischemia) that may be encountered by patients clearly at risk of acute MI (their having already had acute MI, leading to the heart failure and remodeling that is the target setting in this study1).