Mitochondrial Potassium Channels as Pharmacological Target for Cardioprotective Drugs

Abstract

Brief periods of ischemia are known to confer to the myocardium an increased resistance to the injury due to a later and more prolonged ischemic episode. This phenomenon, known as ischemic preconditioning (IPreC), is ensured by different biological mechanisms. Although an exhaustive comprehension of them has not been reached yet, it is widely accepted that mitochondria are pivotally involved in controlling cell life and death, and thus in IPreC. Among the several signaling pathways involved, as triggers and/or end effectors, in the mitochondrial mechanisms of cardioprotection, an important role is played by the activation of potassium channels located in the mitochondrial inner membrane (mitoK) of cardiomyocytes. Presently, different types of mitoK channels have been recognized in the heart, such as ATP-sensitive (mitoKATP) and calcium-activated (mitoBK(Ca) and mitoSK(Ca)) potassium channels. Consistently, drugs modulating mitoK, on one hand, have been employed as useful experimental tools for early basic studies on IPreC. On the other hand, activators of mitoK are promising and innovative therapeutic agents for limiting the myocardial injury due to ischemic episodes. In this review, we report the experimental evidence supporting the role of mitoK in signaling pathways in the mechanisms of cardioprotection and an overview on the most important molecules acting as modulators of these channels, with their profiles of selectivity. Some innovative pharmaceutical strategies for mitochondriotropic drugs have been also reported. Finally, an appendix describing the main experimental approaches usually employed to study mitoK in isolated mitochondria or in intact cells has been added.

The novel H 2 S-donor 4-carboxyphenyl isothiocyanate promotes cardioprotective effects against ischemia/reperfusion injury through activation of mitoK ATP channels and reduction of oxidative stress

“…In contrast, XE991 did not cause any significant influence, indicating that the activation of mitochondrial Kv7 channel does not contribute significantly to cardioprotection. Mitochondrial calcium accumulation is a key event in promoting cell death after I/R, and the inhibition of calcium uptake into the mitochondrial matrix is considered a pivotal mechanism of action of the anti-ischemic effects of mitochondrial potassium channel activators [10]. Consistently, 4CPI strongly prevented calcium accumulation into the mitochondrial matrix, further indicating that the mitoK ATP channel is likely to be a relevant pharmacological target of this novel H 2 S-donor.…”

“…The mechanisms of action accounting for this cardioprotective activity are heterogeneous and not yet completely understood. Mitochondrial ATP-sensitive potassium channels (mitoK ATP ) are well-known effectors of ischemic preconditioning [10]. Their activation by H 2 S is likely to be a relevant cardioprotective mechanism [11], since the anti-ischemic effects of H 2 S are largely antagonized by blockers of mitochondrial potassium channel [12].…”

The Citrus Flavanone Naringenin Protects Myocardial Cells against Age‐Associated Damage

“…This produces a mild depolarization of the membrane potential. This depolarization is responsible for reducing the uptake of Ca 2+ into the mitochondrial matrix and preserving the mitochondria from the Ca 2+ overload and the subsequent MPTP opening [4, 14]. To evaluate the involvement of mitoBK Ca channels in the Nar-mediated CRC effects, the selective mitoBK Ca blocker paxilline was tested in the CRC assessment.…”

“…Nar is a free radical scavenger, a metal ion chelator, and an activator of the antioxidant enzyme defense [1, 2]. In addition, Nar stimulates the mitochondrial calcium-dependent potassium channel (mitoBKCa), which causes an influx of potassium ions, a mild depolarization, and a decrease in the mitochondrial matrix calcium uptake, all of which contribute to stabilizing the mitochondria during cellular damage [3, 4]. Furthermore, Nar has been demonstrated to bind to estrogen receptors [5–8] and shows bidirectional adjusting effects [9].…”

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“…2 Moreover, mitochondrial KATP channels were reported to be in cross-talk with complex II of the respiratory chain, which may contribute to the reported effect of ascorbic acid on the mitochondrial respiration. 6 Taken together, it seems that the significant effects of ascorbic acid supplementation during EVLP result from combined antioxidant and K+ channels enhancing activities (Figure 1). Accordingly, supplementation of the preservation solution with a combination of antioxidants and K+ channel agonists is expected to be, at least, as protective as vitamin C; the notion that was introduced for the first time within Shehata EVLP technique.…”