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Pharmacological modulation of cardiac potassium channels

Bo Hjorth Bentzen

Summary

Pharmacological agents are important tools for investigating the role of cardiac ion channels.
In my thesis I present the electrophysiological characterization of compounds affecting the Kv11.1 (Part I) and the KCa1.1 (Part II) potassium channels, and investigate their role in inherited long QT syndrome and ischemia-reperfusion injuries respectively.

(Part I)
The Long QT syndrome is characterized by delayed ventricular repolarization and increased risk of life threatening arrhythmias. The inherited form is caused by mutations in genes responsible for generating the cardiac action potential, e.g. loss-of-function of cardiac K+- channel genes. Recently drugs aimed at improving the cardiac repolarization by activation of KV11.1 have been described. The two most important currents for repolarization of the human cardiac action potential are IKs and IKr. The voltage-gated potassium channel KV11.1, is the main molecular component of IKr. Several isoforms of Kv11.1 exist. Recent data suggest that not only Kv11.1a but also Kv11.1b contributes to IKr.
The aim of part I of the thesis was to determine if Kv11.1 activators display any isoform specificity. It was also the aim to determine if pharmacological activation of Kv11.1 could normalize the action potential duration in a transgenic rabbit model of LQT type 1. By investigating the effect of two KV11.1 activators, NS1643 and RPR260243, on Kv11.1a and Kv11.1b we found that the compounds display isoform dependent effects (manuscript 1). Using transgenic LQT1 rabbits, I found that NS1643 shortens the QT interval in anaesthetized rabbits. In isolated perfused heart preparations, the administration of NS1643 abbreviated the action potential duration and effective refractory period, but was associated with a higher occurrence of arrhythmia (manuscript 2).
In conclusion, this part demonstrates that Kv11.1 channel isoforms are differentially affected by Kv11.1 channel agonists. In addition, the results demonstrate that KV11.1 current augmentation is capable of shortening the action potential duration in LQT1 rabbits, albeit indiscriminate KV11.1-activation might be detrimental.

(Part II)
The role of KCa channels in cardiomyocytes was for many years neglected because of their absence from the plasma membrane. However, recent data suggest that a channel exist in the inner mitochondrial membrane of cardiomyocytes with properties resembling the large conductance potassium channel (KCa1.1). Furthermore, pharmacological activation of the KCa channel, by the compound NS1619, protected the heart from ischemia-reperfusion injuries. However, the selectivity of NS1619 has been questioned. Therefore, the aim of part II of the thesis was to elucidate the role of KCa channels in cardioprotection by developing a new set of tool compounds.
In manuscript 3 I introduce the compound NS11021 which represents a novel, chemically unrelated, more specific and potent KCa1.1 channel activator as compared to NS1619. Moreover, in isolated perfused rat hearts NS11021 was found to protect against ischemia–reperfusion injuries (manuscript 4). Finally, in an attempt to further support the role of KCa channels in cardioprotection, we designed the compound (NS13558) as a structurally closely related and biologically inactive analogue of NS11021. I found that NS13558 did not elicit any opening of KCa1.1 channels and did not confer any cardioprotection (manuscript 5). In conclusion, my data demonstrate that NS11021 and NS13558 could serve as novel tool compounds for the investigation of KCa channels. Furthermore, the studies indicate an important role of KCa channels in protection against ischemia–reperfusion injury. In summary the thesis focused on validation of KCa1.1 and Kv11.1 channels role in the treatment of ischemia-reperfusion injuries and inherited long QT 1 syndrome respectively, and the use of novel compounds in the investigation of cardiac potassium channel function.