Characterization of different aspects of selective NCX inhibition in the heart: from inotropy to arrhythmias

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The cardiac sodium-calcium exchanger (NCX) has a pivotal role in the Ca2+ homeostasis as well as in several types of arrhythmias; therefore the potential therapeutic application of its modification was intensively studied in the past decade. However, the inotropic and antiarrhythmic effect of its inhibition has not yet been fully clarified due to the lack of appropriately selective inhibitor. The recently developed novel selective NCX inhibitors, ORM-10103 and especially ORM-10962, provided new insights in the understanding of NCX physiology as well as the possible therapeutic implications of these new potential drugs as novel antiarrhythmic agents. This thesis summarizes: 1) The pharmacological profile of the novel NCX inhibitor ORM-10962, compared its selectivity with that of the previously described compound, ORM-10103. ORM-10962 proved to be even more selective and exerts improved effectiveness on NCX current having EC50 values in the nanomolar range, without any influence on ICaL or other currents. 2) In contrast to previous inhibitors like SEA0400 or ORM-10103, we found marginal positive inotropic effect of the ORM-10962 without major influence on the action potential under normal condition. 3) Marginal but statistically significant reduction by ORM-10962 in the spontaneous firing rate of the atrial and Purkinje AP may indicate important role of NCX in the spontaneous pacemaker mechanism, which is in the line with the previously described coupled clock hypothesis. 4) We suggest that NCX inhibition could equally lead to positive and negative inotropy, depending on the actual value of NCX reversal potential. Selective NCX inhibition may have negative inotropic effect when Ca2+ load is coupled with marked increase of intracellular Na+ facilitating the reverse mode activity. This hypothesis was tested in dog Purkinje fibres, where digoxin induced DADs amplitude and incidence were significantly reduced by ORM-10962.

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