Inotropic effect of NCX inhibition depends on the relative activity of the reverse NCX assessed by a novel inhibitor ORM-10962 on canine ventricular myocytes

Abstract

Na⁺/Ca²⁺ exchanger (NCX) is the main Ca²⁺ transporter in cardiac myocytes. Its inhibition could be expected to exert positive inotropic action by accumulation of cytosolic Ca²⁺ ([Ca²⁺]_i). However, we have observed only a marginal positive inotropic effect upon selective inhibition of NCX, which was enhanced when forward activity was facilitated. Here we attempted to clarify the underlying mechanism of the limited inotropic action of selective NCX inhibition by a novel inhibitor ORM-10962 on canine ventricular myocytes. 1µM ORM-10962 reduced the Ca²⁺ content of sarcoplasmic reticulum (SR) when the reverse NCX was favoured, while SR Ca²⁺ content was increased by ORM-10962 under conditions favouring the forward activity, like elevation of [Ca²⁺]_i. L-type Ca²⁺ current (I_Ca) was not affected by 1µM ORM-10962 in the absence of SR Ca²⁺ release, while I_Ca was suppressed by ORM-10962 during normal Ca²⁺ cycling. The apparent degree of forward NCX inhibition was dependent on the elevation of [Ca²⁺]_i, suggesting that an increased driving force of forward NCX can also limit the accumulation of [Ca²⁺_i]. We concluded that in healthy myocardium the possible positive inotropic potential of NCX inhibition is considerably weaker than it was expected earlier by theoretical assumptions. The underlying mechanism may involve the autoregulation of Ca²⁺ handling and/or the preserved inducibility of forward NCX by high [Ca²⁺]_i. This limitation of selective NCX inhibition seen in undiseased myocardium requires further studies in failing heart, which may allow correct evaluation of the potential therapeutic value of selective NCX inhibitors in the treatment of heart failure.

Keywords: Ca(2+) handling; Cardiac inotropy; NCX inhibition; ORM-10962.