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
| Autor: | Gudrun Antoons, Norbert Nagy, Károly Acsai, Piero Pollesello, Zsófia Kohajda, Jouko Levijoki, Kinga Oravecz, Zoltán Márton, Norbert Jost, Leila Mirzaei, Tuula Koskelainen, Andrea Gruber, Péter P. Nánási, András Varró, András Tóth, Leena Otsomaa, Julius Gy. Papp, Anita Kormos |
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| Přispěvatelé: | Fysiologie, RS: CARIM - R2.01 - Clinical atrial fibrillation |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Inotrope medicine.medical_specialty Ca2+ handling Heart Ventricles NA+/CA2+ EXCHANGER 030204 cardiovascular system & hematology Pharmacology CA2+ CURRENT Sodium-Calcium Exchanger ORM-10962 Contractility 03 medical and health sciences Dogs 0302 clinical medicine Piperidines SODIUM-CALCIUM EXCHANGE Internal medicine Acetamides medicine Animals Myocyte Myocytes Cardiac Autoregulation Chromans RELEASE Cardiac inotropy Chemistry Endoplasmic reticulum Transporter KB-R7943 NA+-CA2+ EXCHANGE CONTRACTILITY medicine.disease SARCOPLASMIC-RETICULUM TRANSPORT Electrophysiological Phenomena Sarcoplasmic Reticulum Cytosol 030104 developmental biology Endocrinology Heart failure NCX inhibition HEART-FAILURE Calcium Female |
| Zdroj: | European Journal of Pharmacology, 818, 278-286. Elsevier Science |
| ISSN: | 0014-2999 |
| Popis: | 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. 1 mu M 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 1 mu M 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 [Ca-i(2+)]. 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. |
| Databáze: | OpenAIRE |
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