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Istaroxime stimulates SERCA2a and accelerates calcium cycling in heart failure by relieving phospholamban inhibition.
- Source :
-
British journal of pharmacology [Br J Pharmacol] 2013 Aug; Vol. 169 (8), pp. 1849-61. - Publication Year :
- 2013
-
Abstract
- Background and Purpose: Calcium handling is known to be deranged in heart failure. Interventions aimed at improving cell Ca(2) (+) cycling may represent a promising approach to heart failure therapy. Istaroxime is a new luso-inotropic compound that stimulates cardiac contractility and relaxation in healthy and failing animal models and in patients with acute heart failure (AHF) syndrome. Istaroxime is a Na-K ATPase inhibitor with the unique property of increasing sarcoplasmic reticulum (SR) SERCA2a activity as shown in heart microsomes from humans and guinea pigs. The present study addressed the molecular mechanism by which istaroxime increases SERCA2a activity.<br />Experimental Approach: To study the effect of istaroxime on SERCA2a-phospholamban (PLB) complex, we applied different methodologies in native dog healthy and failing heart preparations and heterologous canine SERCA2a/PLB co-expressed in Spodoptera frugiperda (Sf21) insect cells.<br />Key Results: We showed that istaroxime enhances SERCA2a activity, Ca(2) (+) uptake and the Ca(2) (+) -dependent charge movements into dog healthy and failing cardiac SR vesicles. Although not directly demonstrated, the most probable explanation of these activities is the displacement of PLB from SERCA2a.E2 conformation, independently from cAMP/PKA. We propose that this displacement may favour the SERCA2a conformational transition from E2 to E1, thus resulting in the acceleration of Ca(2) (+) cycling.<br />Conclusions and Implications: Istaroxime represents the first example of a small molecule that exerts a luso-inotropic effect in the failing human heart through the stimulation of SERCA2a ATPase activity and the enhancement of Ca(2) (+) uptake into the SR by relieving the PLB inhibitory effect on SERCA2a in a cAMP/PKA independent way.<br /> (© 2013 The British Pharmacological Society.)
- Subjects :
- Animals
Calcium pharmacokinetics
Dogs
Etiocholanolone pharmacology
Guinea Pigs
Humans
In Vitro Techniques
Male
Microsomes metabolism
Rabbits
Sarcoplasmic Reticulum Calcium-Transporting ATPases drug effects
Sarcoplasmic Reticulum Calcium-Transporting ATPases metabolism
Spodoptera
Calcium metabolism
Calcium-Binding Proteins antagonists & inhibitors
Etiocholanolone analogs & derivatives
Heart Failure drug therapy
Heart Failure metabolism
Sarcoplasmic Reticulum metabolism
Sarcoplasmic Reticulum Calcium-Transporting ATPases pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5381
- Volume :
- 169
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- British journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 23763364
- Full Text :
- https://doi.org/10.1111/bph.12278