The current positive inotropic interventions for the management of heart failure (HF) are all associated to an unchanged or increased long term mortality, which limit their use. Istaroxime (IST) is a novel positive inotrope able to inhibit Na+, K+ ATPase and to stimulate SERCA pump. We employed IST as a tool to assess the role of a mild SERCA stimulation as a positive inotropic intervention. In a guinea pig model of HF, where the sarcoplasmic reticulum (SR) function was deranged, IST was able to restore an optimal SR function, increase the SR Ca2+ content and to improve all the EC coupling parameters considered. The comparison if IST and digoxin, a pure inhibitor of Na+, K+ ATPase, in mouse ventricular myocytes, showed that IST was less pro-arrhythmic than digoxin, as already observed in guinea pig. Digoxin induced a rapid accumulation of cytosolic Ca2+, while IST did not, and neither compound directly affected SR Ca2+ leakage, suggesting that a better compartmentalization of the ion was achieved in the presence of IST by the stimulation of SERCA pump. We concluded that the mild stimulation of SERCA is associated to a reduced pro-arrhythmic effect, and that it might represent a promising target for a new class of positive inotropic interventions associated to a reduced long term mortality.
(2009). The modulation of SERCA pump activity as a tool for management of hearth failure. (Tesi di dottorato, Università degli Studi di Milano-Bicocca, 2009).
|Data di pubblicazione:||26-nov-2009|
|Titolo:||The modulation of SERCA pump activity as a tool for management of hearth failure|
|Settore Scientifico Disciplinare:||BIO/09 - FISIOLOGIA|
|Scuola di dottorato:||Scuola di Dottorato in Medicina Traslazionale e Molecolare|
|Corso di dottorato:||MEDICINA TRASLAZIONALE E MOLECOLARE (DIMET) - 45R|
|Citazione:||(2009). The modulation of SERCA pump activity as a tool for management of hearth failure. (Tesi di dottorato, Università degli Studi di Milano-Bicocca, 2009).|
|Parole Chiave:||mouse, guinea pig, ventricular myocyte, SERCA, istaroxime, digoxin, positive inotrope, Na+-Ca2+ exchanger, sarcoplasmic reticulum, heart failure|
|Appare nelle tipologie:||07 - Tesi di dottorato Bicocca post 2009|
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