Istaroxime, a Stimulator of Sarcoplasmic Reticulum Calcium Adenosine Triphosphatase Isoform 2a Activity, as a Novel Therapeutic Approach to Heart Failure
Section snippets
Calcium Cycling in Heart Failure
Calcium fluxes regulate both contraction and relaxation, potentially increasing oxygen consumption and thus contributing to impaired tissue viability. Myocytes from patients with HF show smaller calcium transients that also decrease more slowly than normal,5, 7 indicating a decrease in the sarcoplasmic reticulum calcium content and in sarcoplasmic reticulum calcium adenosine triphosphatase (ATPase) (SERCA) isoform 2a (SERCA2a) pump activity.
The reduced sarcoplasmic reticulum calcium content in
Istaroxime
Istaroxime is an inhibitor of sodium-potassium ATPase that exhibits the unique property of increasing SERCA2a activity. This has been demonstrated in sarcoplasmic reticulum vesicles from normal guinea pigs, where istaroxime increased SERCA2a affinity for calcium in the calcium physiologic concentration range. Such an effect presumably favors sarcoplasmic reticulum calcium reloading. In fact, the functional correlate of SERCA2a stimulation in isolated guinea pig myocytes was a higher magnitude
In vivo HF model
Guinea pigs were used for the evaluation of cardiac function or SERCA2a activity 12 weeks after banding of the ascending aorta (AoB) performed under ketamine-xylazine, 100 mg/kg intraperitoneally.
For cardiac function, a full transthoracic echocardiographic and Doppler evaluation (Sequoia 512 equipped with a 13-MHz probe; Acuson, Mountain View, CA) under urethane (1.5 g/kg intraperitoneally) anesthesia was performed before and during intravenous infusion of 0.11 mg/kg per min istaroxime or
Results
AoB induced significant hypertrophy of both the intraventricular septum and posterior wall, with an increase in LV mass (1.512 ± 55 mg, 2.220 ± 130 mg, and 2.111 ± 110 mg, in sham, AoB-S, and AoB-I groups, respectively; p <0.005). LVEDD increased in AoB groups to near statistical significance (Table 1). In AoB animals, saline solution infusion significantly increased the LVESD, whereas istaroxime reduced it (Table 1). Therefore, fractional shortening decreased by 7% in the AoB-S group and
Discussion
We have recently reported that the lusitropic properties displayed by istaroxime in normal animals27 may be attributed to its unique ability to stimulate SERCA2a activity.26 Our aim in this study was to extend investigations to animals with cardiac hypertrophy and failure. Because we had characterized the interaction of istaroxime with SERCA2a in guinea pigs, we used a model of guinea pig HF. The pressure overload model described here shows clear evidence of LV hypertrophy and mild cardiac
Conclusion
At the present state of knowledge, istaroxime is the only available compound that stimulates SERCA2a activity and produces a luso-inotropic effect in HF.
Acknowledgment
We are indebted to Dr. P. M. Janssen for teaching us the methodology to study in vitro human trabeculae. We acknowledge the Consiglio Nazionale delle Ricerche–CNR, Institute of Clinical Physiology and the Cardiosurgery Division at the Niguarda Ca’ Granda Hospital for providing us with the human cardiac samples (Ethical Committee Approval No. 3755/99).
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2022, Pharmacological ResearchIstaroxime, a positive inotropic agent devoid of proarrhythmic properties in sensitive chronic atrioventricular block dogs
2018, Pharmacological ResearchCitation Excerpt :Therefore, in this patient group, additional proarrhythmic triggers should be minimized. To date, the proarrhythmic effects of istaroxime and its potency to improve cardiac systolic function in relation with its positive inotropy and molecular mechanisms have been studied exclusively in failing heart animal models [3,6–9] and HF patients [10–12]. Therefore, the proarrhythmic properties of istaroxime remain to be explored in a sensitive animal model representing the proarrhythmic vulnerability of this patient population (compensated/early stage of HF).
TDCPP protects cardiomyocytes from hypoxia-reoxygenation injury induced apoptosis through mitigating calcium overload and promotion GSK-3β phosphorylation
2018, Regulatory Toxicology and PharmacologyCardiac SERCA2A/B: Therapeutic targets for heart failure
2014, European Journal of PharmacologyCitation Excerpt :Similarly, Ivabradine restores SERCA2 function in rat hearts post-myocardial infarction (Maczewski and Mackiewicz, 2008). Istaroxime, an agent exerting inotropic effects by inhibiting Na+-K+ ATPase, also causes up-regulation in the function of SERCA2 in human heart muscles (Khan et al., 2009; Micheletti et al., 2007). This drug is currently enrolled in a phase IIb clinical trial for treating chronic heart failure patients (Ghali et al., 2007).