Chronic Istaroxime Improves Cardiac Function and Heart Rate Variability in Cardiomyopathic Hamsters
Istaroxime is a new luso-inotropic compound. It exerts inotropic action by reducing Na+/K+-ATPase activity, and simultaneously it stimulates sarcoplasmic reticulum Ca2+-ATPase function, thus also inducing lusitropic action. The aim of present study is to assess the effect of chronic istaroxime treatment on cardiac function and heart rate variability in Bio TO.2 Syrian hamster model of progressive heart failure.
Bio TO.2 hamsters were daily treated, from 12 to 28 weeks of age, with 30 mg/kg/day oral istaroxime. Age-matched Bio TO.2 and Bio F1B hamsters were treated with vehicle and used as diseased and healthy controls. At the end of treatment, hearts function and autonomic cardiac control were evaluated.
Hearts from vehicle-treated Bio TO.2 when compared with hearts from Bio F1B showed higher heart/body weight ratio, and lower left ventricular systolic pressure (LVSP), positive and negative derivative of LV pressure (dP/dT), coronary flow rate (CFR). Hearts from istaroxime-treated when compared with those of vehicle-treated hamsters, showed the reduction of heart/body weight ratio, and the increase of LVSP, of both positive and negative dP/dT, and of CFR. Autonomic cardiac control, evaluated by HRV analysis, indicated in vehicle-treated Bio TO.2 hamsters, when compared to healthy, a shift towards increased sympathetic and decreased parasympathetic activities. Istaroxime-treatment preserved parasympathetic activity.
Chronic istaroxime improves cardiac function and heart rate variability in Bio TO.2 Syrian hamster model of progressive heart failure.
Key wordsIstaroxime Na+/K+-ATPase Sarcoplasmic reticulum Ca2+-ATPase Bio TO.2 hamsters Heart failure Heart rate variability
We gratefully acknowledge the technical assistance from Giuseppina Magni and Augusta Bellucci
- 4.Rocchetti M, Besana A, Mostacciuolo G, Micheletti R, Ferrari P, Sarkozi S, et al. Modulation of sarcoplasmic reticulum function by Na+/K+ pump inhibitors with different toxicity: digoxin and PST2744 [(E, Z)-3-((2-aminoethoxy)imino)androstane-6, 17-dione hydrochloride]. J Pharmacol Exp Ther. 2005;313:207–15.PubMedCrossRefGoogle Scholar
- 5.Rocchetti M, Alemanni M, Mostacciuolo G, Barassi P, Altomare C, Chisci R, et al. Modulation of sarcoplasmic reticulum function by PST2744 [Istaroxime; (E, Z)-3-((2-Aminoethoxy)imino) Androstane-6, 17-dione Hydrochloride)] in a pressure-overload heart failure model. J Pharmacol Exp Ther. 2008;326:957–65.PubMedCrossRefGoogle Scholar
- 9.Ghali JK, Smith WB, Torre-Amione G, Haynos W, Rayburn BK, Amato A, et al. A phase 1–2 dose-escalating study evaluating the safety and tolerability of istaroxime and specific effects on electrocardiographic and hemodynamic parameters in patients with chronic heart failure with reduced systolic function. Am J Cardiol. 2007;99:47A–56A.PubMedCrossRefGoogle Scholar
- 15.VanDongen CG, Kenouche A, Banville B, Kale A, Bhagavan H, Amende I, et al. Rapid screen for heart failure autonomic nervous system imbalance in cardiomyopathic BIO TO-2 hamsters. FASEB J. 2007;21:956.2.Google Scholar
- 16.Binkley P, Nunziata E, Haas G, Nelson S, Cody R. Parasympathetic withdrawal is an integral component of autonomic imbalance in congestive heart failure demonstration in human subjects and verification in a paced canine model of ventricular failure. J Am Coll Cardiol. 1991;18:464–72.PubMedCrossRefGoogle Scholar