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European Journal of Heart Failure 2009 11(2):140-146; doi:10.1093/eurjhf/hfn026
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Isoproterenol-induced heart failure in the rat is associated with nitric oxide-dependent functional alterations of cardiac function

Peter Krenek1,*, Jana Kmecova1, Dana Kucerova1, Zuzana Bajuszova1, Peter Musil1, Andrea Gazova2, Peter Ochodnicky1, Jan Klimas1 and Jan Kyselovic1

1 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Odbojárov 10, 832 32 Bratislava, Slovak Republic
2 Institute of Pharmacology, Faculty of Medicine, Comenius University, Sasinkova 4, 811 08 Bratislava, Slovak Republic

* Corresponding author. Tel: +421 2 50117 376, Fax: +421 2 50117 100, Email: krenek{at}fpharm.uniba.sk


  Abstract

Aims: The role of nitric oxide (NO) in heart failure (HF) is complex and remains controversial. We tested the hypothesis that the role of NO in isolated atria and cardiomyocytes is altered in isoproterenol-induced HF.

Methods and results: Rats received isoproterenol (ISO, 5 mg/kg/day, intraperitoneally) or vehicle for 1 week. Haemodynamic parameters were obtained by left ventricular catheterization. Effects of NOS inhibition on isolated atria and on electrically paced left ventricular myocytes were determined. Additionally, expressions of nitric oxide synthases and their allosteric modulators hsp90, caveolin-1, and caveolin-3 proteins in the left ventricles were measured. ISO increased left ventricular mass by 33% and decreased indices of left ventricular systolic and diastolic function dp/dtmin and dp/dtmax (both P < 0.05). Isolated atria from HF rats had a lower spontaneous beating rate (P < 0.05). NOS inhibition by L-NAME increased basal frequency and attenuated the positive chronotropic effect of beta-adrenergic stimulation in the HF group (P < 0.05). Ventricular myocytes from failing hearts had impaired cell shortening. L-NAME decreased contractility of control, but not failing myocytes. Left ventricular expressions of eNOS, hsp90, iNOS, but not nNOS or caveolins, were increased.

Conclusion: Despite the increased capacity for NO synthesis in isoproterenol-induced HF, NO does not sustain contractility of failing myocytes. NO may contribute to the decreased basal heart rate and it may accelerate beta-adrenergic stimulation of chronotropy.

Key Words: Isoproterenol-induced heart failure • Nitric oxide • Nitric oxide synthases • Heart rate • Ventricular function

Received July 7, 2008; Revised October 9, 2008; Accepted October 11, 2008


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