Published Online
on September 17, 2008

A more recent version of this article appeared on November 1, 2008

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Original Article

Elevated Afterload, Neuroendocrine Stimulation and Human Heart Failure Increase BNP Levels and Inhibit Preload-Dependent SERCA Upregulation

Karl Toischer^1,4; Harald Kögler²; Gero Tenderich³; Cornelia Grebe¹; Tim Seidler¹; Phuc Nguyen Van¹; Klaus Jung¹; Ralf Knöll¹; Reiner Körfer³ and Gerd Hasenfuss¹

¹ University of Göttingen, Göttingen, Germany;
² Georg-August-Universitat Göttingen, Germany;
³ Herz- und Diabeteszentrum NRW, Bad Oeynhausen, Germany

⁴ E-mail: toischer{at}gmx.de

Background—In heart failure, brain natriuretic peptide (BNP) is elevated and the sarcoplasmic reticulum Ca²⁺-ATPase 2a (SERCA) downregulated. We previously showed that preload-induced SERCA-upregulation is suppressed by exogenous BNP.

Methods and Results—Here we tested the hypothesis that afterload and neurohumoral activation would counterregulate preload-dependent SERCA upregulation through BNP, which finally results in decreased SERCA levels. We studied the effects of 6 hours preload, afterload and isoproterenol stimulation on BNP and SERCA mRNA expression in rabbit and human failing muscles strips. Preload resulted in a pronounced upregulation of SERCA by 149% (isotonic vs. slack, P<0.01). This upregulation was largely suppressed in afterloaded muscles (isometric vs. slack: +32%; P<0.05). Similarly, presence of isoproterenol prevented SERCA upregulation in isotonic muscles. Afterload and isoproterenol resulted in a pronounced increase in BNP-expression compared to slack by 225% (P<0.05) and 198% (P<0.01), respectively. Isoproterenol also increased expression of PLB by 84% (p<0.01). SERCA-upregulation in preloaded muscles is associated with frequency potentiation of contractile force, which is absent in afterloaded muscles. In failing human myocardium, BNP expression was upregulated compared to nonfailing (+631%; p<0.05). Neither unloading, nor pre- or afterload induced a change in SERCA or BNP expression after 6 hours.

Conclusions—Afterload and neuroendocrine stimulation increase BNP expression thereby causing inhibition of preload-dependent SERCA upregulation. In failing human myocardium, high BNP expression may underlie the loss of preload-dependent upregulation of SERCA. BNP may thus contribute to adverse myocardial remodelling in heart failure.

Key Words: calcium • heart failure • mechanics • natriuretic peptides • sarcoplasmic reticulum