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Original Articles

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

Karl Toischer, MD; Harald Kögler, MD; Gero Tenderich, MD; Cornelia Grebe, MSc; Tim Seidler, MD; Phuc Nguyen Van, PhD; Klaus Jung, PhD; Ralph Knöll, MD; Reiner Körfer, MD and Gerd Hasenfuss, MD

From the Abteilung Kardiologie und Pneumologie, Georg-August-Universität, Göttingen, Germany (K.J., H.K., C.G., T.S., P.N.V., G.H.); Abteilung Herz- und Thoraxchirurgie, Herz- und Diabeteszentrum NRW, Bad Oeynhausen, Germany (G.T., R.K.); and Abteilung Medizinische Statistik (K.J.) and Kardiovaskuläre Molekulargenetik, Herzzentrum, Georg-August-Universität, Göttingen, Germany (R.K.).

Correspondence to Karl Toischer, MD, Abteilung Kardiologie und Pneumologie, Universität Göttingen, Robert-Koch-Str. 40, D – 37075 Göttingen, Germany. E-mail ktoischer{at}med.uni-goettingen.de

Received April 15, 2008; accepted August 26, 2008.

Background— In heart failure, brain-type natriuretic peptide (BNP) is elevated and the sarcoplasmic reticulum Ca²⁺-ATPase (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 versus slack, P<0.01). This upregulation was largely suppressed in afterloaded muscles (isometric versus 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 with slack by 225% (P<0.05) and 198% (P<0.01), respectively. Isoproterenol also increased expression of phospholamban by 84% (P<0.01). SERCA upregulation in preloaded muscles is associated with frequency-dependent potentiation of contractile force, which is absent in afterloaded muscles. In failing human myocardium, BNP expression was upregulated compared with nonfailing (+631%; P<0.05). Neither unloading nor preload 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

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