Journal of Pharmacology and Experimental Therapeutics 2014-09-01

Different compartmentation of responses to brain natriuretic peptide and C-type natriuretic peptide in failing rat ventricle.

Lise Román Moltzau, Jan Magnus Aronsen, Silja Meier, Jonas Skogestad, Øivind Ørstavik, Gustav B Lothe, Ivar Sjaastad, Tor Skomedal, Jan-Bjørn Osnes, Finn Olav Levy, Eirik Qvigstad

Index: J. Pharmacol. Exp. Ther. 350(3) , 681-90, (2014)

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Abstract

We previously found a negative inotropic (NIR) and positive lusitropic response (LR) to C-type natriuretic peptide (CNP) in the failing heart ventricle. In this study, we investigated and compared the functional responses to the natriuretic peptides (NPs), brain (BNP) and C-type natriuretic peptide (CNP), and relate them to cGMP regulation and effects on downstream targets. Experiments were conducted in left ventricular muscle strips and ventricular cardiomyocytes from Wistar rats with heart failure 6 weeks after myocardial infarction. As opposed to CNP, BNP did not cause an NIR or LR, despite increasing cGMP levels. The BNP-induced cGMP elevation was mainly and markedly regulated by phosphodiesterase (PDE) 2 and was only marginally increased by PDE3 or PDE5 inhibition. Combined PDE2, -3, and -5 inhibition failed to reveal any functional responses to BNP, despite an extensive cGMP elevation. BNP decreased, whereas CNP increased, the amplitude of the Ca(2+) transient. BNP did not increase phospholamban (PLB) or troponin I (TnI) phosphorylation, Ca(2+) extrusion rate constant, or sarcoplasmatic reticulum Ca(2+) load, whereas CNP did. Both BNP and CNP reduced the peak of the L-type Ca(2+) current. Cyclic GMP elevations by BNP and CNP in cardiomyocytes were additive, and the presence of BNP did not alter the NIR to CNP or the CNP-induced PLB and TnI phosphorylation. However, a small increase in the LR to maximal CNP was observed in the presence of BNP. In conclusion, different responses to cGMP generated by BNP and CNP suggest different compartmentation of the cGMP signal and different roles of the two NPs in the failing heart. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.