RT Journal Article
SR Electronic
T1 Different Compartmentation of Responses to Brain Natriuretic Peptide and C-Type Natriuretic Peptide in Failing Rat Ventricle
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 681
OP 690
DO 10.1124/jpet.114.214882
VO 350
IS 3
A1 Moltzau, Lise Román
A1 Aronsen, Jan Magnus
A1 Meier, Silja
A1 Skogestad, Jonas
A1 Ørstavik, Øivind
A1 Lothe, Gustav B.
A1 Sjaastad, Ivar
A1 Skomedal, Tor
A1 Osnes, Jan-Bjørn
A1 Levy, Finn Olav
A1 Qvigstad, Eirik
YR 2014
UL http://jpet.aspetjournals.org/content/350/3/681.abstract
AB 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 Ca2+ transient. BNP did not increase phospholamban (PLB) or troponin I (TnI) phosphorylation, Ca2+ extrusion rate constant, or sarcoplasmatic reticulum Ca2+ load, whereas CNP did. Both BNP and CNP reduced the peak of the L-type Ca2+ 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.