title: Different compartmentation of responses to brain natriuretic peptide and C-type natriuretic peptide in failing rat ventricle.
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.
authors.affiliation: Department of Pharmacology (L.R.M., S.M., Ø.Ø., T.S., J.-B.O., F.O.L., E.Q.) and Institute for Experimental Medical Research (J.M.A., J.S., G.B.L., I.S.), Institute of Clinical Medicine, University of Oslo and Oslo University Hospital; K. G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway (L.R.M., S.M., J.S., Ø.Ø., I.S., T.S., J.-B.O., F.O.L., E.Q.); and Bjørknes College, Oslo, Norway (J.M.A., G.B.L.).
authors.forename: Lise Román
authors.initials: LR
authors.lastname: Moltzau
authors.affiliation: Department of Pharmacology (L.R.M., S.M., Ø.Ø., T.S., J.-B.O., F.O.L., E.Q.) and Institute for Experimental Medical Research (J.M.A., J.S., G.B.L., I.S.), Institute of Clinical Medicine, University of Oslo and Oslo University Hospital; K. G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway (L.R.M., S.M., J.S., Ø.Ø., I.S., T.S., J.-B.O., F.O.L., E.Q.); and Bjørknes College, Oslo, Norway (J.M.A., G.B.L.).
authors.forename: Jan Magnus
authors.initials: JM
authors.lastname: Aronsen
authors.affiliation: Department of Pharmacology (L.R.M., S.M., Ø.Ø., T.S., J.-B.O., F.O.L., E.Q.) and Institute for Experimental Medical Research (J.M.A., J.S., G.B.L., I.S.), Institute of Clinical Medicine, University of Oslo and Oslo University Hospital; K. G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway (L.R.M., S.M., J.S., Ø.Ø., I.S., T.S., J.-B.O., F.O.L., E.Q.); and Bjørknes College, Oslo, Norway (J.M.A., G.B.L.).
authors.forename: Silja
authors.initials: S
authors.lastname: Meier
authors.affiliation: Department of Pharmacology (L.R.M., S.M., Ø.Ø., T.S., J.-B.O., F.O.L., E.Q.) and Institute for Experimental Medical Research (J.M.A., J.S., G.B.L., I.S.), Institute of Clinical Medicine, University of Oslo and Oslo University Hospital; K. G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway (L.R.M., S.M., J.S., Ø.Ø., I.S., T.S., J.-B.O., F.O.L., E.Q.); and Bjørknes College, Oslo, Norway (J.M.A., G.B.L.).
authors.forename: Jonas
authors.initials: J
authors.lastname: Skogestad
authors.affiliation: Department of Pharmacology (L.R.M., S.M., Ø.Ø., T.S., J.-B.O., F.O.L., E.Q.) and Institute for Experimental Medical Research (J.M.A., J.S., G.B.L., I.S.), Institute of Clinical Medicine, University of Oslo and Oslo University Hospital; K. G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway (L.R.M., S.M., J.S., Ø.Ø., I.S., T.S., J.-B.O., F.O.L., E.Q.); and Bjørknes College, Oslo, Norway (J.M.A., G.B.L.).
authors.forename: Øivind
authors.initials: Ø
authors.lastname: Ørstavik
authors.affiliation: Department of Pharmacology (L.R.M., S.M., Ø.Ø., T.S., J.-B.O., F.O.L., E.Q.) and Institute for Experimental Medical Research (J.M.A., J.S., G.B.L., I.S.), Institute of Clinical Medicine, University of Oslo and Oslo University Hospital; K. G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway (L.R.M., S.M., J.S., Ø.Ø., I.S., T.S., J.-B.O., F.O.L., E.Q.); and Bjørknes College, Oslo, Norway (J.M.A., G.B.L.).
authors.forename: Gustav B
authors.initials: GB
authors.lastname: Lothe
authors.affiliation: Department of Pharmacology (L.R.M., S.M., Ø.Ø., T.S., J.-B.O., F.O.L., E.Q.) and Institute for Experimental Medical Research (J.M.A., J.S., G.B.L., I.S.), Institute of Clinical Medicine, University of Oslo and Oslo University Hospital; K. G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway (L.R.M., S.M., J.S., Ø.Ø., I.S., T.S., J.-B.O., F.O.L., E.Q.); and Bjørknes College, Oslo, Norway (J.M.A., G.B.L.).
authors.forename: Ivar
authors.initials: I
authors.lastname: Sjaastad
authors.affiliation: Department of Pharmacology (L.R.M., S.M., Ø.Ø., T.S., J.-B.O., F.O.L., E.Q.) and Institute for Experimental Medical Research (J.M.A., J.S., G.B.L., I.S.), Institute of Clinical Medicine, University of Oslo and Oslo University Hospital; K. G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway (L.R.M., S.M., J.S., Ø.Ø., I.S., T.S., J.-B.O., F.O.L., E.Q.); and Bjørknes College, Oslo, Norway (J.M.A., G.B.L.).
authors.forename: Tor
authors.initials: T
authors.lastname: Skomedal
authors.affiliation: Department of Pharmacology (L.R.M., S.M., Ø.Ø., T.S., J.-B.O., F.O.L., E.Q.) and Institute for Experimental Medical Research (J.M.A., J.S., G.B.L., I.S.), Institute of Clinical Medicine, University of Oslo and Oslo University Hospital; K. G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway (L.R.M., S.M., J.S., Ø.Ø., I.S., T.S., J.-B.O., F.O.L., E.Q.); and Bjørknes College, Oslo, Norway (J.M.A., G.B.L.).
authors.forename: Jan-Bjørn
authors.initials: JB
authors.lastname: Osnes
authors.affiliation: Department of Pharmacology (L.R.M., S.M., Ø.Ø., T.S., J.-B.O., F.O.L., E.Q.) and Institute for Experimental Medical Research (J.M.A., J.S., G.B.L., I.S.), Institute of Clinical Medicine, University of Oslo and Oslo University Hospital; K. G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway (L.R.M., S.M., J.S., Ø.Ø., I.S., T.S., J.-B.O., F.O.L., E.Q.); and Bjørknes College, Oslo, Norway (J.M.A., G.B.L.) f.o.levy@medisin.uio.no.
authors.forename: Finn Olav
authors.initials: FO
authors.lastname: Levy
authors.affiliation: Department of Pharmacology (L.R.M., S.M., Ø.Ø., T.S., J.-B.O., F.O.L., E.Q.) and Institute for Experimental Medical Research (J.M.A., J.S., G.B.L., I.S.), Institute of Clinical Medicine, University of Oslo and Oslo University Hospital; K. G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway (L.R.M., S.M., J.S., Ø.Ø., I.S., T.S., J.-B.O., F.O.L., E.Q.); and Bjørknes College, Oslo, Norway (J.M.A., G.B.L.).
authors.forename: Eirik
authors.initials: E
authors.lastname: Qvigstad
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D020098:Natriuretic Peptide, C-Type / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology
chemical_list: D020097:Natriuretic Peptide, Brain; D020098:Natriuretic Peptide, C-Type