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Differential regulation of C-type natriuretic peptide-induced cGMP and functional responses by PDE2 and PDE3 in failing myocardium

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Abstract

Recently, we showed C-type natriuretic peptide (CNP)-induced negative inotropic (NIR) and positive lusitropic response (LR) in failing rat heart. We wanted to study whether, and if so, how phosphodiesterases (PDEs) regulate CNP-induced cyclic 3′,5′-guanosine monophosphate (cGMP) elevation and functional responses. Inotropic and lusitropic responses were measured in left ventricular muscle strips and cyclic nucleotide levels, PDE activity and phospholamban (PLB) and troponin I (TnI) phosphorylation were measured in ventricular cardiomyocytes from Wistar rats with heart failure 6 weeks after myocardial infarction. CNP-mediated increase in global cGMP was mainly regulated by PDE2, as reflected by a marked amplification of the cGMP increase during PDE2 inhibition and by a high PDE2 activity in cardiomyocytes. PDE3 inhibition, on the other hand, caused no significant cGMP increase by CNP. The functional consequences did not correspond to the changes of cGMP. PDE3 inhibition increased the potency of the CNP-induced NIR and LR, while PDE2 inhibition desensitized the CNP-induced NIR, but not LR. A role for PDE2 on the maximal LR and PDE5 on the maximal NIR to CNP was revealed in the presence of PDE3 inhibition. CNP increased PLB phosphorylation about 25- to 30-fold and tended to increase TnI phosphorylation about twofold. As a whole, CNP-induced functional responses were only modestly regulated by PDEs compared to the cAMP-mediated functional responses to β1-adrenoceptor stimulation, which are highly regulated by PDEs. There is a mismatch between the CNP-induced cGMP increase and functional responses. Global cGMP levels are mainly regulated by PDE2 after CNP stimulation, whereas the functional responses are modestly regulated by both PDE2 and PDE3, indicating cGMP compartmentation by PDEs affecting CNP-induced responses in failing hearts.

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Acknowledgments

We would like to thank Iwona Gutowska Schiander for isolation of cardiomyocytes and Cam HT Nguyen and Marie Dahl for performing Western blot experiments. This work was supported by The Norwegian Council on Cardiovascular Disease, The Research Council of Norway, Stiftelsen Kristian Gerhard Jebsen, Anders Jahre’s Foundation for the Promotion of Science, The Family Blix Foundation, The Simon Fougner Hartmann Foundation, South-Eastern Norway Regional Health Authority, University of Oslo and the COST Action BM1005 (European Network on Gasotransmitters).

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Authors and Affiliations

  1. Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Sognsvannsveien 20, P.O. Box 1057 Blindern, N-0316, Oslo, Norway

    Lise Román Moltzau, Silja Meier, Faraz Afzal, Tor Skomedal, Jan-Bjørn Osnes, Finn Olav Levy & Eirik Qvigstad

  2. K.G. Jebsen Cardiac Research Centre and Centre for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway

    Lise Román Moltzau, Silja Meier, Jan Magnus Aronsen, Faraz Afzal, Ivar Sjaastad, Tor Skomedal, Jan-Bjørn Osnes, Finn Olav Levy & Eirik Qvigstad

  3. Institute for Experimental Medical Research, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway

    Jan Magnus Aronsen & Ivar Sjaastad

  4. Bjørknes College, Oslo, Norway

    Jan Magnus Aronsen

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  1. Lise Román Moltzau
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Correspondence to Finn Olav Levy.

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Moltzau, L.R., Meier, S., Aronsen, J.M. et al. Differential regulation of C-type natriuretic peptide-induced cGMP and functional responses by PDE2 and PDE3 in failing myocardium. Naunyn-Schmiedeberg's Arch Pharmacol 387, 407–417 (2014). https://doi.org/10.1007/s00210-013-0953-1

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