Compartmentalization of cardiac β-adrenergic inotropy modulation by phosphodiesterase type 5

Eiki Takimoto, Diego Belardi, Carlo G. Tocchetti, Susan Vahebi, Gianfrancesco Cormaci, Elizabeth A. Ketner, An L. Moens, Hunter C. Champion, David A. Kass

Research output: Contribution to journalArticle

Abstract

BACKGROUND - Recent cell-based studies have found that cGMP synthesis and hydrolysis by phosphodiesterase (PDE) appear compartmentalized, with nitric oxide synthase-derived and/or PDE type 5 (PDE-5)-hydrolyzable cGMP undetected at the sarcolemmal membrane in contrast to cGMP stimulated by natriuretic peptide. In the present study, we determine the functional significance of such compartments with a comparison of β-adrenergic modulation by PDE-5 inhibition to that of natriuretic peptide stimulation in both cardiomyocytes and intact hearts. The potential role of differential cGMP and protein kinase G stimulation by these 2 modulators was also studied. METHODS AND RESULTS - Intact C57/BL6 mouse hearts were studied with pressure-volume analysis, and adult isolated myocytes were studied with fluorescence microscopy. PDE-5 inhibition with 0.1 to 1 μmol/L sildenafil (SIL) suppressed isoproterenol (ISO)-stimulated contractility, whereas 10 μmol/L atrial natriuretic peptide (ANP) had no effect. ISO suppression by SIL was prevented in cells pretreated with a protein kinase G inhibitor. Surprisingly, myocardial cGMP changed little with SIL+ISO yet rose nearly 5-fold with ANP, whereas protein kinase G activation (vasodilator-stimulated protein phosphorylation; ELISA assay) displayed the opposite: increased with SIL+ISO but unaltered by ANP+ISO. PDE-5 and ANP compartments were functionally separated, as inhibition of nitric oxide synthase by N-nitro-L-arginine methyl ester eliminated antiadrenergic effects of SIL, yet this was not restorable by co-stimulation with ANP. CONCLUSIONS - Regulation of cardiac β-adrenergic response by cGMP is specifically linked to a nitric oxide-synthesis/PDE-5-hydrolyzed pool signaling via protein kinase G. Natriuretic peptide stimulation achieves greater detectable increases in cGMP but not protein kinase G activity and does not modulate β-adrenergic response. Such disparities likely contribute to differential cardiac regulation by drugs that modulate cGMP synthesis and hydrolysis.

Original languageEnglish (US)
Pages (from-to)2159-2167
Number of pages9
JournalCirculation
Volume115
Issue number16
DOIs
StatePublished - Apr 2007

Keywords

  • Catecholamines
  • Contractility
  • Cyclic GMP
  • Myocytes
  • Natriuretic peptides
  • Nitric oxide synthase
  • Phosphodiesterases, type 5

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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  • Cite this

    Takimoto, E., Belardi, D., Tocchetti, C. G., Vahebi, S., Cormaci, G., Ketner, E. A., Moens, A. L., Champion, H. C., & Kass, D. A. (2007). Compartmentalization of cardiac β-adrenergic inotropy modulation by phosphodiesterase type 5. Circulation, 115(16), 2159-2167. https://doi.org/10.1161/CIRCULATIONAHA.106.643536