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

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Type 5 Cyclic Nucleotide Phosphodiesterases
Cyclic GMP-Dependent Protein Kinases
Atrial Natriuretic Factor
Isoproterenol
Adrenergic Agents
Natriuretic Peptides
Nitric Oxide Synthase
Hydrolysis
Adrenergic Antagonists
Drug and Narcotic Control
Phosphoric Diester Hydrolases
Protein Kinase Inhibitors
Vasodilator Agents
Fluorescence Microscopy
Cardiac Myocytes
Muscle Cells
Nitric Oxide
Enzyme-Linked Immunosorbent Assay
Phosphorylation
Sildenafil Citrate

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Takimoto, E., Belardi, D., Tocchetti, C. G., Vahebi, S., Cormaci, G., Ketner, E. A., ... 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

Compartmentalization of cardiac β-adrenergic inotropy modulation by phosphodiesterase type 5. / Takimoto, Eiki; Belardi, Diego; Tocchetti, Carlo G.; Vahebi, Susan; Cormaci, Gianfrancesco; Ketner, Elizabeth A.; Moens, An L.; Champion, Hunter C.; Kass, David A.

In: Circulation, Vol. 115, No. 16, 04.2007, p. 2159-2167.

Research output: Contribution to journalArticle

Takimoto, E, Belardi, D, Tocchetti, CG, Vahebi, S, Cormaci, G, Ketner, EA, Moens, AL, Champion, HC & Kass, DA 2007, 'Compartmentalization of cardiac β-adrenergic inotropy modulation by phosphodiesterase type 5', Circulation, vol. 115, no. 16, pp. 2159-2167. https://doi.org/10.1161/CIRCULATIONAHA.106.643536
Takimoto E, Belardi D, Tocchetti CG, Vahebi S, Cormaci G, Ketner EA et al. Compartmentalization of cardiac β-adrenergic inotropy modulation by phosphodiesterase type 5. Circulation. 2007 Apr;115(16):2159-2167. https://doi.org/10.1161/CIRCULATIONAHA.106.643536
Takimoto, Eiki ; Belardi, Diego ; Tocchetti, Carlo G. ; Vahebi, Susan ; Cormaci, Gianfrancesco ; Ketner, Elizabeth A. ; Moens, An L. ; Champion, Hunter C. ; Kass, David A. / Compartmentalization of cardiac β-adrenergic inotropy modulation by phosphodiesterase type 5. In: Circulation. 2007 ; Vol. 115, No. 16. pp. 2159-2167.
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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.",
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AU - Takimoto, Eiki

AU - Belardi, Diego

AU - Tocchetti, Carlo G.

AU - Vahebi, Susan

AU - Cormaci, Gianfrancesco

AU - Ketner, Elizabeth A.

AU - Moens, An L.

AU - Champion, Hunter C.

AU - Kass, David A

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N2 - 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.

AB - 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.

KW - Catecholamines

KW - Contractility

KW - Cyclic GMP

KW - Myocytes

KW - Natriuretic peptides

KW - Nitric oxide synthase

KW - Phosphodiesterases, type 5

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