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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

Circulation (New York, N.Y.), 2007-04, Vol.115 (16), p.2159-2167 [Periódico revisado por pares]

Hagerstown, MD: Lippincott Williams & Wilkins

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Título:
Compartmentalization of cardiac β-adrenergic inotropy modulation by phosphodiesterase type 5
Autor: TAKIMOTO, Eiki ; BELARDI, Diego ; TOCCHETTI, Carlo G ; VAHEBI, Susan ; CORMACI, Gianfrancesco ; KETNER, Elizabeth A ; MOENS, An L ; CHAMPION, Hunter C ; KASS, David A
Assuntos: 3',5'-Cyclic-GMP Phosphodiesterases - antagonists & inhibitors ; 3',5'-Cyclic-GMP Phosphodiesterases - physiology ; Animals ; Arterial hypertension. Arterial hypotension ; Atrial Natriuretic Factor - pharmacology ; Biological and medical sciences ; Blood and lymphatic vessels ; Cardiology. Vascular system ; Cell Compartmentation - physiology ; Cell Membrane - enzymology ; Cells, Cultured - drug effects ; Cells, Cultured - physiology ; Clinical manifestations. Epidemiology. Investigative techniques. Etiology ; Cyclic GMP - physiology ; Cyclic GMP-Dependent Protein Kinases - antagonists & inhibitors ; Cyclic GMP-Dependent Protein Kinases - physiology ; Cyclic Nucleotide Phosphodiesterases, Type 5 ; Cytosol - enzymology ; Diabetes. Impaired glucose tolerance ; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous ; Endocrine pancreas. Apud cells (diseases) ; Endocrinopathies ; Enzyme Activation - drug effects ; Guanylate Cyclase - metabolism ; Isoproterenol - pharmacology ; Male ; Management. Various non-drug treatments. Langerhans islet grafts ; Medical sciences ; Mice ; Mice, Inbred C57BL ; Myocardial Contraction - drug effects ; Myocardial Contraction - physiology ; Myocytes, Cardiac - drug effects ; Myocytes, Cardiac - physiology ; NG-Nitroarginine Methyl Ester - pharmacology ; Nitric Oxide - physiology ; Phosphodiesterase Inhibitors - pharmacology ; Piperazines - pharmacology ; Protein Kinase Inhibitors - pharmacology ; Purines - pharmacology ; Receptors, Adrenergic, beta - drug effects ; Receptors, Adrenergic, beta - physiology ; Second Messenger Systems - physiology ; Sildenafil Citrate ; Sulfones - pharmacology
É parte de: Circulation (New York, N.Y.), 2007-04, Vol.115 (16), p.2159-2167
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
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Descrição: 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 beta-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. 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 micromol/L sildenafil (SIL) suppressed isoproterenol (ISO)-stimulated contractility, whereas 10 micromol/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(w)-nitro-L-arginine methyl ester eliminated antiadrenergic effects of SIL, yet this was not restorable by co-stimulation with ANP. Regulation of cardiac beta-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 beta-adrenergic response. Such disparities likely contribute to differential cardiac regulation by drugs that modulate cGMP synthesis and hydrolysis.
Editor: Hagerstown, MD: Lippincott Williams & Wilkins
Idioma: Inglês

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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

Hagerstown, MD: Lippincott Williams & Wilkins

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