Document Detail

Cyclic guanosine monophosphate compartmentation in rat cardiac myocytes.
MedLine Citation:
PMID:  16651469     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Cyclic guanosine monophosphate (cGMP) is the common second messenger for the cardiovascular effects of nitric oxide (NO) and natriuretic peptides, such as atrial or brain natriuretic peptide, which activate the soluble and particulate forms of guanylyl cyclase, respectively. However, natriuretic peptides and NO donors exert different effects on cardiac and vascular smooth muscle function. We therefore tested whether these differences are due to an intracellular compartmentation of cGMP and evaluated the role of phosphodiesterase (PDE) subtypes in this process.
METHODS AND RESULTS: Subsarcolemmal cGMP signals were monitored in adult rat cardiomyocytes by expression of the rat olfactory cyclic nucleotide-gated (CNG) channel alpha-subunit and recording of the associated cGMP-gated current (ICNG). Atrial natriuretic peptide (10 nmol/L) or brain natriuretic peptide (10 nmol/L) induced a clear activation of ICNG, whereas NO donors (S-nitroso-N-acetyl-penicillamine, diethylamine NONOate, 3-morpholinosydnonimine, and spermine NO, all at 100 micromol/L) had little effect. The ICNG current was strongly potentiated by nonselective PDE inhibition with isobutyl methylxanthine (100 micromol/L) and by the PDE2 inhibitors erythro-9-(2-hydroxy-3-nonyl)adenine (10 micromol/L) and Bay 60-7550 (50 nmol/L). Surprisingly, sildenafil, a PDE5 inhibitor, produced a dose-dependent increase of I(CNG) activated by NO donors but had no effect (at 100 nmol/L) on the current elicited by atrial natriuretic peptide.
CONCLUSIONS: These results indicate that in rat cardiomyocytes (1) the particulate cGMP pool is readily accessible at the plasma membrane, whereas the soluble pool is not; and (2) PDE5 controls the soluble but not the particulate pool, whereas the latter is under the exclusive control of PDE2. Differential spatiotemporal distributions of cGMP may therefore contribute to the specific effects of natriuretic peptides and NO donors on cardiac function.
Liliana R V Castro; Ignacio Verde; Dermot M F Cooper; Rodolphe Fischmeister
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-05-01
Journal Detail:
Title:  Circulation     Volume:  113     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2006 May 
Date Detail:
Created Date:  2006-05-10     Completed Date:  2006-06-07     Revised Date:  2013-06-07    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2221-8     Citation Subset:  AIM; IM    
INSERM, U769, Châtenay-Malabry, France.
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MeSH Terms
1-Methyl-3-isobutylxanthine / pharmacology
3',5'-Cyclic-GMP Phosphodiesterases / physiology
Adenine / analogs & derivatives,  pharmacology
Atrial Natriuretic Factor / pharmacology
Biological Transport
Cell Compartmentation*
Cell Membrane / metabolism
Cyclic AMP / pharmacology
Cyclic GMP / metabolism*,  pharmacology
Cyclic Nucleotide Phosphodiesterases, Type 2
Cyclic Nucleotide Phosphodiesterases, Type 5
Cyclic Nucleotide-Gated Cation Channels
Heart Ventricles / cytology
Ion Channel Gating / drug effects
Ion Channels / analysis,  antagonists & inhibitors,  physiology*
Isoenzymes / antagonists & inhibitors,  physiology
Myocytes, Cardiac / chemistry*,  drug effects,  ultrastructure
Natriuretic Peptide, Brain / pharmacology
Nitric Oxide Donors / pharmacology
Phosphodiesterase Inhibitors / pharmacology
Phosphoric Diester Hydrolases / physiology
Piperazines / pharmacology
Rats, Wistar
Recombinant Fusion Proteins / analysis,  physiology
Sarcolemma / metabolism
Second Messenger Systems*
Reg. No./Substance:
0/Cyclic Nucleotide-Gated Cation Channels; 0/Ion Channels; 0/Isoenzymes; 0/Nitric Oxide Donors; 0/Phosphodiesterase Inhibitors; 0/Piperazines; 0/Purines; 0/Recombinant Fusion Proteins; 0/Sulfones; 114471-18-0/Natriuretic Peptide, Brain; 28822-58-4/1-Methyl-3-isobutylxanthine; 3M7OB98Y7H/sildenafil; 59262-86-1/9-(2-hydroxy-3-nonyl)adenine; 60-92-4/Cyclic AMP; 73-24-5/Adenine; 7665-99-8/Cyclic GMP; 85637-73-6/Atrial Natriuretic Factor; EC 3.1.4.-/Phosphoric Diester Hydrolases; EC Nucleotide Phosphodiesterases, Type 2; EC protein, human; EC protein, rat; EC',5'-Cyclic-GMP Phosphodiesterases; EC Nucleotide Phosphodiesterases, Type 5; EC protein, human; EC protein, rat

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