Published online before print May 1, 2006, doi: 10.1161/CIRCULATIONAHA.105.599241
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(Circulation. 2006;113:2221-2228.)
© 2006 American Heart Association, Inc.
Molecular Cardiology |
Cyclic Guanosine Monophosphate Compartmentation in Rat Cardiac Myocytes
From INSERM, U769, Châtenay-Malabry, France (L.R.V.C., R.F.); University Paris-Sud 11, Faculté de Pharmacie, Châtenay-Malabry, France (L.R.V.C., R.F.); Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, Covilhã, Portugal (L.R.V.C., I.V.); and Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom (D.M.F.C.).
Correspondence to Rodolphe Fischmeister, PhD, INSERM, U769, Faculté de Pharmacie, 5 Rue J.-B. Clément, F-92296 Châtenay-Malabry Cedex, France. E-mail fisch{at}vjf.inserm.fr
Received November 2, 2005; revision received February 23, 2006; accepted March 3, 2006.
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 
-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 µmol/L) had little effect. The ICNG current was strongly potentiated by nonselective PDE inhibition with isobutyl methylxanthine (100 µmol/L) and by the PDE2 inhibitors erythro-9-(2-hydroxy-3-nonyl)adenine (10 µmol/L) and Bay 60-7550 (50 nmol/L). Surprisingly, sildenafil, a PDE5 inhibitor, produced a dose-dependent increase of ICNG 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.
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