Cyclic guanosine monophosphate compartmentation in rat cardiac myocytes.
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.


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.
Castro
Liliana R V
LR
INSERM, U769, Châtenay-Malabry, France.
Verde
Ignacio
I
Cooper
Dermot M F
DM
Fischmeister
Rodolphe
R
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000502:physiology; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D001692:Biological Transport; D002451:Cell Compartmentation; D002462:Cell Membrane / Q000378:metabolism; D000242:Cyclic AMP / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism* / Q000494:pharmacology; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D054815:Cyclic Nucleotide-Gated Cation Channels; D006352:Heart Ventricles / Q000166:cytology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D007473:Ion Channels / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology; D008297:Male; D032383:Myocytes, Cardiac / Q000737:chemistry* / Q000187:drug effects / Q000648:ultrastructure; D020097:Natriuretic Peptide, Brain / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology; D011687:Purines; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000032:analysis / Q000502:physiology; D012508:Sarcolemma / Q000378:metabolism; D015290:Second Messenger Systems; D000068677:Sildenafil Citrate; D012995:Solubility; D013450:Sulfones
D054815:Cyclic Nucleotide-Gated Cation Channels; D007473:Ion Channels; D007527:Isoenzymes; D020030:Nitric Oxide Donors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D011993:Recombinant Fusion Proteins; D013450:Sulfones; D020097:Natriuretic Peptide, Brain; C010192:9-(2-hydroxy-3-nonyl)adenine; D009320:Atrial Natriuretic Factor; D000068677:Sildenafil Citrate; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; C517275:PDE2A protein, human; C517278:Pde2a protein, rat; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; C517384:Pde5a protein, rat; D006152:Cyclic GMP; D000225:Adenine; D015056:1-Methyl-3-isobutylxanthine