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Advisor(s)
Abstract(s)
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 mol/L)
had little effect. The ICNG current was strongly potentiated by nonselective PDE inhibition with isobutyl methylxanthine (100
mol/L) and by the PDE2 inhibitors erythro-9-(2-hydroxy-3-nonyl)adenine (10 mol/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.