Efficacy of B-Type Natriuretic Peptide Is Coupled to Phosphodiesterase 2A in Cardiac Sympathetic Neurons.
Elevated B-type natriuretic peptide (BNP) regulates cGMP-phosphodiesterase activity. Its elevation is regarded as an early compensatory response to cardiac failure where it can facilitate sympathovagal balance and cardiorenal homeostasis. However, recent reports suggest a paradoxical proadrenergic action of BNP. Because phosphodiesterase activity is altered in cardiovascular disease, we tested the hypothesis that BNP might lose its efficacy by minimizing the action of cGMP on downstream pathways coupled to neurotransmission. BNP decreased norepinephrine release from atrial preparations in response to field stimulation and also significantly reduced the heart rate responses to sympathetic nerve stimulation in vitro. Using electrophysiological recording and fluorescence imaging, BNP also reduced the depolarization evoked calcium current and intracellular calcium transient in isolated cardiac sympathetic neurons. Pharmacological manipulations suggested that the reduction in the calcium transient was regulated by a cGMP/protein kinase G pathway. Fluorescence resonance energy transfer measurements for cAMP, and an immunoassay for cGMP, showed that BNP increased cGMP, but not cAMP. In addition, overexpression of phosphodiesterase 2A after adenoviral gene transfer markedly decreased BNP stimulation of cGMP and abrogated the BNP responses to the calcium current, intracellular calcium transient, and neurotransmitter release. These effects were reversed on inhibition of phosphodiesterase 2A. Moreover, phosphodiesterase 2A activity was significantly elevated in stellate neurons from the prohypertensive rat compared with the normotensive control. Our data suggest that abnormally high levels of phosphodiesterase 2A may provide a brake against the inhibitory action of BNP on sympathetic transmission.
From the Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom. dan.li@dpag.ox.ac.uk david.paterson@dpag.ox.ac.uk.
Dan
D
Li
From the Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
Chieh-Ju
CJ
Lu
From the Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
Guoliang
G
Hao
From the Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
Hannah
H
Wright
From the Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
Lavinia
L
Woodward
From the Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
Kun
K
Liu
From the Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
Elisa
E
Vergari
From the Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
Nicoletta C
NC
Surdo
From the Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
Neil
N
Herring
From the Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
Manuela
M
Zaccolo
From the Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom. dan.li@dpag.ox.ac.uk david.paterson@dpag.ox.ac.uk.
David J
DJ
Paterson
D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000502:physiology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000502:physiology; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000235:genetics / Q000502:physiology*; D006329:Heart Conduction System / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D006339:Heart Rate; D006973:Hypertension / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D007510:Isatin / Q000494:pharmacology; D008297:Male; D020097:Natriuretic Peptide, Brain / Q000494:pharmacology* / Q000502:physiology; D009474:Neurons / Q000201:enzymology / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017461:Receptors, Atrial Natriuretic Factor / Q000187:drug effects / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015290:Second Messenger Systems / Q000187:drug effects; D013233:Stellate Ganglion / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology
D011993:Recombinant Fusion Proteins; C058930:brain natriuretic peptide receptor; D020097:Natriuretic Peptide, Brain; D007510:Isatin; D017869:Cyclic GMP-Dependent Protein Kinases; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; C517278:Pde2a protein, rat; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A; D006152:Cyclic GMP
calcium; natriuretic peptide, brain; sympathetic nervous system; synaptic transmission