Efficacy of B-Type Natriuretic Peptide Is Coupled to Phosphodiesterase 2A in Cardiac Sympathetic Neurons

Autor: Dan Li, Lavinia Woodward, David J. Paterson, Chieh-Ju Lu, Nicoletta C. Surdo, Neil Herring, Elisa Vergari, Guoliang Hao, Hannah Wright, Manuela Zaccolo, Kun Liu
Rok vydání: 2015
Předmět:
Isatin
Male
medicine.medical_specialty
Sympathetic nervous system
Sympathetic Nervous System
medicine.drug_class
Recombinant Fusion Proteins
Stellate Ganglion
Phosphodiesterase 3
chemistry.chemical_element
Stimulation
Calcium
Biology
Second Messenger Systems
Synaptic Transmission
Calcium in biology
Rats
Sprague-Dawley
Heart Conduction System
Heart Rate
Internal medicine
Natriuretic Peptide
Brain
Cyclic GMP-Dependent Protein Kinases
Internal Medicine
Natriuretic peptide
medicine
Animals
cardiovascular diseases
Calcium Signaling
Cyclic GMP
Cells
Cultured
Neurons
Phosphodiesterase
Cyclic Nucleotide Phosphodiesterases
Type 2
Rats
Endocrinology
medicine.anatomical_structure
chemistry
Hypertension
cardiovascular system
Receptors
Atrial Natriuretic Factor
cGMP-dependent protein kinase
hormones
hormone substitutes
and hormone antagonists
Zdroj: Hypertension. 66:190-198
ISSN: 1524-4563
0194-911X
Popis: 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.
Databáze: OpenAIRE
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