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

ABSTRACT: 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.

SUBMITTER: Li D

PROVIDER: S-EPMC4487831 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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

Li Dan D Lu Chieh-Ju CJ Hao Guoliang G Wright Hannah H Woodward Lavinia L Liu Kun K Vergari Elisa E Surdo Nicoletta C NC Herring Neil N Zaccolo Manuela M Paterson David J DJ

Hypertension (Dallas, Tex. : 1979) 20150427 1

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 ...[more]

PMID: 25916722

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Project description:AimsCardiac sympathetic overactivation is an important trigger of ventricular arrhythmias in patients with chronic heart failure (CHF). Our previous study demonstrated that N-type calcium (Cav2.2) currents in cardiac sympathetic post-ganglionic (CSP) neurons were increased in CHF. This study investigated the contribution of Cav2.2 channels in cardiac sympathetic overactivation and ventricular arrhythmogenesis in CHF.Methods and resultsRat CHF was induced by surgical ligation of the left coronary artery. Lentiviral Cav2.2-α shRNA or scrambled shRNA was transfected in vivo into stellate ganglia (SG) in CHF rats. Final experiments were performed at 14 weeks after coronary artery ligation. Real-time polymerase chain reaction and western blot data showed that in vivo transfection of Cav2.2-α shRNA reduced the expression of Cav2.2-α mRNA and protein in the SG in CHF rats. Cav2.2-α shRNA also reduced Cav2.2 currents and cell excitability of CSP neurons and attenuated cardiac sympathetic nerve activities (CSNA) in CHF rats. The power spectral analysis of heart rate variability (HRV) further revealed that transfection of Cav2.2-α shRNA in the SG normalized CHF-caused cardiac sympathetic overactivation in conscious rats. Twenty-four-hour continuous telemetry electrocardiogram recording revealed that this Cav2.2-α shRNA not only decreased incidence and duration of ventricular tachycardia/ventricular fibrillation but also improved CHF-induced heterogeneity of ventricular electrical activity in conscious CHF rats. Cav2.2-α shRNA also decreased susceptibility to ventricular arrhythmias in anaesthetized CHF rats. However, Cav2.2-α shRNA failed to improve CHF-induced cardiac contractile dysfunction. Scrambled shRNA did not affect Cav2.2 currents and cell excitability of CSP neurons, CSNA, HRV, and ventricular arrhythmogenesis in CHF rats.ConclusionsOveractivation of Cav2.2 channels in CSP neurons contributes to cardiac sympathetic hyperactivation and ventricular arrhythmogenesis in CHF. This suggests that discovering purely selective and potent small-molecule Cav2.2 channel blockers could be a potential therapeutic strategy to decrease fatal ventricular arrhythmias in CHF.

Dataset Information

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

Publications

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

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