Cyclic nucleotide regulation of cardiac sympatho‐vagal responsiveness

Abstract

Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are now recognized as important intracellular signalling molecules that modulate cardiac sympatho‐vagal balance in the progression of heart disease. Recent studies have identified that a significant component of autonomic dysfunction associated with several cardiovascular pathologies resides at the end organ, and is coupled to impairment of cyclic nucleotide targeted pathways linked to abnormal intracellular calcium handling and cardiac neurotransmission. Emerging evidence also suggests that cyclic nucleotide coupled phosphodiesterases (PDEs) play a key role limiting the hydrolysis of cAMP and cGMP in disease, and as a consequence this influences the action of the nucleotide on its downstream biological target. In this review, we illustrate the action of nitric oxide–CAPON signalling and brain natriuretic peptide on cGMP and cAMP regulation of cardiac sympatho‐vagal transmission in hypertension and ischaemic heart disease. Moreover, we address how PDE2A is now emerging as a major target that affects the efficacy of soluble/particulate guanylate cyclase coupling to cGMP in cardiac dysautonomia.

Sympathetic neurons are a powerful driver of myocyte function in cardiovascular disease

“…Emerging evidence suggests oxidative stress leading to dysregulation of cyclic nucleotide signalling plays a major role behind the elevated Ca 2+ . These neurons show impaired nitric oxide (NO) - cGMP signalling resulting in lower cGMP levels and disinhibition of neurotransmission51525354. Moreover we recently reported that the neuronal Ca 2+ channel phenotype in the SHR is linked to a phosphodiesterase – cyclic nucleotide impairment and failure of cGMP signalling to inhibit I CaN 16.…”

Cardiac sympathetic innervation, from a different point of (re)view

“…Several comprehensive articles (for a topical collection see The Journal of Physiology , June 2016) have reviewed various aspects of the neurocardiology of the autonomic nervous system, including the sophisticated regulation of its ‘proximal’ pre‐ganglionic section (Ardell & Armour, ; Habecker et al . ; Janig, ), brainstem and higher centres processing (Shivkumar & Ardell, ), and the role of cyclic nucleotide signalling in the modulation of sympatho‐vagal balance (Li & Paterson, ).…”

Cardiac autonomic control in health and disease

“…At the level of peripheral autonomic ganglia, alterations in cyclic nucleotide pathways are discussed in relation to neurotransmitter release (Kalla et al . ; Li & Paterson, ). Consequences for peripheral neural network control of cardiac electrical and mechanical function is presented with a primary focus on neural transduction of cardiac pathology relative to heart failure and arrhythmias (Ardell et al .…”

“…At the level of the cardiomyocyte, alterations in excitation-contraction coupling, substrate utilization and receptor signalling are considered in normal vs. pathological conditions (Gloschat et al 2016). At the level of peripheral autonomic ganglia, alterations in cyclic nucleotide pathways are discussed in relation to neurotransmitter release (Kalla et al 2016;Li & Paterson, 2016). Consequences for peripheral neural network control of cardiac electrical and mechanical function is presented with a primary focus on neural transduction of cardiac pathology relative to heart failure and arrhythmias (Ardell et al 2016).…”