Impaired cAMP-cGMP cross-talk during cardiac sympathetic dysautonomia

Abstract

Dysautonomia is a well-established contributor to the development and progression of hypertension and many other cardiovascular diseases. Sympathetic hyperactivity and vagal impairment are features of human hypertension, as well as in subjects with a familial predisposition for hypertension. This neural phenotype is also observed in the spontaneously hypertensive rat (SHR). Moreover, it is widely accepted that autonomic imbalance contributes to the pathogenesis of hypertension itself, where emerging research is beginning to shed light on the key cellular and molecular changes that occur in diseased neurons. The postganglionic sympathetic stellate neurons (PGSNs) of the SHR that predominantly innervate the heart, display increased intracellular calcium [Ca2C]i transients linked to impaired neuronal nitric oxide synthase (nNOS) activity. Together, with downstream reductions in nitric oxide (NO)-cyclic guanosine monophosphate (cGMP), this results in enhanced end-organ neurotransmission. Pharmacological and genetic techniques aimed at enhancing NO-cGMPprotein kinase G (PKG) signaling have been successful in rectifying the Ca2C phenotype in SHR PGSNs and decreasing sympathetic hyperactivity. Interestingly, sympathetic impairment is present in young prohypertensive SHRs (pro-SHR), suggesting that these intracellular changes form early hallmarks of hypertension; however, the precise nature of events that trigger sympathetic dysfunction remain unclear. Recently, we published data suggesting that sympathetic hyperactivity in the stellate neurons from the pro-SHR may be triggered by dysregulated Ca2C channel activity, resulting in greater Ca2C influx. N-type Ca channels (Cav2.2) were identified as the major contributor to Ca2C entry in PGSNs, that in turn facilitate sympathetic neurotransmission. Inhibition of the N-type Ca2C channel also reduces the propensity for fatal ventricular arrhythmias and ameliorates autonomic dysfunction in a heart failure mouse model. When taken together these findings support a significant physiological role of the N-type Ca2C channel in neural modulation associated with cardiovascular disease. In our study we reported that PGSNwhole-cell Ca2C currents of the pro-SHR are greater when compared to normotensive rats. Moreover, we demonstrated a novel link between impaired cyclic nucleotide signaling and increased N-type Ca2C channel activity in prohypertension. cAMP and cGMP are ubiquitous second messenger cyclic nucleotide signaling molecules that regulate fundamental intracellular processes through direct activation of their respective kinases: protein kinase A (PKA) and PKG. Importantly, cyclic nucleotide regulation of neuronal [Ca2C]i is necessary for normal PGSN function. Indeed, site-specific phospho-regulation of several voltage-gated Ca2C channel subtypes has been well documented, where a fine balance between PKA and PKG activity is maintained in order to regulate Ca2C-dependent neurotransmission. Additional regulatory mechanisms are also maintained to ensure high signaling fidelity, whereby cAMP and cGMP are able to modulate alternative signaling