Downregulation of M Current Is Coupled to Membrane Excitability in Sympathetic Neurons Before the Onset of Hypertension

Abstract

Neurohumoral activation is an early hallmark of cardiovascular disease and contributes to the etiology of the pathophysiology. Stellectomy has reemerged as a positive therapeutic intervention to modify the progression of dysautonomia, although the biophysical properties underpinning abnormal activity of this ganglia are not fully understood in the initial stages of the disease. We investigated whether stellate ganglia neurons from prehypertensive SHRs (spontaneously hypertensive rats) are hyperactive and describe their electrophysiological phenotype guided by single-cell RNA sequencing, molecular biology, and perforated patch clamp to uncover the mechanism of abnormal excitability. We demonstrate the contribution of a plethora of ion channels, in particular inhibition of M current to stellate ganglia neuronal firing, and confirm the conservation of expression of key ion channel transcripts in human stellate ganglia. We show that hyperexcitability was curbed by M-current activators, nonselective sodium current blockers, or inhibition of Na v 1.1-1.3, Na v 1.6, or I NaP . We conclude that reduced activity of M current contributes significantly to abnormal firing of stellate neurons, which, in part, contributes to the hyperexcitability from rats that have a predisposition to hypertension. Targeting these channels could provide a therapeutic opportunity to minimize the consequences of excessive sympathetic activation.