1. Role of Na V 1.7 in postganglionic sympathetic nerve function in human and guinea-pig arteries.
- Author
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Kim JS, Meeker S, Ru F, Tran M, Zabka TS, Hackos D, and Undem BJ
- Subjects
- Animals, Guinea Pigs, Humans, Male, Action Potentials drug effects, Action Potentials physiology, Sympathetic Fibers, Postganglionic physiology, Sympathetic Fibers, Postganglionic drug effects, Female, Arteries physiology, Arteries drug effects, Arteries innervation, Sodium Channel Blockers pharmacology, Stellate Ganglion physiology, Sympathetic Nervous System physiology, Sympathetic Nervous System drug effects, NAV1.7 Voltage-Gated Sodium Channel genetics, NAV1.7 Voltage-Gated Sodium Channel physiology, NAV1.7 Voltage-Gated Sodium Channel metabolism
- Abstract
Na
V 1.7 plays a crucial role in inducing and conducting action potentials in pain-transducing sensory nociceptor fibres, suggesting that NaV 1.7 blockers could be effective non-opioid analgesics. While SCN9A is expressed in both sensory and autonomic neurons, its functional role in the autonomic system remains less established. Our single neuron rt-PCR analysis revealed that 82% of sympathetic neurons isolated from guinea-pig stellate ganglia expressed NaV 1.7 mRNA, with NaV 1.3 being the only other tetrodotoxin-sensitive channel expressed in approximately 50% of neurons. We investigated the role of NaV 1.7 in conducting action potentials in postganglionic sympathetic nerves and in the sympathetic adrenergic contractions of blood vessels using selective NaV 1.7 inhibitors. Two highly selective NaV 1.7 blockers, GNE8493 and PF 05089771, significantly inhibited postganglionic compound action potentials by approximately 70% (P < 0.01), with residual activity being blocked by the NaV 1.3 inhibitor, ICA 121431. Electrical field stimulation (EFS) induced rapid contractions in guinea-pig isolated aorta, pulmonary arteries, and human isolated pulmonary arteries via stimulation of intrinsic nerves, which were inhibited by prazosin or the NaV 1 blocker tetrodotoxin. Our results demonstrated that blocking NaV 1.7 with GNE8493, PF 05089771, or ST2262 abolished or strongly inhibited sympathetic adrenergic responses in guinea-pigs and human vascular smooth muscle. These findings support the hypothesis that pharmacologically inhibiting NaV 1.7 could potentially reduce sympathetic and parasympathetic function in specific vascular beds and airways. KEY POINTS: 82% of sympathetic neurons isolated from the stellate ganglion predominantly express NaV 1.7 mRNA. NaV 1.7 blockers inhibit action potential conduction in postganglionic sympathetic nerves. NaV 1.7 blockade substantially inhibits sympathetic nerve-mediated adrenergic contractions in human and guinea-pig blood vessels. Pharmacologically blocking NaV 1.7 profoundly affects sympathetic and parasympathetic responses in addition to sensory fibres, prompting exploration into the broader physiological consequences of NaV 1.7 mutations on autonomic nerve activity., (© 2024 The Authors. The Journal of Physiology © 2024 The Physiological Society.)- Published
- 2024
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