Increased intrinsic excitability of muscle vasoconstrictor preganglionic neurons may contribute to the elevated sympathetic activity in hypertensive rats

Hypertension is associated with pathologically increased sympathetic drive to the vasculature. This has been attributed to increased excitatory drive to sympathetic preganglionic neurons (SPN) from brainstem cardiovascular control centers. However, there is also evidence supporting increased intrins...

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Bibliographic Details
Published in:Journal of neurophysiology 2014-12, Vol.112 (11), p.2756-2778
Main Authors: Briant, Linford J B, Stalbovskiy, Alexey O, Nolan, Matthew F, Champneys, Alan R, Pickering, Anthony E
Format: Article
Language:English
Subjects:
Action Potentials
Animals
Brain Stem - cytology
Brain Stem - physiology
Control of Homeostasis
Heart - innervation
Heart - physiology
Hypertension - physiopathology
Male
Models, Neurological
Neurons - drug effects
Neurons - metabolism
Neurons - physiology
Potassium - metabolism
Potassium Channel Blockers - pharmacology
Potassium Channels, Inwardly Rectifying - antagonists & inhibitors
Potassium Channels, Inwardly Rectifying - metabolism
Rats
Rats, Inbred SHR
Rats, Wistar
Respiratory Muscles - blood supply
Respiratory Muscles - innervation
Respiratory Muscles - physiology
Spinal Cord Lateral Horn - cytology
Spinal Cord Lateral Horn - physiology
Sympathetic Nervous System - cytology
Sympathetic Nervous System - physiology
Vasoconstriction
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Summary:Hypertension is associated with pathologically increased sympathetic drive to the vasculature. This has been attributed to increased excitatory drive to sympathetic preganglionic neurons (SPN) from brainstem cardiovascular control centers. However, there is also evidence supporting increased intrinsic excitability of SPN. To test this hypothesis, we made whole cell recordings of muscle vasoconstrictor-like (MVClike) SPN in the working-heart brainstem preparation of spontaneously hypertensive (SH) and normotensive Wistar-Kyoto (WKY) rats. The MVClike SPN have a higher spontaneous firing frequency in the SH rat (3.85 ± 0.4 vs. 2.44 ± 0.4 Hz in WKY; P = 0.011) with greater respiratory modulation of their activity. The action potentials of SH SPN had smaller, shorter afterhyperpolarizations (AHPs) and showed diminished transient rectification indicating suppression of an A-type potassium conductance (IA). We developed mathematical models of the SPN to establish if changes in their intrinsic properties in SH rats could account for their altered firing. Reduction of the maximal conductance density of IA by 15-30% changed the excitability and output of the model from the WKY to a SH profile, with increased firing frequency, amplified respiratory modulation, and smaller AHPs. This change in output is predominantly a consequence of altered synaptic integration. Consistent with these in silico predictions, we found that intrathecal 4-aminopyridine (4-AP) increased sympathetic nerve activity, elevated perfusion pressure, and augmented Traube-Hering waves. Our findings indicate that IA acts as a powerful filter on incoming synaptic drive to SPN and that its diminution in the SH rat is potentially sufficient to account for the increased sympathetic output underlying hypertension.
ISSN:0022-3077
1522-1598
DOI:10.1152/jn.00350.2014