Abstract
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.
Highlights
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We find that the spontaneously hypertensive (SH) rat muscle vasoconstrictor-like (MVClike) sympathetic preganglionic neurons (SPN) have a 1.6-fold higher frequency of action potential discharge with a greater degree of respiratory modulation of their firing than MVClike SPN in WKY rats
The voltage-clamp recordings obtained from the MVClike SPN showed common patterns of input across strains, with a trend towards an elevation in the respiratory-coupled excitatory drive in SH rats, but we found no evidence for a change in the basal rate or amplitude of synaptic events
Summary
General rights This document is made available in accordance with publisher policies. SYMPATHETIC ACTIVITY IS ELEVATED in hypertensive patients in prehypertensive conditions and in animal models of hypertension (reviewed in Esler 2011; Fisher and Paton 2012; Grassi 1998) This has recently led to trials of novel therapeutic interventions aimed at reducing the sympathetic overactivity, for example, renal nerve denervation (Schlaich et al 2009) and carotid sinus stimulation (Jordan et al 2012). The sympathetic outflow is specialized according to the target organs, and the muscle vasoconstrictor class (MVC) of sympathetic neuron is believed to be important in the control of blood pressure (Janig 2006). These sympathetic vasoconstrictor pathways produce a tonic release of norepineprine that maintains vascular tone. As yet the cellular mechanisms for this spinally mediated increase in sympathetic discharge have received relatively little attention
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