Substance P Targets Sympathetic Control Neurons in the Paraventricular Nucleus

Substance P Targets Sympathetic Control Neurons in the Paraventricular Nucleus,Matthew D. Womack,Richard Morris,Thomas C. Gent,Richard Barrett-Jolley

Substance P Targets Sympathetic Control Neurons in the Paraventricular Nucleus  
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The paraventricular nucleus (PVN) contains spinally-projecting neurons implicated in fine-tuning the cardio- vascular system. In vivo activity of "presympathetic" parvocellular neurons is suppressed by tonic inhibition from GABA-ergic inputs, inhibition of which increases sympathetic pressor activity and heart rate. Targeting of this specific neuronal population could potentially limit elevations of heart rate and blood pressure associated with disease. Here we show, for the first time, that "presympathetic" PVN neurons are disinhibited by the neuropeptide substance P (SP) acting via tachykinin NK1 receptor inhibition of GABAA currents. Application of SP to the paraventricular nucleus of rats increases heart rate and blood pressure. In in vitro brain slice experiments, in the presence of GABA, 1mol/L SP increased action current frequency by a factor of 2.70.6 (n5, P0.05, ANOVA). Furthermore, 1mol/L SP inhibited GABAA currents by 708% (n8, P0.005 paired t test). These effects were abolished by NK1 antagonists, but not NK2 and NK3 antagonists. GABAA inhibition was not reproduced by NK2 or NK3 agonists. The inhibition of parvocellular GABAA currents by SP was also abolished by a protein kinase C (PKC) inhibitor peptide and mimicked by application of phorbol-12-myristate-13-acetate (PMA), implicating a PKC-dependent mechanism. Single-channel analysis indicates that SP acts through reduction of channel mean open-time (cmot): GABAA cmot being reduced by approximately 60% by SP (P0.05 ANOVA, Bonferroni). These data suggest that tachykinins mediate their pressor activity by increasing the excitability of spinally-projecting neurons and identifies NK1 receptors as potential targets for therapeutic modulation of the cardiovascular system. (Circ Res. 2007;100:1650-1658.)
Published in 2010.
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