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(Circulation Research. 2007;100:1650.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Substance P Targets Sympathetic Control Neurons in the Paraventricular Nucleus

Matthew D. Womack, Richard Morris, Thomas C. Gent, Richard Barrett-Jolley

From the Veterinary Sciences Faculty, Brownlow Hill, University of Liverpool, UK.

Correspondence to Dr Richard Barrett-Jolley, University of Liverpool, Department of Preclinical Veterinary Sciences, Faculty of Veterinary Sciences, Liverpool L69 7ZJ, United Kingdom. E-mail RBJ{at}LIV.AC.UK

The paraventricular nucleus (PVN) contains spinally-projecting neurons implicated in fine-tuning the cardiovascular 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 GABA_A 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, 1µmol/L SP increased action current frequency by a factor of 2.7±0.6 (n=5, P0.05, ANOVA). Furthermore, 1µmol/L SP inhibited GABA_A currents by 70±8% (n=8, P0.005 paired t test). These effects were abolished by NK1 antagonists, but not NK2 and NK3 antagonists. GABA_A inhibition was not reproduced by NK2 or NK3 agonists. The inhibition of parvocellular GABA_A 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): GABA_A 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.

Key Words: cardiovascular control • GABA • substance P