Imbalanced K+ and Ca2+ subthreshold interactions contribute to increased hypothalamic presympathetic neuronal excitability in hypertensive rats

• Published in: The Journal of physiology 2011-02, Vol.589 (3), p.667-683
• Main Authors: Sonner, P. M., Lee, S., Ryu, P. D., Lee, S. Y., Stern, J. E.
• Format: Article
• Language: English
• Subjects: 4-Aminopyridine - pharmacology; Action Potentials - drug effects; Action Potentials - physiology; Animals; Calcium; Calcium Channel Blockers - pharmacology; Calcium channels (T-type); Calcium channels (voltage-gated); Calcium Channels, T-Type - genetics; Calcium Channels, T-Type - metabolism; Calcium Channels, T-Type - physiology; Calcium imaging; Calcium Signaling - drug effects; Calcium Signaling - physiology; Dendrites - metabolism; Electrophysiological Phenomena - drug effects; Electrophysiological Phenomena - physiology; Electrophysiological recording; Excitability; Firing pattern; Gene expression; Gene Expression - genetics; Hypertension; Hypertension, Renovascular - metabolism; Hypertension, Renovascular - physiopathology; Hypothalamus; Hypothalamus - cytology; Hypothalamus - physiopathology; Kinetics; Male; Medulla oblongata; Medulla Oblongata - cytology; Medulla Oblongata - physiology; Membrane Potentials - physiology; Mortality; mRNA; Neuroimaging; Neurons - drug effects; Neurons - physiology; Neuroscience; Nickel - pharmacology; Oxytocin - metabolism; Paraventricular Hypothalamic Nucleus - cytology; Paraventricular Hypothalamic Nucleus - physiopathology; Paraventricular nucleus; Patch-Clamp Techniques; Polymerase chain reaction; Potassium; Potassium channels (voltage-gated); Rats; Rats, Wistar; Rodents; Shal Potassium Channels - antagonists & inhibitors; Shal Potassium Channels - physiology; Sympathetic Nervous System - physiopathology; Vasopressins - metabolism
• ISSN: 0022-3751; 1469-7793; 1469-7793
• DOI: 10.1113/jphysiol.2010.198556

Non‐technical summary Despite the importance of brain‐mediated sympathetic activation in the morbidity and mortality of patients with high blood pressure, the precise cellular mechanisms involved remain largely unknown. We show that an imbalanced interaction between two opposing currents mediated by potassium (IA) and calcium (IT) channels occurs in sympathetic‐related hypothalamic neurons in hypertensive rats. We show that this imbalance contributes to enhanced membrane excitability and firing activity in this neuronal population. Knowledge of how these opposing ion channels interact in normal and disease states increases our understanding of underlying brain mechanisms contributing to the high blood pressure condition.   We investigated here whether an opposing interplay between the subthreshold currents A‐type potassium (IA) and T‐type calcium (IT) influences membrane excitability in presympathetic neurones of the hypothalamic paraventricular nucleus (PVN) that innervate the rostral ventrolateral medulla (RVLM). Moreover, we assessed whether a shift in the balance between these two subthreshold currents contributed to increased neuronal activity in hypertension. To this end, we obtained simultaneous electrophysiological recordings, confocal Ca2+ imaging, and single‐cell RT‐PCR samples from identified PVN‐RVLM neurones in sham and renovascular hypertensive rats. Our results indicate that IA and IT, displaying overlapping voltage‐dependent and kinetic properties, are present in PVN‐RVLM neurones. We found that the relative predominance of each current at hyperpolarized membrane potentials dictates whether PVN‐RVLN neurones express a low‐threshold spike (LTS) or a transient outward rectification (TOR). Moreover, we report the IA/IT balance to be correlated with the relative expression of Kv4.3 and Cav3.1 subunit mRNA within individual neurones. Pharmacological blockade of IA resulted in an enhanced IT‐mediated LTS, as well as LTS‐mediated somatodendritic Ca2+ transients. In hypertensive rats, we found a shift in the IT/IA balance, towards an IT predominance, due in part to a diminished Kv4.3 and enhanced Cav3.1 mRNA subunits expression. The imbalanced IT/IA relationship resulted in enhanced LTS, LTS‐mediated somatodendritic Ca2+ transients, and increased firing activity in hypertensive rats. Taken together, our results support that a balanced IT/IA interaction influences membrane excitability and Ca2+ dynamics in PVN‐RVLM neurones. Moreover, an imbalanced