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

We investigated here whether an opposing interplay between the subthreshold currents A-type potassium (I_A) and T-type calcium (I_T) 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 I_A and I_T, 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 I_A/I_T balance to be correlated with the relative expression of Kv4.3 and Cav3.1 subunit mRNA within individual neurones. Pharmacological blockade of I_A resulted in an enhanced I_T-mediated LTS, as well as LTS-mediated somatodendritic Ca²⁺ transients. In hypertensive rats, we found a shift in the I_T/I_A balance, towards an I_T predominance, due in part to a diminished Kv4.3 and enhanced Cav3.1 mRNA subunits expression. The imbalanced I_T/I_A 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 I_T/I_A interaction influences membrane excitability and Ca²⁺ dynamics in PVN-RVLM neurones. Moreover, an imbalanced relationship favouring I_T results in enhanced neuronal excitability and firing discharge in hypertensive rats, constituting thus a likely mechanism contributing to the characteristic sympathoexcitation observed in this disease.