A Reduction in SK Channel Function Contributes to Increased Excitability of Hypothalamic Magnocellular Neurons During Heart Failure

Abstract

Neurohumoral activation, which includes elevated plasma levels of vasopressin, is a hallmark of heart failure (HF) and contributes to morbidity and mortality in this disease. Here, we evaluated whether changes in Ca2+‐activated K+ (SK) channels contribute to enhanced hypothalamic magnocellular neurosecretory cell (MNCs) activity in HF rats. Whole‐cell patch clamp recordings obtained from MNCs in slices from Sham and HF rats showed that the spike frequency evoked by direct current injection was significantly higher in the HF rats compared to Sham rats (Sham 16±0.9 vs HF 24±1.2 spikes, p<0.001). Bath application of the SK channel blocker apamin significantly increased the evoked firing frequency in MNCs from Sham rats, but no effect was observed in HF rats (Sham 23±0.9, p< 0.05 vs control; HF 26±0.7 spikes, p>0.05 vs control). The medium afterhyperpolarization potential (mAHP) following a train of spikes was significantly smaller in MNCs from HF rats compared to Sham rats (Sham 9.7±1.1 vs HF 6.6±0.6 mV, p<0.05) and apamin reduced the mAHP in both groups (Sham 2.9±0.5 vs HF 1.6±1.1 mV). Voltage‐clamp recordings of SK tail currents revealed that the apamin‐sensitive current amplitude and area were significantly smaller in MNCs from HF rats (amplitude: Sham 0.2±0.03 vs HF 0.09±0.03 nA, p<0.05; area: Sham 15.4±2.5 vs HF 7.2±1.2 nA.ms, p<0.01) whereas intracellular dialysis of MNCs with BAPTA reduced the currents in both groups to the same extent. No significant differences were observed in cell capacitance (Sham 30±2 vs HF 26±3 pF, p>0.05) or input resistance (Sham 960±87 vs HF 945±167 MΩ, p>0.05) between groups. Taken together, our data indicates that a decrease in SK channel function/activity and/or expression contributes to the increased excitability of MNCs in HF rats.Support or Funding InformationNIH R01HL090948