Kv4.2/4.3 Channels in the Hypothalamic PVN Contribute to Sympathetic Activation in Angiotensin II‐Salt Hypertension

Recent studies in mice implicate increased NMDA receptor expression and function in the PVN in development of the slow pressor model of angiotensin II (AngII) hypertension. Here, we studied adult male rats with AngII‐salt hypertension. Rat were placed on a high salt (2% NaCl) diet for 6 weeks with systemic AngII treatment (150 ng/kg/min, s.c.) for the final 2 weeks. Consistent with studies in mice, we found that responsiveness to PVN NMDA was increased in hypertensive rats as was PVN NMDA receptor tonus. Previous studies of rats with reno‐vascular hypertension reported increased excitability of pre‐sympathetic PVN neurons accompanied by diminution of the transient potassium A‐current. In the PVN, Kv4.2/4.3 channels are major mediators of A‐current, but the present studies revealed that acute and selective blockade of these channels with phrixotoxin (5 pmol in 50 nl) had no effect on resting MAP, RSNA or SSNA in anesthetized normotensive or AngII‐salt hypertensive rats – suggesting that A‐current is not a significant determinant of in vivo spike probability among PVN pre‐sympathetic neurons of either group. However, phrixotoxin did enhance pressor and sympatho‐excitatory response to PVN injections of NMDA (200 nmol in 50 nl) in normotensive rats (P<0.05 – 0.01), while failing to do so in hypertensive rats. These findings suggest several alternative explanation for A‐current function in the PVN. Most parsimoniously, Vm of pre‐sympathetic neurons could be sufficiently hyperpolarized and discharge sufficiently sparse under normal conditions that A‐current is maintained at a relatively low level of steady state inactivation, allowing it to actively attenuate spiking induced by activation of glutamatergic input (NMDA). By contrast, Vm depolarization and more frequent spiking of neurons in rats with AngII‐salt hypertension could prevent hyperpolarization‐induced de‐inactivation of A‐current and thereby increase steady‐state inactivation such that A‐current mediated by Kv4.2/4.3 channels cannot effectively oppose spiking. The latter is consistent with lack of enhancement of responses to PVN NMDA by phrixotoxin in hypertensive rats. The above model of diminished PVN A‐current contribution to AngII‐salt hypertension requires further study to assess whether diminished Kv4.2/4.3 channel expression and ongoing covalent modulation of channel gating might also contribute to PVN activation and heightened PVN support of sympathetic activity in AngII‐salt hypertension. Support or Funding Information HL102310 & HL088052 (GMT)