Vasopressin (VP), an antidiuretic hormone, is also a potent vasoconstrictor and has been found at high levels in salt‐sensitive hypertensives. Hypertension normally reduces VP secretion by MNCs in the SON, by GABA‐dependent synaptic inhibition of their firing activities. However, in rats under chronic hypernatremia, GABAA receptor‐mediated synaptic inhibition is abolished in SON neurons due to a depolarization in chloride reversal potential (ECl), suggesting that continued VP secretion despite BP elevations may underlie the development of salt‐dependent hypertension. In order to test this hypothesis, we measured the mean arterial pressure (MAP) by radio telemetry in freely moving rats made chronically hypernatremic by 2% saline drinking. MAP of these rats rose steadily rise during the course of the 7‐day SL treatment (basal BP: 97.7±1.9 mmHg; day 7: 113.5±2.1 mmHg; n=10; P<0.05), however remained stable in euhydrated rats over the same time period (basal BP: 98.3±2.5 mmHg; day 7: 100.6±2.2 mmHg; n=6; P=0.50). Furthermore, the SL‐mediated increase in MAP was significantly reduced by continuous systemic infusion of a VP receptor type 1 (V1R) antagonist (αday 7; +8.8±2.5 mmHg; n=6) when compared to SL controls (α15.1±1.0 mmHg; n=10; P<0.05). These findings confirm our hypothesis that circulating VP contributes to increases in BP during chronic hypernatremia. Brain‐derived neurotrophic factor (BDNF) is a high‐affinity TrkB agonist previously shown to be responsible for chloride gradient collapse. In order to investigate this possibility in the SON, we induced a specific knockdown of this protein in SL rats in vivo by stereotaxic injections of adeno‐associated virus (AAV) containing BDNF‐shRNA into the SON. ECl measurements via Gramicidin perforated patch‐clamp revealed that this treatment significantly hyperpolarized the ECl of SON neurons (‐56.2±5.4 mV; n=10) when compared to values measured in SL rats injected with control AAV containing a scrambled sequence of shRNA (‐40.1±2.4 mV; n=7; p<0.05). These results strongly suggest that BDNF is the TrkB agonist responsible for producing the chloride gradient collapse in SON neurons under chronic hypernatremia, a phenomenon which potentially underlie the development of salt‐sensitive hypertension. Funding source: Canadian Institutes of Health Research.Grant Funding Source: CIHR
