Renal Afferent Nerves Regulate Salt Appetite in DOCA Hypertensive Rats

Approximately 90% of hypertension is essential, driven by a mix of environmental and genetic factors. One major environmental factor is dietary salt, with 50% of essential hypertension thought to be salt sensitive. The average American consumes 3,400 mg of sodium a day, 1000 mg more than the American Heart Association's recommended daily allowance. Moreover, the World Health Organization estimates that reducing salt intake to the recommended level could prevent 2.5 million deaths per year globally. Therefore, an improved understanding of the mechanisms regulating the consumption of sodium may provide a novel therapeutic target for the treatment of hypertension. In the current study, we examined whether renal afferent nerves play a role in the control of sodium intake. To test this hypothesis, we examined the effect of afferent renal denervation (ADNX) on sodium intake in DOCA hypertensive rats, a model in which sodium appetite has been shown to be elevated. Male Sprague Dawley rats were surgically prepared at 8-10 weeks. All rats were implanted with radio-telemetry catheters in the femoral artery for the measurement of mean arterial pressure (MAP). DOCA was administered using a subcutaneous silicon pellet (100 mg). In half of the DOCA rats, ADNX was performed using the peri-axonal application of capsaicin (33 mM). In a separate group of Sham rats, a drug-free silicon pellet was implanted, and the renal nerves were left intact. For ~7-days before surgery, and throughout the study, all rats were offered two drinking bottles, one containing water and the other 1.8% NaCl. Bottle position was alternated every 24 hours to prevent side preference. 24-hours after surgery we began daily measurements of fluid intake and MAP. These measurements continued for 3-weeks. DOCA rats had a significantly higher saline intake than the Sham rats. After 3-weeks saline intake was 24.7 ± 4 ml/24hr in the DOCA rats (n=17) compared to 13.1 ± 2.3 ml/24hr in the Sham rats (n=13). ADNX caused a significant reduction in saline intake in DOCA rats. Saline intake was significantly lower in the ADNX rats than the DOCA rats from day-3 onwards (DOCA: 21.7 ± 2.5 ml/24hr vs ADNX: 12.7 ± 1.2 ml/24hr). Notably, after 3-weeks saline intake in ADNX rats was comparable to that of the Sham rats at 10.8 ± 1.8 ml/24hr (n=18). Water intake was also significantly higher in the DOCA rats than the Sham rats throughout the study. After 3-weeks water intake averaged 42.0 ± 2.5 ml/24hr compared to 29.1 ± 1.6 ml/24hr in the Sham rats. In contrast to the effects on saline intake, ADNX had no significant effect on water intake, which averaged 39.8 ± 2.1 ml/24hr after 3-weeks. Indeed, water intake was only significantly different between the ADNX and DOCA rats on 4 of the 21-days. Interestingly, in this two-bottle model of DOCA hypertension, ADNX did not have a significant effect on MAP, which after 3-weeks averaged 143 ± 5 mmHg in the DOCA vs. 136 ± 6 mmHg in the ADNX rats. These studies suggest that afferent renal nerves increase sodium appetite in DOCA rats. Disruption of afferent signals from the kidney caused a significant and sustained reduction in sodium intake, with minimal effects on water intake. These results suggest that reduction of sodium intake may be an additional benefit of renal denervation as a treatment for salt-dependent hypertension.