Reduced Sympathetic Tone by Overexpression of Kv4.3 in the Rostral Ventrolateral Medulla (RVLM) of Rats with Heart Failure

Abstract

Chronic heart failure (CHF) is characterized by excess sympathetic tone that exacerbates cardiovascular damage. Our previous work demonstrated reduced Kv4.3 expression in the RVLM, a key cardiovascular control center regulating sympathetic tone. Kv4.3 channels contribute to polarizing, outward potassium currents, which desensitize and limit neuronal activity. Reduced expression of Kv4.3 leads to increased neuronal excitability; however, the physiological importance of Kv4.3 in the RVLM has not been investigated during CHF. We hypothesized that overexpression of Kv4.3 in the RVLM of rats with CHF would reduce sympathetic tone. To test this hypothesis, rats with confirmed CHF were implanted with radiotelemetry and were bilaterally injected with 250 nL of adenoviral‐associated Kv4.3 (adKv4.3; n = 4) or GFP (adGFP; n = 3) into the RVLM. Telemetry recordings were collected for 14 days post‐injection followed by terminal/anesthetized baroreflex renal sympathetic nerve activity (RSNA) experiments. Mean arterial pressure remained the same in both groups following injection; however, heart rate was reduced after adKv4.3 relative to baseline (‐16.4 ± 2.7 bpm) but not adGFP (+6.1 ± 6.1 bpm; p < 0.05 between groups). Both heart rate variability as measured by the standard deviation of beat to beat intervals (10.4 ± 0.8 vs. 8.0 ± 0.3 ms; p = 0.09) and frequency‐domain analysis of LF/HF ratio (0.90 ± 0.13 vs. 1.66 ± 0.37) trended toward improvement in adKv4.3 compared to adGFP. Baseline RSNA trended lower (22. 8 ± 0.4 vs. 42.4 ± 8.5 % of max; p = 0.15), and the baroreflex sensitivity was higher (3.9 ± 0.4 vs. 1.43 ± 0.22 Gmax; p < 0.005) in adKv4.3 compared to adGFP. These data support the hypothesis that overexpression of Kv4.3 in the RVLM reduces sympathetic tone in the CHF state.