ET B Receptor Mediated Increases in Vasomotor Sympathetic Activity

Dysfunctional autonomic balance is a hallmark of many forms of hypertension. Endothelin B receptors (ET B ‐Rs) are present throughout the autonomic nervous system, but their role in modulating autonomic balance remains unclear. We have previously demonstrated that acute activation of ET B ‐Rs on sympathetic nerves increases blood pressure via a‐1 adrenoceptor‐mediated vasoconstriction. ET B ‐R deficient (ET B ‐def) rats lack functional ET B ‐Rs except on adrenergic tissues where functional ET B ‐Rs are expressed via transgene and have elevated vasomotor sympathetic tone compared to transgenic control (TG) rats, which express functional ET B ‐Rs and possess the transgene. We hypothesized that selective ET B ‐R blockade lowers blood pressure and sympathetic tone in ET B ‐def rats but raises blood pressure and sympathetic tone in TG controls. We anticipated that ET B ‐R blockade would create an intermediate blood pressure and sympathetic tone phenotype where ET B ‐def and TG controls would meet in the middle. We implanted male and female ET B ‐def rats and controls with telemetry to monitor freely‐moving, conscious blood pressure, heart rate, and frequency domain parameters. Following baseline recordings, we implanted osmotic minipumps to deliver 10 mg/kg/d of A‐192621, a selective ET B ‐R antagonist. We also injected 1.0 mg/kg chlorisondamine to directly measure vasomotor sympathetic tone both during baseline and drug infusion periods. All statistical comparisons were evaluated by 2‐way RM ANOVA followed by Sidak's post hoc test. Following 3‐4 days of A‐192621 treatment, systolic blood pressure (SBP) did not change from baseline in ET B ‐def rats (+ 0.1 ± 3.2 mmHg; p = 0.99); however, SBP rose dramatically in TG controls (+ 18.0 ± 1.4 mmHg; p < 0.001). During A‐192621 infusion, SBP in ET B ‐def and TG controls were similar (150.1 ± 2.7 vs 148.5 ± 2.3 mmHg, respectively, p = 0.85). In essence, TG controls became like ET B ‐def rats following ET B ‐R antagonism. At baseline, ET B ‐def exhibited higher vasomotor sympathetic tone as demonstrated by a greater decline in SBP following ganglionic blockade from chlorisondamine relative to TG controls (‐61.0 ± 2.7 vs. ‐47.1 ± 2.1 mmHg, respectively; p = 0.01). A‐192621 did not alter this response in ET B ‐def rats (‐ 64.6 ± 3.3 mmHg; p = 0.61 vs. baseline) but increased vasomotor tone in TG controls (‐ 56.8 ± 3.0; p = 0.03 vs. baseline). Frequency domain analysis also indicated that TG controls had increased sympathetic to parasympathetic vasomotor balance following A‐192621 as measured by the low frequency to high frequency ratio (LF/HF) of SBP variability (+ 0.43 ± 0.11 LF/HF; p = 0.02) whereas ET B ‐def did not have a significant difference between baseline and treatment periods (‐0.04 ± 0.18 LF/HF; p = 0.96). Taken together, these results indicate that selective ET B ‐R antagonism had no effect on blood pressure or vasomotor sympathetic tone in ET B ‐def animals but increased both parameters in TG controls to levels comparable to ET B ‐def. Contrary to our hypothesis, these results suggest that ET B ‐Rs on efferent sympathetic nerves may not influence blood pressure of vasomotor autonomic tone under normal physiological conditions; however, blockade or absence of ET B ‐Rs on sensory pathways may be responsible for the elevation of sympathetic tone and blood pressure.