ET B Receptor Mediated Increases in Vasomotor Sympathetic Activity

Abstract

Dysfunctional autonomic balance is a hallmark of many forms of hypertension. Endothelin B receptors (ETB-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 ETB-Rs on sympathetic nerves increases blood pressure via a-1 adrenoceptor-mediated vasoconstriction. ETB-R deficient (ETB-def) rats lack functional ETB-Rs except on adrenergic tissues where functional ETB-Rs are expressed via transgene and have elevated vasomotor sympathetic tone compared to transgenic control (TG) rats, which express functional ETB-Rs and possess the transgene. We hypothesized that selective ETB-R blockade lowers blood pressure and sympathetic tone in ETB-def rats but raises blood pressure and sympathetic tone in TG controls. We anticipated that ETB-R blockade would create an intermediate blood pressure and sympathetic tone phenotype where ETB-def and TG controls would meet in the middle. We implanted male and female ETB-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 ETB-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 ETB-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 ETB-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 ETB-def rats following ETB-R antagonism. At baseline, ETB-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 ETB-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 ETB-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 ETB-R antagonism had no effect on blood pressure or vasomotor sympathetic tone in ETB-def animals but increased both parameters in TG controls to levels comparable to ETB-def. Contrary to our hypothesis, these results suggest that ETB-Rs on efferent sympathetic nerves may not influence blood pressure of vasomotor autonomic tone under normal physiological conditions; however, blockade or absence of ETB-Rs on sensory pathways may be responsible for the elevation of sympathetic tone and blood pressure.