Endothelin B Receptors on Sympathetic Nerves Impact Blood Pressure Variability

Abstract

Salt‐sensitive hypertension is characterized by increased sympathetic tone and renal damage. We and others have previously demonstrated the involvement of the endothelin‐1 type B receptor (ETB‐R) on sympathetic nerves towards increasing sympathetic tone and blood pressure during high salt diet. This is in contrast to their established role in the kidney promoting sodium excretion and thereby lowering blood pressure. Increased variation and lability of blood pressure is also a risk factor for cardiovascular disease independent of the degree of hypertension. However, the association between the endothelin system, salt‐sensitive hypertension, and blood pressure variation is unknown. We hypothesized that high salt diet would increase blood pressure variability and urinary protein excretion via ETB‐R activity on sympathetic nerves. Male rats deficient of functional ETB‐R except on sympathetic neurons (ETB‐def) and littermate controls were fed a normal salt (0.4% NaCl) or high salt diet (4% NaCl). Systolic blood pressure (SBP) was recorded via telemetry, and SBP variance [Σ(SBP‐meanSBP)2/(n‐1)] was calculated using 10 second bins of telemetry data. Urine was collected via metabolic cages and urine protein measured by a Bradford assay. There was a significant increase in the slope of the correlation between SBP and SBP variance following two weeks of high salt diet compared to normal salt diet (3.3 ± 0.2 vs 1.6 ± 0.4 mmHg2/mmHg, p < 0.001). The slope during high salt diet was not different between controls or ETB‐def animals (p = 0.6). During normal salt diet, there was a non‐significant relationship between SBP variance and urinary protein excretion (p = 0.5); however, following high salt diet, there was a strong correlation between SBP variance and urinary protein excretion (1.9 ± 0.6 mg protein/day/mmHg2, p = 0.003). Because ETB‐def and controls still have functional ETB‐R on sympathetic nerves, we treated male Sprague‐Dawley rats with 10 mg/kg/day of the specific ETB‐R antagonist A‐192621 to block all ETB‐R activity in order to determine if the actions of ETB‐R on sympathetic nerves were responsible for the association between SBP variance and urinary protein excretion. ETB‐R blockade increased SBP relative to baseline (152 ± 8 vs 131 ± 7 mmHg, respectively, n = 8, p < 0.001). Surprisingly, this increase in SBP was accompanied by decreased SBP variance compared to baseline (57.2 ± 15 vs 71 ± 17 mmHg2, p = 0.008) indicating that ETB‐R signaling on sympathetic nerves may be important in mediating increased fluctuations in SBP. This decreased variance was also associated with a decrease in urinary protein excretion compared to baseline (8.1 ± 1.8 vs 9.8 ± 1.8 mg/day, p = 0.02). These data provide evidence that ETB‐R on sympathetic nerves contribute to increased SBP fluctuations during high salt diet and that these fluctuations are correlated with markers of kidney damage such as urinary protein excretion.Support or Funding InformationAHA grant 19POST34380109 to BKB and NIH grants HL136267 and HL069999 to DMP