Angiotensin-(1-7) improves blood pressure and cardiovascular autonomic function in human aging

Background: Aging is the largest independent risk factor for developing hypertension and cardiovascular disease (CVD); however, the molecular mechanisms underlying age-related CVD remain poorly understood. Our laboratory recent published that levels of angiotensin (Ang)-(1-7), a protective hormone of the renin-angiotensin system, are reduced in healthy aged mice and that chronic restoration of Ang-(1-7) levels lowers blood pressure and sympathetic tone in aged mice. In this translational study, we hypothesized that, aging in humans is associated with low Ang-(1-7) and that restoring levels of Ang-(1-7) can decrease blood pressure via modulation of the autonomic nervous system. Methods: To test this hypothesis, plasma Ang-(1-7) levels and blood pressure were measured in older (>60 yrs n=8) and younger (<40 yrs, n=10) healthy humans. In a separate double-blind, randomized, crossover study, we performed acute intravenous (IV) infusion of Ang-(1-7) and saline in older adults (n=3). Ang-(1-7) was infused at escalating doses (2ng/kg, 6ng/kg, 8ng/kg; 10 minutes per dose), with the highest dose held for an additional 70 minutes. Blood pressure, heart rate, and muscle sympathetic nerve activity (MSNA) were measured continuously before and during Ang-(1-7) and saline treatments. Heart rate variability (HRV) and low frequency systolic blood pressure variability (LFSBP) were calculated via spectral analysis methods. Results: Plasma Ang-(1-7) levels were lower in older versus younger adults (9.4±1.5 vs. 28.0±4.9 pg/mL, respectively; p = 0.005), with no differences in plasma Ang II levels. Ang-(1-7) was inversely correlated to systolic blood pressure in older adults (r2=0.497, p=0.034), but not in younger adults (r2=0.110, p=0.384). In older adults, acute IV Ang-(1-7) infusion lowered blood pressure [Δ from baseline: -12±10 Ang-(1-7) vs. 4±2 mmHg saline, p < 0.050]. This depressor effect of Ang-(1-7) was associated with decreased measures of sympathetic tone [LFSBP (Δ from baseline: 0.35±0.08 Ang-(1-7) vs. 1.94±0.79 mmHg2 saline; p=0.0372) and MSNA burst incidence (Δ from baseline: -9 Ang-(1-7) vs. 8 A.U. saline)] as well as increased vagal tone (high frequency HRV, Δ from baseline: 295±117 Ang-(1-7) vs. 7±96 s2 saline, p = 0.050). Conclusions: These findings suggest that Ang-(1-7) is lower in healthy aged humans and associated with systolic hypertension. Additionally, acute infusion of Ang-(1-7) decreases blood pressure and sympathetic tone and increase vagal tone in this population. Overall, these data provide further rationale for targeting Ang-(1-7) to improve cardiovascular autonomic control in aging. NIH: K99HL159272, American Heart Association: 18POST33960087 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.