High blood pressure (BP), particularly systolic BP (SBP), is the major modifiable risk factor for
cardiovascular diseases and related disorders of aging. SBP increases markedly with aging in women such
that the prevalence of above-normal SBP (i.e., =120 mmHg) in postmenopausal (PM) women exceeds rates
in age-matched men. This increase in SBP is associated with vascular endothelial dysfunction, mediated by
excessive reactive oxygen species (ROS)-induced oxidative stress and consequent reductions in nitric oxide
(NO) bioavailability. Moderate-intensity aerobic exercise (AE) of 150 min/week is a clinical guideline-based
(standard-of-care) lifestyle therapy for reducing SBP. However, in estrogen-deficient PM (PME-) women, the
effects of AE on SBP are modest and do not persist >4 weeks after AE cessation. AE also does not
consistently enhance endothelial function and is associated with poor adherence (<30%) in this group.
High-resistance inspiratory muscle strength training (IMST) is a novel lifestyle intervention involving
repeated inhalations against a resistive load using a hand-held device. In a randomized, double-blind, sham-
controlled, parallel group design R21-funded pilot study in midlife/older men and women (n=36 [17 PME-
women]), we showed that IMST (30 breaths [5 minutes]/day at 75% of maximal inspiratory pressure, 6 days
[30 minutes]/week for 6 weeks), lowered casual (resting) SBP by 9±2 mmHg (6±2 mmHg 6 weeks after
cessation of IMST) and 24-hour SBP by 3±3 mmHg. IMST improved endothelial function (brachial artery flow-
mediated dilation, FMDBA), by ~40%, while promoting excellent adherence (95% of prescribed sessions
completed). Importantly, the effects of IMST on SBP and FMDBA in the PME- women were all = those in men.
Here we propose a larger, randomized clinical trial with a guideline-based treatment duration (3 months) to
directly compare the efficacy of IMST vs. standard-of-care AE (150 min/week brisk walking) for decreasing
SBP and improving FMDBA in PME- women with above-normal SBP (=120 mmHg) at baseline. We hypothesize
that IMST will reduce and largely sustain reductions in SBP and increase FMDBA > AE. Increases in FMDBA
with IMST will be mediated by reduced ROS/oxidative stress, and serum post-IMST will decrease ROS and
increase NO in endothelial cells > post-AE. Adherence, safety and tolerability will be > with IMST vs. AE.
Aim 1: To measure casual SBP (primary outcome) and 24-hour (ambulatory) SBP (secondary outcome)
before (baseline), after 3 months of IMST or AE, and 6 weeks following cessation of IMST or AE;
Aim 2: To measure FMDBA (secondary outcome) before, after IMST or AE, and 6 weeks post-IMST or -AE;
Aim 3: To determine in vivo ROS-mediated suppression of FMDBA (FMDBA ± vitamin C infusion); markers of
oxidative stress and antioxidant status in biopsied endothelial cells; and endothelial cell culture NO and ROS
production pre-post IMST or AE serum exposure and the identity of the plasma metabolites involved;
Aim 4: To assess adherence (completed:prescribed sessions), safety and tolerability with IMST vs. AE.