Project SummaryExercise has well-documented benefits for systolic blood pressure (SBP) and cardiovascular health. Whereascurrent guidelines advocate ~150 min moderate intensity exercise/week our preliminary data show ~5min/day of inspiratory muscle strength training (IMST) for 6 weeks lowers casual (resting) SBP by ~12 mmHg. This simple approach to lowering BP could be applied to almost any population however we propose tostudy IMST in older adults with obstructive sleep apnea (OSA). OSA is an ideal population to target becauseOSA prevalence is growing and because snoring and apneas result in chronic intermittent hypoxemia thatdrives sympathetic nervous system (SNS) hyperactivity endothelial dysfunction and hypertension. Thesesubstantive risks for cardiovascular disease are compounded by poor adherence to the mainstay treatmentcontinuous positive airway pressure (<50%) obesity fatigue and a robust intolerance for exercise. Our findings in healthy young adults (n=50) show IMST-related reductions in BP are mediated bydecreases in systemic vascular resistance suggesting changes in vascular tone and function. Consistent withthis hypothesis our results from a pilot clinical trial in adults with OSA (n=24) show IMST-related reductions inplasma norepinephrine levels (PNE) and muscle sympathetic nerve activity (MSNA) both markers of SNSactivity. Our preliminary mechanistic assessments indicate IMST may lower circulating concentrations of othervasoconstrictor factors and increase nitric oxide (NO)-mediated endothelium-dependent dilation. And findingsin a novel endothelial cell culture model point to increases in NO and declines in reactive oxygen species(ROS) and oxidative stress. However it is unknown if: 1) IMST lowers casual and 24-h (ambulatory) SBP inolder adults with OSA; 2) the reductions in SBP are long-lasting; 3) arterial stiffness NO-mediated endothelialdilation and/or oxidative stress are improved; and 4) if adherence in this population is high long term. We propose a randomized double-blind placebo-controlled clinical trial to establish the efficacy of IMST(75% maximum inspiratory pressure [PImax]) 5 days/week for 24 weeks vs. placebo (15%PImax) (n=61/group)for lowering SBP in adults (>50 years) with above normal BP and OSA. We hypothesize that IMST will lowerSBP via reductions in SNS activity and circulating vasoconstrictor factors improvements in vascular functionand reductions in oxidative stress/inflammation and that reductions in SBP will be sustained after IMST.Aim 1: To determine casual and 24-h ambulatory BP; before/after and 4- and 12-weeks post-IMST/placebotraining. Safety tolerability and adherence also will be assessed.Aim 2: To measure arterial stiffness brachial artery flow-mediated dilation (FMDBA) plasma PNE MSNAvasoconstrictor factors and inflammation; before/after and 4- and 12-weeks post-IMST/placebo training.Aim 3: To evaluate superoxide related suppression of FMDBA and markers of oxidative stress and antioxidantdefense in endothelial cells from subjects before/after and 4- and 12-weeks post-IMST/placebo training.