Impact of short-term chlorthalidone treatment on resting sympathetic transduction in older women with hypertension

Background: Older women experience greater hypertension prevalence and increased sympathetic activation. Our group and others have shown that certain diuretics (e.g., chlorthalidone [CTD], hydrochlorothiazide) elicit additional sympathoexcitation at rest and during physiological stressors (e.g., orthostasis). Despite the blood pressure (BP) lowering effects of diuretics and the subsequent sympathoexcitation that occurs, it is unknown whether sympathetic transduction to BP or peripheral vasoconstriction is altered in women with treated hypertension compared to women with untreated, yet BP-matched, hypertension. Therefore, we hypothesized that women taking CTD would have attenuated resting sympathetic transduction compared to women with untreated hypertension (CON). Methods: Thirty older women with hypertension were studied. All women completed 24 h BP monitoring following anti-hypertensive drug washout. Those with awake BP between 130-149/80-95 mmHg remained off medication (CON, n=15, 69±5y); those with awake BP between 150-179/96-109 mmHg began ~2 weeks of CTD (n=15, 68±5y) before repeating 24-h BP monitoring. Systolic and diastolic BP (SBP and DBP; electrosphygmomanometry, finger photoplethysmography), heart rate (HR; electrocardiogram), stroke volume (SV; ModelFlow), and muscle sympathetic nerve activity (MSNA; microneurography) were measured during 5-6 min of supine rest. Systemic vascular conductance (SVC) was calculated as (SV•HR)/mean arterial BP (MAP). Signal averaging was used to track the beat-by-beat changes (Δ) in MAP and SVC following bursts or non-bursts of MSNA for 10 cardiac cycles, with the peak Δ representing sympathetic transduction. Results: Awake SBP (142±80 vs. 141±7 mmHg; P =0.79) and DBP (80±7 vs. 81±5; P =0.70) were not different between CON and CTD, respectively. There were no differences between CON and CTD for in-laboratory resting SBP, DBP, HR, SV, or SVC ( P range: 0.18-0.75) nor for MSNA burst frequency (34±13 vs. 40±17 bursts/min; P =0.33). Following bursts of MSNA, there were no differences between CON and CTD for ΔMAP (0.95±0.49 vs. 1.13±1.00 mmHg; P =0.55) or ΔSVC (-0.67±0.49 vs. -1.17±1.55 mL/min/mmHg; P =0.55). Following non-bursts, ΔMAP was not different between CON and CTD (-1.25±0.67 vs. -1.25±0.57 mmHg; P =0.97). However, ΔSVC was significantly smaller in CON than CTD (0.85±0.47 vs. 1.38±0.79 mL/min/mmHg; P =0.04). Conclusions: Contrary to our hypothesis, sympathetic transduction following bursts of MSNA was not different between CON and CTD. Following non-bursts, though, despite no difference in ΔMAP, CTD experienced a greater rise in SVC than CON. Accordingly, these data suggest that CTD treatment in older women with hypertension alters sympathetic transduction during periods of sympathetic quiescence, which may implicate a greater reliance on cardiac output to maintain BP. Future research is needed to determine if these observations are unique to specific vascular beds and the specific mechanisms that may regulate these differences. Supported by the National Institutes of Health (R01AG059314 and F32HL167556) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.