# Hydrochlorothiazide combined with exercise training attenuates blood pressure variability and renal dysfunctions in an experimental model of hypertension and ovarian hormone deprivation

## TL;DR

Combining hydrochlorothiazide with exercise training improves kidney health and reduces blood pressure variability in hypertensive rats without ovarian hormones.

## Contribution

The study demonstrates that combining hydrochlorothiazide with exercise training provides greater renal and cardiovascular benefits than the drug alone in a postmenopausal hypertension model.

## Key findings

- The combination of hydrochlorothiazide and exercise training reduced systolic blood pressure and blood pressure variability.
- Treated groups showed improved renal function, reduced inflammation, and less kidney fibrosis.
- The combination therapy increased antioxidant activity and reduced oxidative stress markers in kidney tissue.

## Abstract

Considering that blood pressure variability (BPV) has been associated with damage to target organs such as the kidneys, this study aimed to investigate the effects of the association of hydrochlorothiazide (HCTZ) combined with exercise training (CET) on BPV, as well as morphology, function, inflammation, and oxidative stress in renal tissue. Our study was designed to experimentally simulate arterial hypertension associated with the postmenopausal period in females, a condition linked to a considerable increase in cardiovascular risk. To replicate the physiological cessation of ovarian hormones, we performed a bilateral ovariectomy. Female spontaneously hypertensive rats (SHR) were distributed into 4 ovariectomized groups (n = 5–6/group): sedentary (OS), sedentary + HCTZ (OSH), trained (OT), and trained + HCTZ (OTH). Both HCTZ (3 mg/kg) and CET (3 days/week) were performed for 8 weeks. Blood pressure (BP) was directly recorded for BPV analyses. Renal function, morphology, inflammation, and oxidative stress were evaluated. The OSH, OT, and OTH groups had lower systolic BP (SBP) (OSH: 189 ± 13; OT: 179 ± 5; OTH: 174 ± 15 mmHg) when compared to the OS group (208 ± 15 mmHg). Only the association of the drug with CET promoted a reduction in variance of SBP. The groups treated with HCTZ showed lower plasma creatinine levels and increased creatinine clearance compared to the OS group. Treated groups showed a reduction in fields of 51%–100% of interstitial tubule fibrosis when compared to the OS group, and the OTH group also showed reduction in fields in the range of 26%–50% versus other groups. There was an increase in renal catalase, a reduction in IL‐6, and an increase in IL‐10 in the OTH group. Positive correlations were obtained between variance of SBP and SBP (r = 0.72), plasma creatinine (r = 0.58), IL‐6 (r = 0.62), hydrogen peroxide (r = 0.61), and protein oxidation (r = 0.66), as well as between vascular sympathetic modulation and lipoperoxidation (r = 0.62) in kidney tissue. In conclusion, our findings highlight the enhanced effectiveness of combining HCTZ and CET compared to using the drug alone in the studied model. This dual approach may provide additional cardiovascular and renal benefits beyond reduction of BP, potentially leading to improved quality of life and reduced morbidity associated with systemic arterial hypertension.

Hydrochlorothiazide plus combined exercise training provides superior benefits compared to medication alone in female spontaneously hypertensive rats subjected to ovarian hormone deprivation. This combined approach significantly reduced blood pressure variability, improved inflammatory and redox profiles, and provided functional and morphological benefits to renal tissue. From a translational perspective, replicating similar results in humans would underscore the fundamental importance of incorporating regular exercise training into antihypertensive pharmacological treatment, providing additional benefits beyond blood pressure reduction, potentially reducing hypertension‐related complications.