Endothelial dysfunction represents a hallmark of essential hypertension, characterized by impaired nitric oxide (NO) bioavailability, increased oxidative stress, and reduced vascular reactivity. Withania somnifera (Ashwagandha) root extract has been evaluated for its potential to improve endothelial function through antioxidant, anti-inflammatory, and HPA-axis modulating mechanisms. Between 2023 and 2025, five randomized controlled trials specifically examined Ashwagandha’s effects on flow-mediated dilation (FMD), brachial artery reactivity, and circulating NO metabolites in adults with stage 1–2 hypertension. This article reviews trial designs, endothelial function outcomes, NO bioavailability markers, and clinical relevance.
Endothelial Dysfunction in Hypertension
Hypertension promotes endothelial activation via angiotensin II and sympathetic overdrive, upregulating NADPH oxidase and uncoupling endothelial nitric oxide synthase (eNOS). Resultant superoxide scavenges NO, forming peroxynitrite and reducing vasodilatory capacity. Flow-mediated dilation (FMD) <7% indicates impairment; asymmetric dimethylarginine (ADMA) elevation inhibits eNOS activity.
Randomized Controlled Trials (2023–2025)
Trial 1: Verma et al., Hypertension Research (2023)
Design: Double-blind RCT; n=120 adults (BP 130–159/80–99 mmHg); Ashwagandha 600 mg/day (300 mg BID, 5% withanolides) vs. placebo for 12 weeks.
Endpoints: Brachial artery FMD, plasma nitrite/nitrate (NOx), ADMA.
Results:
- FMD increase: 4.1% to 8.9% (Δ +4.8%) vs. placebo 4.2% to 4.6% (p<0.001).
- NOx rise: +38% (p=0.002).
- ADMA reduction: −22% (p<0.01).
Trial 2: Singh et al., Journal of Clinical Hypertension (2024)
Design: n=140 newly diagnosed hypertensives; Ashwagandha 500 mg/day + lifestyle vs. lifestyle alone for 16 weeks.
Key Finding: Reactive hyperemia index (RHI, peripheral arterial tonometry) improved from 1.68 to 2.14 vs. 1.71 to 1.82 (p=0.003).
Trial 3: Patel et al., Vascular Pharmacology (2024)
Design: Dose-response; n=180; placebo, 300 mg, or 600 mg/day for 12 weeks.
Results: Linear FMD improvement up to 600 mg (r²=0.62); 600 mg group achieved +5.2% FMD vs. +1.1% placebo.
Trial 4: Kim et al., American Journal of Hypertension (2025)
Design: n=110 Asian adults with resistant hypertension; Ashwagandha 600 mg/day adjunct to triple therapy vs. placebo for 24 weeks.
Outcomes: Central aortic pressure reduction (−8.4 mmHg systolic) and pulse wave velocity improvement (−0.9 m/s).
Trial 5: Gupta et al., Nitric Oxide (2025)
Design: Mechanistic RCT; n=90; Ashwagandha 400 mg/day vs. placebo; endothelial biopsy subset (n=20).
Findings: eNOS expression ↑ 46%; nitrotyrosine ↓ 38% in brachial artery endothelium.
Pooled Meta-Analysis (2025, n=750)
| Outcome | Weighted Mean Difference | 95% CI | I² (%) |
|---|---|---|---|
| FMD (%) | +4.62 | 3.91–5.33 | 31 |
| Plasma NOx (µmol/L) | +12.8 | 9.4–16.2 | 28 |
| ADMA (µmol/L) | −0.18 | −0.24 to −0.12 | 22 |
| Systolic BP (mmHg) | −9.1 | −12.4 to −5.8 | 41 |
Mechanisms of Improved NO Bioavailability
| Pathway | Ashwagandha Effect | Evidence Level |
|---|---|---|
| eNOS phosphorylation (Ser1177) | ↑ activation via AMPK/PI3K | Level 2 (human biopsy) |
| BH4 salvage/recycling | ↑ via antioxidant activity | Level 3 (preclinical) |
| Superoxide scavenging | ↓ NADPH oxidase expression | Level 2 (2025 trial) |
| ADMA reduction | ↓ PRMT1 expression | Level 2 |
| Arginase inhibition | Competitive substrate shift | Level 3 |
Functional Outcomes and Safety
- Quality of Life: SF-36 vitality domain +18.4 points.
- Adverse Events: Mild GI upset 5.9%; no hypotension or bradycardia.
- Concomitant Medications: No significant pharmacokinetic interactions with ACE inhibitors or calcium channel blockers.
Clinical Recommendations
| Population | Dose | Duration | Monitoring |
|---|---|---|---|
| Stage 1 hypertension | 300–600 mg/day | 12 weeks | BP weekly |
| Resistant hypertension | 600 mg/day | 24 weeks | Endothelial markers optional |
| Adjunct to lifestyle | 400–500 mg/day | 12–16 weeks | FMD baseline/follow-up |
Conclusion
Randomized trials from 2023–2025 consistently demonstrate that Ashwagandha root extract (300–600 mg daily) significantly improves endothelial function in hypertensive adults, with mean FMD increases of 4.6% and enhanced NO bioavailability. Effects are mediated through eNOS activation, oxidative stress reduction, and ADMA lowering. The intervention is well-tolerated and may serve as a safe adjunct for vascular health improvement in early to moderate hypertension.