Beyond Conventional Antihypertensives: RNA Interference, Endothelin Antagonism, and Aldosterone-Synthase Inhibition in the Current Therapeutic Landscape.

Hypertension is the leading modifiable cardiovascular risk factor, yet long-term adherence to antihypertensive therapy remains suboptimal. RNA-based approaches targeting hepatic angiotensinogen (AGT) have emerged as an attractive strategy for upstream renin-angiotensin-aldosterone system suppression and warrant a timely, focused review of the field. PubMed/MEDLINE, ClinicalTrials.gov and the most relevant scientific and academic databases were searched up to February 2026 to draft a narrative review of peer-reviewed clinical trials, pivotal translational studies, contemporary hypertension guidelines, and official regulatory documents relevant to innovative antihypertensive treatments, such as antisense AGT suppression (zilebesiran), endothelin antagonism (aprocitentan), and aldosterone-synthase inhibition (baxdrostat). Zilebesiran demonstrated durable blood-pressure lowering in monotherapy (KARDIA-1: placebo-adjusted ambulatory systolic blood pressure (BP) - 16.7 mmHg at month 3) and as add-on therapy (KARDIA-2: greatest effect with indapamide background). KARDIA-3 extended evaluation to a higher-risk, heavily medicated population, in which the primary endpoint was not met. The ongoing ZENITH outcomes trial will determine whether AGT silencing reduces hard cardiovascular end-points. Aprocitentan reduced office and ambulatory systolic BP in resistant hypertension (PRECISION trial) and has received regulatory approval in the USA, EU, and UK, with specific monitoring requirements for fluid retention and hematological effects. Baxdrostat demonstrated selective aldosterone-synthase inhibition with meaningful BP reductions across two phase II trials. RNA interference targeting AGT represents one of the most advanced disease-modifying platforms in hypertension, alongside the already-approved endothelin antagonism and the emerging aldosterone synthase inhibition strategy. The available evidence supports cautious optimism and continued translational investment, but not premature adoption into routine practice.