Resistant Hypertension Beyond Spironolactone: Endothelin, Denervation and Aldosterone Synthase

Key Takeaways

• Resistant hypertension is a condition in which blood pressure remains above target values despite the use of three drugs from different classes, including a long-acting thiazide-type diuretic, at maximal or maximally tolerated doses, or when four or more drugs are required for control. Refractory hypertension, in contrast, is a narrower phenotype that remains uncontrolled despite five or more medications, including chlorthalidone and a mineralocorticoid receptor antagonist. Before either of these diagnoses is made, pseudoresistance must be excluded through ambulatory blood pressure monitoring, objective assessment of treatment adherence, and screening for secondary causes, particularly primary aldosteronism.
• The dominant mechanisms in the fourth-line treatment space are aldosterone excess leading to sodium retention and vascular fibrosis; an activated endothelin-1 axis that is salt-sensitive and unaffected by any of the existing antihypertensive classes; and persistent renal afferent and efferent sympathetic signaling.
• In cases where the potassium level is 5.0 mmol/L or lower and the eGFR is above 45 mL/min/1.73 m2, spironolactone 25 mg daily titrated to 50 mg remains the evidence-based fourth-line agent. Aprocitentan 12.5 mg daily is now an approved alternative; although aldosterone synthase inhibitors such as baxdrostat and lorundrostat have completed phase 3 trials, they are not yet in routine therapy.
• Class-specific adverse effects are predominant during monitoring: hyperkalemia and creatinine elevation with mineralocorticoid receptor antagonists and aldosterone synthase inhibitors; dose-dependent fluid retention and anemia with dual endothelin antagonism; and an absolute contraindication during pregnancy for the endothelin class.
• Renal denervation is a procedure reserved for treatment-adherent patients with ambulatory-confirmed uncontrolled hypertension, preserved renal function, and suitable renal artery anatomy; it is not a solution for nonadherence, white-coat effect, or unrecognized primary aldosteronism.

Introduction and Clinical Background

Resistant hypertension is defined as a condition in which blood pressure remains above the therapeutic target despite the concurrent use of at least three antihypertensive agents from different classes, including a diuretic, at maximum or maximally tolerated doses, or when four or more medications are required for blood pressure control^[1]. Although this definition is deceptively simple, it can be clinically problematic, as the vast majority of patients who appear to meet the definition may not actually have resistant hypertension. Apparent treatment resistance can often be a result of nonadherence to therapy, suboptimal diuretic choice or dosing, white-coat effect, or interfering substances such as nonsteroidal anti-inflammatory drugs, sympathomimetic decongestants, oral contraceptives, cyclosporine, or excessive alcohol consumption. A diagnosis of resistant hypertension should be made after these factors have been investigated.

Once these conditions are systematically excluded, true resistant hypertension affects approximately 10% of patients treated for hypertension, and the diagnosis requires that secondary causes be ruled out^[2]. The reported prevalence in published populations varies considerably, from approximately 6% to 18% of hypertensive patients, depending on the case definition and detection method^[3]. The clinical stakes in resistant hypertension are high: this phenotype increases the short- and long-term risk of heart failure, ischemic heart disease, stroke, and kidney failure, and it is associated with left ventricular hypertrophy, albuminuria, and an accelerated decline in eGFR at presentation.

The current therapeutic landscape is sobering. Hypertension affects approximately 30.4% of the global adult population and remains the leading preventable risk factor for death; despite this, fewer than 20% of affected individuals are controlled^[4]. For seventeen years after 2007, no entirely new class of antihypertensive medication was approved, leaving clinicians managing fourth-line therapy to recombine agents with largely overlapping mechanisms of action. This period of stagnation appears to have ended. Dual endothelin receptor antagonism has entered clinical practice, aldosterone synthase inhibition has yielded two positive phase 3 programs, and two catheter-based renal denervation systems received regulatory approval in late 2023. The practical question for 2025 is no longer whether options exist, but how to sequence and deploy them against a defined phenotype.

Molecular and Pathophysiological Mechanisms

Aldosterone Excess, Receptor Blockade, and Terminal Synthesis Blockade

Resistant hypertension can largely present as a low-renin, salt-sensitive state characterized by volume expansion. Inappropriate aldosterone secretion, ranging from overt primary aldosteronism to subclinical autonomous production, increases epithelial sodium channel activity in the distal nephron, expands plasma volume, and promotes perivascular fibrosis, inflammation, and arterial stiffening through non-epithelial mineralocorticoid receptor signaling in vascular smooth muscle, endothelium, myocardium, and immune cells. High aldosterone levels are mechanistically linked to inflammation and organ fibrosis and to the increased cardiovascular events observed in this population.^[5]

Three pharmacological strategies target this axis, and they are not interchangeable. Steroidal mineralocorticoid receptor antagonists—spironolactone and eplerenone—competitively block the receptor but leave the upstream feedback loop intact; plasma aldosterone levels therefore rise with treatment. Spironolactone also binds to androgen and progesterone receptors, leading to gynecomastia and menstrual irregularities. Non-steroidal antagonists such as finerenone, in contrast, bind to the receptor with a bulkier, non-steroidal scaffold, distribute more evenly between the kidney and heart, and do not cross-react with sex steroids; however, these agents also permit aldosterone breakthrough. Aldosterone synthase inhibitors—baxdrostat, lorundrostat, and the investigational agent vicadrostat—act one step earlier, blocking CYP11B2 and lowering circulating aldosterone itself. They thus silence both genomic and non-genomic mineralocorticoid signaling pathways, leaving no ligand that could overcome receptor blockade.^[4] The key pharmacological challenge for this class is selectivity: CYP11B2 shares approximately 93% amino acid homology with CYP11B1, the 11-beta-hydroxylase that produces cortisol. Insufficient selectivity therefore carries a risk of adrenocortical insufficiency and a compensatory rise in corticotropin.

The Endothelin-1 Axis and the Salt-Sensitive Phenotype

Endothelin-1 is a potent endothelium-derived vasoconstrictor that also triggers neurohormonal and sympathetic activation, stimulates aldosterone synthesis and secretion, and causes endothelial dysfunction, vascular hypertrophy, and fibrosis. It signals through two receptors: ETA activation on vascular smooth muscle causes vasoconstriction, whereas ETB mediates vasoconstriction in smooth muscle but vasodilation in endothelial cells via nitric oxide release.^[6] ETB also governs renal sodium excretion, which explains why dual antagonism leads to more sodium and fluid retention than selective ETA blockade.

Critically, no existing antihypertensive class targets this pathway, which may explain some of the residual blood pressure seen in resistant disease. The endothelin system is stimulated by dietary salt and is activated in the very groups that are overrepresented among patients with resistant hypertension—individuals of African descent, patients with obesity, and those with obstructive sleep apnea.^[7] The dual ETA/ETB antagonist aprocitentan, approved in early 2024, reaches maximum plasma concentration in four to five hours, has an effective half-life of 41 hours, and achieves steady state by day 8. Its volume of distribution is 20 liters, it is highly bound to albumin, and it is eliminated via UGT1A1- and UGT2B7-mediated N-glucosylation and non-enzymatic hydrolysis.^[8] The long half-life provides an advantageous pharmacokinetic profile in a population defined in part by poor treatment adherence.

Renal Sympathetic Signaling and Determinants of Effective Denervation

Efferent renal sympathetic discharge promotes renin release, sodium reabsorption, and renal vasoconstriction, while afferent fibers coursing through the renal adventitia signal to the hypothalamus and rostral ventrolateral medulla to maintain central sympathetic tone. Catheter-based ablation interrupts both pathways. In murine models and cultured BV2 microglia cells, renal denervation has been shown to downregulate the interferon-inducible gene Ifi27l2a and coordinately suppress inflammatory cytokine release via cGAS-STING signaling, a finding that suggests its antihypertensive effect may have a central neuroinflammatory component.^[9] These are preclinical observations and have not been demonstrated in humans.

In humans, the dominant variable is the completeness of the ablation. In 21 patients with resistant hypertension studied with renal 123-I-meta-iodobenzylguanidine scintigraphy before and six weeks after radiofrequency denervation, office systolic blood pressure fell from 172 to 153 mmHg (p = 0.036), but 24-hour ambulatory systolic blood pressure did not change significantly (p = 0.602). The fact that renal tracer uptake and washout also did not change supports incomplete nerve injury as an explanation for inconsistent efficacy.^[10] Anatomy is also important: among 564 patients treated with a mono-electrode radiofrequency catheter at nine European and Australian centers, blood pressure fell by 19/8 mmHg at six months (p < 0.001), a reduction that was unaffected by accessory renal arteries or renal artery disease. However, patients with bilateral renal artery diameters of 4 mm or less achieved a systolic reduction of 29 mmHg, compared with 26 mmHg for unilateral small-diameter vessels and 17 mmHg for bilateral larger vessels (p < 0.001).^[11] This cohort was unblinded and lacked a sham control group; the absolute magnitudes therefore overstate the true non-pharmacologic effect.

Clinical Evidence and Guideline Comparison

The PRECISION Trial and Dual Endothelin Antagonism

In the PRECISION trial, 730 patients with resistant hypertension on standard triple background therapy were randomized. At week 4, the least-squares mean office systolic blood pressure had fallen by 15.3 mmHg with aprocitentan 12.5 mg, 15.2 mmHg with 25 mg, and 11.5 mmHg with placebo. These results correspond to placebo-corrected differences of 3.8 mmHg (97.5% CI, – 6.8 to – 0.8; p = 0.0042) and 3.7 mmHg (97.5% CI, – 6.7 to – 0.8; p = 0.0046), respectively; the corresponding differences in 24-hour ambulatory systolic blood pressure were 4.2 mmHg (95% CI, – 6.2 to – 2.1) and 5.9 mmHg (95% CI, – 7.9 to – 3.8).^[12] The effect appeared durable: in the group rerandomized to placebo at week 36, office systolic blood pressure increased by 5.8 mmHg (95% CI, 3.7 to 7.9; p < 0.0001) compared with the group that continued aprocitentan. The most common adverse event during the double-blind phase was mild-to-moderate edema or fluid retention, which occurred in 9%, 18%, and 2% of the 12.5-mg, 25-mg, and placebo groups, respectively. Two points bear emphasis for clinical practice: the 25-mg dose doubled the edema signal without providing additional blood pressure reduction, and the placebo-corrected office blood pressure effect of under 4 mmHg is modest compared with the absolute 15-mmHg reduction seen in both active arms.^[12]

Aldosterone Synthase Inhibition: The BrigHTN, HALO, and BaxHTN Trials

In the phase 2 BrigHTN trial of patients with treatment-resistant hypertension on at least three agents (including a diuretic), 248 patients completed treatment, and dose-dependent systolic reductions of 20.3, 17.5, 12.1, and 9.4 mmHg were observed in the 2-mg, 1-mg, 0.5-mg, and placebo groups, respectively; the placebo-corrected difference was 11.0 mmHg for the 2-mg dose (95% CI, – 16.4 to – 5.5; p < 0.001) and 8.1 mmHg for the 1-mg dose (95% CI, – 13.5 to – 2.8; p = 0.003), while two patients had a potassium level of 6.0 mmol/L or greater and no patient had adrenocortical insufficiency.^[13] The subsequent HALO trial in patients with uncontrolled hypertension failed to show any blood-pressure-lowering benefit for baxdrostat compared with placebo, a discrepancy generally attributed in the literature to differences in adherence and population.^[5]

The phase 3 BaxHTN trial resolved much of this uncertainty. Among 794 patients with uncontrolled hypertension on two agents or resistant hypertension on three or more agents including a diuretic, seated systolic blood pressure at week 12 fell by 14.5 mmHg with 1 mg and 15.7 mmHg with 2 mg, compared with 5.8 mmHg with placebo. The placebo-corrected differences were 8.7 mmHg (95% CI, – 11.5 to – 5.8) and 9.8 mmHg (95% CI, – 12.6 to – 7.0), respectively, with a p value of less than 0.001 for both; a potassium level above 6.0 mmol/L occurred in 2.3%, 3.0%, and 0.4% of the groups, respectively.^[14] The incremental benefit of the 2-mg dose over the 1-mg dose was approximately 1 mmHg, at the cost of a higher rate of hyperkalemia.

Lorundrostat: The Advance-HTN and Launch-HTN Trials

The Advance-HTN trial studied 285 participants on a standard two- to five-drug regimen with uncontrolled hypertension confirmed by ambulatory blood pressure measurement. At week 12, the 24-hour mean systolic blood pressure had fallen by 15.4 mmHg with fixed-dose 50 mg lorundrostat, 13.9 mmHg in the dose-titration arm, and 7.4 mmHg with placebo. These results correspond to placebo-adjusted reductions of 7.9 mmHg (97.5% CI, – 13.3 to – 2.6) and 6.5 mmHg (97.5% CI, – 11.8 to – 1.2), respectively; a potassium level above 6.0 mmol/L occurred in 5% and 7% of participants receiving lorundrostat, whereas it was observed in no participants receiving placebo.^[15] The use of ambulatory monitoring as the primary endpoint and the fact that 53% of the cohort was Black make this one of the more methodologically rigorous datasets in the field.

The Launch-HTN trial expanded this scope to 1083 participants at 159 centers, of whom 60.1% were taking three or more antihypertensive drugs. In the pooled 50-mg group, automated office systolic blood pressure at week 6 fell by 16.9 mmHg (95% CI, – 19.0 to – 14.9), compared with 7.9 mmHg in the placebo group (95% CI, – 11.5 to – 4.2); the least-squares mean difference was 9.1 mmHg (95% CI, – 13.3 to – 4.9; p < 0.001); hyponatremia, hyperkalemia, and decreased renal function were more common with lorundrostat, although each of these adverse effects led to treatment discontinuation in far fewer than 1% of participants.^[16] Taken together, the two aldosterone synthase programs deliver placebo-corrected systolic blood pressure reductions roughly double those achieved with dual endothelin antagonism in the PRECISION trial; however, no head-to-head trial has compared the two approaches, and background treatment regimens differ.

Renal Denervation and Its Place in the Guidelines

Endovascular renal denervation is the interventional procedure with the strongest evidence base in hypertension, and two systems—one radiofrequency, the other ultrasound—received FDA approval in late 2023 based on a series of sham-controlled trials in patients ranging from drug-naïve to those with true resistant disease.^[17] Current guidelines from leading societies recommend lifestyle modification plus renin-angiotensin blockade, a calcium-channel blocker, and a long-acting thiazide-type or thiazide-like diuretic as the foundation of therapy, with a mineralocorticoid receptor antagonist as the evidence-based fourth agent.^[1] Current reviews position both spironolactone and renal denervation as effective options for lowering blood pressure once true resistance has been established.^[2]

Practical Implications and Safety Profile

Determining the Phenotype Before Treatment Escalation

The decision to initiate fourth-line therapy should not be based solely on office measurements. The decision should be confirmed with 24-hour ambulatory blood pressure monitoring or validated home measurements. Where possible, treatment adherence should be confirmed using objective methods—such as directly observed therapy, pharmacy records, or urine/serum drug level analysis—as these methods reclassify a significant proportion of apparent resistance. Admittedly, drug level analysis is challenging in clinical practice. First, diuretic therapy should be optimized: chlorthalidone 12.5 to 25 mg daily is preferred over hydrochlorothiazide due to its longer duration of action. When the eGFR falls below 30 mL/min/1.73 m², a switch should be made to a loop diuretic (furosemide twice daily or torsemide 10 to 20 mg daily). The term refractory hypertension should be reserved for patients who remain uncontrolled despite five or more agents, including chlorthalidone and a mineralocorticoid receptor antagonist. This group is characterized by sympathetic overactivity rather than volume excess and responds poorly to further intensification of diuretic therapy.

Screening for Primary Aldosteronism Without Losing Blood Pressure Control

Every patient with resistant hypertension should be screened with a plasma aldosterone-to-renin ratio. First, hypokalemia should be corrected to raise the potassium level above 4.0 mmol/L, sodium intake should be liberalized, and the blood sample should be drawn mid-morning after the patient has been upright for at least two hours. Mineralocorticoid receptor antagonists, amiloride, and high-dose diuretics should be discontinued for four to six weeks. Beta-blockers and centrally acting agonists suppress renin, leading to false positives, whereas ACE inhibitors, angiotensin receptor blockers, and diuretics elevate renin, leading to false negatives. During this period, bridging should be done with agents that minimally affect the axis: slow-release verapamil 180 to 240 mg daily, hydralazine 25 to 50 mg three times daily, and doxazosin 2 to 8 mg daily. An aldosterone-to-renin ratio above 30 ng/dL per ng/mL/h, with a plasma aldosterone level of at least 10 ng/dL, is a commonly used threshold; however, cut-off values may vary by assay kit and guideline. A positive screening result requires confirmation with a saline infusion or captopril challenge test, followed by adrenal vein sampling in surgical candidates.

Sequencing and Dosing in Fourth-Line Therapy

Spironolactone 25 mg once daily remains the standard fourth-line agent. If the potassium level is 5.0 mmol/L or less and the eGFR is above 45 mL/min/1.73 m², the dose can be titrated to 50 mg after four weeks. When gynecomastia or menstrual irregularities occur, eplerenone 50 mg once or twice daily is an alternative. In patients with a low-renin phenotype, amiloride 5 to 10 mg daily is a reasonable option. In patients with type 2 diabetes and albuminuric chronic kidney disease, finerenone 10 to 20 mg daily is appropriate, though this agent should be viewed primarily as a renal and cardiovascular risk-reducing agent rather than a potent antihypertensive.

When a mineralocorticoid receptor antagonist is contraindicated, not tolerated, or insufficient, the next approved step is aprocitentan 12.5 mg once daily; higher doses increase fluid retention without providing additional efficacy. In refractory disease with predominant sympathetic activity, a beta-blocker with vasodilatory properties is added to the regimen, followed by clonidine or hydralazine, with attention to tolerability issues. Among the aldosterone synthase inhibitors, baxdrostat has been studied at doses of 1 to 2 mg daily and lorundrostat at 50 mg daily (optionally titrated to 100 mg); however, the availability of these drugs varies by country, and clinicians must confirm all doses against the approved local product monograph.

Safety Monitoring

For any agent acting on the mineralocorticoid axis, potassium and creatinine levels should be checked at baseline, one to two weeks after initiation or dose increase, again at four weeks, and then every three to six months. If potassium rises above 5.5 mmol/L, the dose should be halved or the drug discontinued; if it rises above 6.0 mmol/L, therapy should be held. An increase in creatinine of up to 30% is hemodynamic and does not require drug discontinuation; for increases above this threshold, volume status and concomitant use of NSAIDs, trimethoprim, or potassium supplements should be reassessed.

Dual endothelin antagonism requires a different set of monitoring parameters: daily weight monitoring, hemoglobin measurement at baseline and periodically due to the risk of dilutional and true anemia, and baseline liver enzymes. Fluid retention is managed in most cases by intensifying loop diuretic therapy rather than discontinuing the drug directly, but new-onset dyspnea in a patient with a low ejection fraction necessitates discontinuation. This class is teratogenic and absolutely contraindicated in pregnancy; a negative pregnancy test before starting therapy, monthly testing during therapy, and the use of two reliable methods of contraception are mandatory. Endothelin receptor antagonists also carry a risk of dose-dependent fluid retention and heart failure in chronic kidney disease. To mitigate this risk, approaches such as the combination of selective ETA blockade with an SGLT2 inhibitor have been specifically investigated in this patient population^[18].

Candidate Selection for Renal Denervation

The optimal candidate is an adherent patient with uncontrolled hypertension confirmed by ambulatory measurements despite two to four agents, an eGFR of 40 mL/min/1.73 m² or greater, a main renal artery diameter of approximately 3 to 8 mm with at least 20 mm of treatable vessel length, and no fibromuscular dysplasia, significant stenosis, or prior history of renal stenting. Patients who should not be referred include those with undetected nonadherence, isolated white-coat hypertension, untreated primary aldosteronism, or severe obstructive sleep apnea, as well as patients with advanced chronic kidney disease whose elevated blood pressure is due to a fixed volume load. The patient should receive realistic counseling: the placebo-adjusted effect observed in sham-controlled trials is substantially less than the reductions reported in unblinded registries, and the procedure is an adjunct to, not a replacement for, pharmacotherapy. At experienced centers, expected procedural complications—access-site hematoma, transient bradycardia during ablation, renal artery dissection—occur at rates in the low single digits and below 1%, respectively.

Future Perspectives and Open Questions

The most important unanswered question is whether any of these strategies not only lower blood pressure but also reduce hard cardiovascular or renal endpoints. Every pivotal trial discussed here used a surrogate endpoint over a period of 6 to 40 weeks. Given that resistant hypertension carries a significant additional risk for heart failure, stroke, and kidney failure, the priority should now be on endpoint trials, not more blood-pressure-lowering studies.

Second, the discrepancy between the BrigHTN and HALO trials reveals how sensitive this field is to background treatment adherence, run-in period design, and endpoint modality. Studies using ambulatory monitoring with standardized and verified background regimens produce more reliable and generally more conservative estimates than those based on office measurements; cross-trial comparisons that ignore this distinction are misleading.

Third, combination pharmacology represents the most promising direction in the near future. The endothelin field is moving toward molecules that combine ETA antagonism with angiotensin II type 1 receptor blockade in a single small molecule, as exemplified by sparsentan, and toward combinations with phosphodiesterase-5 inhibitors and SGLT2 inhibitors, which aim to provide synergistic benefit while mitigating fluid retention^[19]. Whether pairing an aldosterone synthase inhibitor with a nonsteroidal mineralocorticoid receptor antagonist provides additive blood pressure reduction or merely additive hyperkalemia has not yet been resolved.

Fourth, device-based therapies need an endpoint that demonstrates procedural integrity. Until an intraprocedural marker is available to confirm that sufficient nerve damage has occurred, responder heterogeneity will persist, and patient selection will remain probabilistic. Alternative neuromodulation approaches, such as carotid baroreceptor stimulation and arteriovenous anastomosis, are still under investigation for patients who derive insufficient benefit from medical therapy^[3].

Finally, this field must confront issues of cost and accessibility. Three new mechanisms and an approved interventional procedure will not change population-level control rates if they are implemented only at specialist referral centers. In most practices, the most important interventions remain the meticulous exclusion of pseudoresistance, the optimal use of chlorthalidone, and systematic screening for primary aldosteronism. These steps, despite being low-cost, are still omitted in the majority of patients labeled as resistant.

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