The very molecule that constricts our blood vessels might be key to solving a life-threatening COVID-19 complication.
When the COVID-19 pandemic surged across the globe, clinicians faced a daunting challenge: a mysterious illness that could suddenly plunge patients into life-threatening shock. As scientists raced to understand the novel coronavirus, a surprising candidate emerged from within human biology itself—angiotensin II, a potent hormone long known for regulating blood pressure.
This article explores the compelling science and clinical evidence behind using this powerful vasoconstrictor to treat COVID-19's most critical manifestations. The story revolves around a complex physiological system hijacked by the virus and the clinicians who dared to re-purpose a known therapy for a new battlefield.
To understand the theory behind angiotensin II therapy, we must first explore the renin-angiotensin-aldosterone system (RAAS), a crucial hormone system that regulates blood pressure, fluid balance, and vascular resistance.
"Harmful" Axis
ACE → Ang II → AT1R
Vasoconstriction, Inflammation, Tissue Damage
"Protective" Axis
ACE2 → Ang-(1-7) → MASR
Vasodilation, Anti-inflammatory, Antioxidant
Under normal conditions, these two systems maintain a delicate balance. Then came SARS-CoV-2.
The plot twist in our story comes when we understand how SARS-CoV-2 invades human cells. The virus enters by binding to the ACE2 receptor3 , which is abundantly expressed in various tissues, including the lungs, heart, kidneys, and blood vessels.
SARS-CoV-2 spike protein binds to ACE2 receptors, facilitating cellular entry and infection.
Viral binding triggers downregulation of ACE2, disrupting the delicate RAAS balance.
Reduced ACE2 activity disrupts the RAAS balance, suppressing the protective pathway.
The ACE-Ang II-AT1R axis dominates unchecked, creating a perfect storm for severe COVID-19.
Here lies the paradox: if angiotensin II is part of the problem, how could administering it possibly help?
Research revealed that in critically ill COVID-19 patients, the functional ACE needed to produce natural angiotensin II is severely disrupted8 . Without it, the body cannot generate sufficient angiotensin II to maintain blood pressure, leading to vasodilatory shock that doesn't respond well to conventional treatments.
Angiotensin II directly activates AT1 receptors, causing blood vessels to constrict and raising blood pressure.
By improving renal perfusion, angiotensin II decreases production of harmful angiotensin I.
Replacement therapy could potentially reduce excessive accumulation of vasodilatory substances like bradykinin8 .
While no large-scale trials exclusively studied angiotensin II in COVID-19, the critical ATHOS-3 trial provided crucial evidence for its use in vasodilatory shock, which became highly relevant for pandemic care.
This randomized, controlled trial investigated angiotensin II versus placebo in patients with vasodilatory shock that was refractory to conventional vasopressors.
The trial demonstrated that angiotensin II was significantly effective at increasing mean arterial pressure and reducing background norepinephrine requirements8 .
| Patient Subgroup | Finding with Angiotensin II | Statistical Significance |
|---|---|---|
| Overall mortality | No significant difference | Neutral |
| Rapid responders (≤5 ng/kg/min within 30 min) | 41% mortality vs. 66% in non-rapid responders | P < .001 |
| Patients with APACHE II score >30 | 51.8% mortality vs. 70.8% with conventional vasopressors | P = .037 |
| Patients with AKI on renal replacement therapy | 47% mortality vs. 70% with conventional vasopressors | P = .012 |
| Liberation from RRT by day 7 | 38% for Ang-II vs. 15% for conventional vasopressors | P = .007 |
These findings suggested that specific patient populations, particularly those with high illness severity and kidney dysfunction, might derive significant benefit from angiotensin II therapy—a profile that often matched critically ill COVID-19 patients.
Angiotensin II represents just one approach to manipulating the renin-angiotensin system against COVID-19. The table below outlines various therapeutic strategies that have been investigated:
| Therapeutic Approach | Mechanism of Action | Clinical Evidence |
|---|---|---|
| Angiotensin II | Replaces depleted endogenous Ang-II, agonizes AT1 receptors to increase vascular tone | Supported by physiologic rationale and pre-COVID trials; no dedicated large RCTs for COVID-198 |
| ACE Inhibitors/ARBs | Inhibit harmful RAS axis; may upregulate ACE2 | Not associated with increased infection risk or mortality; recommended to continue in most patients1 4 |
| Recombinant ACE2 | Acts as decoy receptor for virus; restores protective RAS axis | Early clinical trials showed reduced systemic inflammation; rescues lung injury in animal models3 |
| Angiotensin-(1-7) | Activates protective MAS receptor pathway | Phase 1-2 trials showed safety; mixed efficacy results in clinical outcomes9 |
| Research Tool | Function/Application | Example in Context |
|---|---|---|
| Vero E6-ACE2 Cells | Mammalian cell line with high ACE2 expression; used for in vitro infection studies | Testing SARS-CoV-2 infectivity and viral load in presence of angiotensin peptides6 |
| SARS-CoV-2 Variants | Different viral lineages with potentially varying infectivity and clinical impact | Studying drug efficacy against specific variants (e.g., Delta, Omicron lineages)1 2 |
| ELISA Kits | Quantify protein concentrations in patient samples | Measuring levels of ACE, ACE2, Angiotensin-(1-7), and other RAS components in serum6 |
| Recombinant Angiotensin Peptides | Pharmaceutical-grade compounds for clinical administration | Continuous intravenous infusion of Angiotensin-(1-7) in clinical trials9 |
The investigation into angiotensin II for COVID-19 represents a fascinating chapter in medical science—where understanding a virus's mechanism led to re-purposing a known therapy against a newfound complication. While conclusive evidence establishing angiotensin II as standard treatment for COVID-19-related shock remains elusive, the physiological rationale is strong enough that it remains a compelling option for rescue therapy.
The story of angiotensin research in COVID-19 underscores a broader principle in medicine: sometimes solutions to novel challenges lie in re-examining and re-purposing our existing knowledge of human physiology. As research continues, manipulating the renin-angiotensin system may yet yield more insights for treating not only COVID-19 but other conditions characterized by inflammatory damage and vascular instability.
The angiotensin paradox—that a molecule known for its harmful effects in chronic disease might provide rescue in acute critical illness—reminds us that in biology, context is everything.