Mechanism of Action
AT1R: Vasoconstriction and Pathological Signaling
AT1R is a Gq-coupled GPCR expressed in vascular smooth muscle, adrenal cortex, kidney, heart, and brain. Ang II binding triggers IP3-mediated calcium release and PKC activation causing potent vasoconstriction. AT1R also activates the JAK-STAT, MAPK, and NF-kB pathways that drive vascular inflammation, fibrosis, and cardiac hypertrophy. Aldosterone release from the adrenal cortex further promotes sodium retention and potassium excretion.
AT2R: Counter-Regulatory Effects
AT2R expression is high during fetal development and increases pathologically in injury states. AT2R activation through Gi-coupling and bradykinin/NO production opposes AT1R-mediated vasoconstriction and fibrosis. AT2R agonists are under investigation as cardiovascular and neuroprotective drugs. The balance between AT1R and AT2R signaling determines the net cardiovascular and fibrotic outcome of RAAS activation.
Relationship to Angiotensin 1-7
Ang II is converted to Angiotensin 1-7 by ACE2, shifting signaling from the vasoconstrictive AT1R axis to the vasodilatory Mas receptor axis. This ACE2-mediated conversion explains why Ang 1-7 levels rise when ACE2 activity is high and fall when ACE2 is inhibited or downregulated (as in COVID-19, where SARS-CoV-2 uses ACE2 as its entry receptor, reducing Ang 1-7 availability).
Research Summary
Vasodilatory Shock Treatment
HumanThe ATHOS-3 Phase III trial showed IV Angiotensin II (Giapreza) significantly increased mean arterial pressure in vasodilatory shock patients with inadequate response to catecholamines. Ang II vasopressor action does not depend on adrenergic receptors, making it uniquely effective in catecholamine-depleted shock states. FDA approval in 2017 established a new vasopressor class.
RAAS Pathophysiology Research
HumanIV Angiotensin II infusion in human volunteers is a validated model for studying RAAS-driven hypertension, vascular inflammation, and aldosterone physiology. These infusion protocols have enabled mechanistic dissection of AT1R versus AT2R contributions to vascular biology, informing the development of ARBs, ACE inhibitors, and direct renin inhibitors.
COVID-19 and RAAS Dysregulation
HumanSARS-CoV-2 entry via ACE2 downregulates ACE2 expression, reducing Ang 1-7 production and increasing Ang II accumulation. This RAAS dysregulation contributes to COVID-19-associated lung injury, hypertension exacerbation, and cardiac damage. Understanding this mechanism drove research into Ang 1-7 supplementation and RAS-modulating therapies in COVID-19.
Calculate your Angiotensin II dose Vial strength, BAC water, exact syringe draw in IU. Free, no signup. Open Calc →
Research Protocols
| Goal | Dose | Frequency | Route |
|---|---|---|---|
| Vasodilatory shock | 20-40 ng/kg/min (starting) | Continuous IV infusion, titrate to MAP | Intravenous |
| RAAS physiology research | 2-4 ng/kg/min | Research infusion x 30-60 min | Intravenous |
Ang II clinical use is as Giapreza for vasopressor indication. RAAS research infusions use carefully controlled doses with blood pressure monitoring.
Interactions
Safety Profile
Giapreza (Ang II) in clinical vasopressor use causes expected hypertension if over-dosed and requires continuous blood pressure monitoring. Thromboembolism incidence was increased in the ATHOS-3 trial compared to placebo, requiring anticoagulation consideration. The extremely short plasma half-life allows rapid titration. Prolonged high-dose Ang II signaling through AT1R is pathological (hypertension, fibrosis), limiting long-term administration.
References
- [1]Khanna A, et al. Angiotensin II for the Treatment of Vasodilatory Shock (ATHOS-3). N Engl J Med. 2017;377(5):419-430.
- [2]Dzau VJ, et al. The relevance of tissue angiotensin-converting enzyme. Manifestations in mechanistic and endpoint data. Am J Cardiol. 2001.
- [3]Verdecchia P, et al. The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Eur J Intern Med. 2020.