Angiotensin II
Evidence: C+Evidence: BGrade C+ — Applies to native, non-manufactured Angiotensin II's own direct human physiology evidence: three small, controlled, direct intravenous-infusion studies in healthy human volunteers (PMID 1984867, PMID 1315650, PMID 8214044) covering pressor/sympathetic, systemic/renal hemodynamic, and metabolic domains respectively, plus one reused comparator data point from an existing Angiotensin-(1-7) trial (study-b14-ang17-renal-2013-pmid23918750) and two dual-use Angiotensin-I-vs-II dissociation studies (PMID 10826400, PMID 9683924). This is genuine, multi-domain, directly-administered human evidence — not merely mechanistic assertion — but it consists of small (N=6-14), decades-old, acute-infusion physiology studies, not a therapeutic-outcome trial program for native Angiotensin II itself. 'C+' rather than a flat 'C' reflects the genuine breadth across independent physiological domains found by more than one independent research group. This grade does NOT extend to or from Giapreza's related-programme grade below, and does NOT extend to or from Angiotensin-(1-7)'s independently-assigned grade (C, unchanged) despite the shared RAAS pathway and the one reused comparator study..
Grade B — Giapreza (synthetic human angiotensin II) approved-product programme.
Giapreza is, per DailyMed's own label description and every independent secondary regulatory source found across this project's research, chemically synthesized (not recombinant), exact-sequence human Angiotensin II acetate — same sequence as native Angiotensin II. Its clinical-development programme includes one adequately powered, placebo-controlled Phase III RCT (ATHOS-3, PMID 28528561, N=344 randomized/321 analyzed) that met its primary blood-pressure-response endpoint decisively (69.9% vs. 23.4%, P<0.001, OR 7.95) and showed a real catecholamine-sparing effect and reduced renal-replacement-therapy initiation (19.0% vs. 32.4%), supporting its FDA approval for septic/distributive shock. However, 28-day mortality was NOT significantly improved (46.0% vs. 53.8%, HR 0.78, P=0.12) — no mortality benefit is established, and this must never be implied. The label's own adverse-reaction table further documents a real, statistically apparent excess of arterial/venous thromboembolic events (12.9% vs. 5.1%, including DVT 4.3% vs. 0.0%) — a genuine, labeled, product-specific safety signal, originally reported by the ATHOS-3 investigators themselves and reconfirmed unchanged on a freshly re-fetched current label. 'B' (matching this project's Terlipressin precedent for a real, FDA-approved, single pivotal-RCT-supported product with a genuine, labeled safety signal and no demonstrated mortality benefit) reflects a real approval with real efficacy on its primary endpoint, capped below 'A' by the non-significant mortality result and the labeled thromboembolic signal. This related-programme grade must NEVER be used to inflate native/endogenous Angiotensin II's own 'C+' grade, and native Angiotensin II's grade must never be read as implying anything about Giapreza's approval-supporting trial data or vice versa.
Renal / Fluid-Balance Signaling
Evidence Snapshot
What this grade covers
Applies to native, non-manufactured Angiotensin II's own direct human physiology evidence: three small, controlled, direct intravenous-infusion studies in healthy human volunteers (PMID 1984867, PMID 1315650, PMID 8214044) covering pressor/sympathetic, systemic/renal hemodynamic, and metabolic domains respectively, plus one reused comparator data point from an existing Angiotensin-(1-7) trial (study-b14-ang17-renal-2013-pmid23918750) and two dual-use Angiotensin-I-vs-II dissociation studies (PMID 10826400, PMID 9683924). This is genuine, multi-domain, directly-administered human evidence — not merely mechanistic assertion — but it consists of small (N=6-14), decades-old, acute-infusion physiology studies, not a therapeutic-outcome trial program for native Angiotensin II itself. 'C+' rather than a flat 'C' reflects the genuine breadth across independent physiological domains found by more than one independent research group. This grade does NOT extend to or from Giapreza's related-programme grade below, and does NOT extend to or from Angiotensin-(1-7)'s independently-assigned grade (C, unchanged) despite the shared RAAS pathway and the one reused comparator study.
Regulatory Context
Native Angiotensin II is an endogenous hormone, not itself an FDA-approved drug. Giapreza (angiotensin II), a chemically synthesized, exact-sequence product, is FDA-approved specifically to increase blood pressure in adults with septic or other distributive shock; this is a product-specific approval, carries a labeled thromboembolic-risk warning, and does not extend to native Angiotensin II physiology or to any unapproved use.
Research Takeaway
Angiotensin II is the native human octapeptide (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe) formed by ACE-mediated cleavage of Angiotensin I, and is the primary active effector of the renin-angiotensin-aldosterone system acting via AT1 and AT2 receptors.
See all 7 evidence claims →Quick Summary
Angiotensin II is the primary active hormone of the renin-angiotensin-aldosterone system, and, as the exact-sequence synthetic product Giapreza, an FDA-approved vasopressor for septic/distributive shock refractory to standard therapy. Native Angiotensin II's own direct human evidence comes from small, controlled infusion physiology studies; Giapreza's evidence comes from one large, positive pivotal RCT (ATHOS-3) for blood-pressure response — but that trial did not establish a mortality benefit and its own label documents a real excess of blood-clot-related events, both limitations central to this molecule's evidence picture.
Mechanism & Research Overview
Angiotensin II is the primary active hormone of the renin-angiotensin-aldosterone system, and, as the exact-sequence synthetic product Giapreza, an FDA-approved vasopressor for septic/distributive shock refractory to standard therapy. Native Angiotensin II's own direct human evidence comes from small, controlled infusion physiology studies; Giapreza's evidence comes from one large, positive pivotal RCT (ATHOS-3) for blood-pressure response — but that trial did not establish a mortality benefit and its own label documents a real excess of blood-clot-related events, both limitations central to this molecule's evidence picture.
Evidence Claims
Individual scientific statements drawn from the sources cited below, each shown with the specific evidence boundary that statement does not establish.
Supported
Angiotensin II is the native human octapeptide (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe) formed by ACE-mediated cleavage of Angiotensin I, and is the primary active effector of the renin-angiotensin-aldosterone system acting via AT1 and AT2 receptors.
Sources: Effect of ACE inhibition on pressor, renal vascular, and adrenal responses to infusion of angiotensin I in normal subjects eating a low-salt diet; Dissociation between the renal effects of angiotensin I and II in sodium-restricted normal subjects; FDA Label / DailyMed Record for GIAPREZA (Angiotensin II)
Supported
Directly infused into healthy human volunteers, native Angiotensin II raises blood pressure, increases total peripheral resistance, reduces cardiac output and renal blood flow, and (at pressor doses) increases insulin-mediated glucose uptake — effects demonstrated across multiple small, independent, controlled human infusion studies.
Sources: Effect of a pressor infusion of angiotensin II on sympathetic activity and heart rate in normal humans; Dose-response study of the redistribution of intravascular volume by angiotensin II in man; Pressor doses of angiotensin II increase insulin-mediated glucose uptake in normotensive men
Supported
GIAPREZA (angiotensin II), a chemically synthesized, exact-sequence human Angiotensin II product, is FDA-approved specifically to increase blood pressure in adults with septic or other distributive shock; this approval is product-specific and does not constitute approval of native Angiotensin II for any other use.
Sources: FDA Label / DailyMed Record for GIAPREZA (Angiotensin II)
Supported
In the pivotal ATHOS-3 trial, GIAPREZA achieved its primary blood-pressure-response endpoint in 69.9% of treated patients versus 23.4% of placebo patients (P<0.001), with a catecholamine-sparing effect and a lower rate of new renal-replacement-therapy initiation (19.0% vs. 32.4%).
Sources: Angiotensin II for the Treatment of Vasodilatory Shock (ATHOS-3)
Supported
ATHOS-3 did not show a statistically significant reduction in overall 28-day mortality for GIAPREZA versus placebo (46.0% vs. 53.8%, HR 0.78, P=0.12); no mortality benefit is established for GIAPREZA, and this must not be inferred from its blood-pressure-response efficacy.
Does not establish
Evidence boundary: Positive post-hoc subgroup mortality signals (e.g., in patients on lower background vasopressor doses) are hypothesis-generating only, not the trial's primary, confirmed result.
Sources: Angiotensin II for the Treatment of Vasodilatory Shock (ATHOS-3)
Supported
GIAPREZA's current FDA label (DailyMed, Version 18, revised July 22, 2026) documents a higher incidence of arterial and venous thromboembolic events among GIAPREZA-treated patients than placebo in the pivotal ATHOS-3 trial (12.9% [21/163] vs. 5.1% [8/158]), including deep vein thrombosis specifically (4.3% [7/163] vs. 0.0% [0/158]), and its Warnings and Precautions recommend concurrent venous thromboembolism (VTE) prophylaxis. A separate 2025 exploratory systematic review of ATHOS-3 (PMID 40548153) reports that overall/aggregate adverse events, including a composite serious-adverse-event rate, were not significantly different between groups — this is an aggregate-level restatement of the original ATHOS-3 publication's own top-line adverse-event framing, not an independent statistical analysis of the thromboembolic/DVT category specifically, and it does not dispute, recalculate, or contradict the label's category-specific figures. The label's thromboembolic-event finding is the controlling, product-specific safety statement.
Sources: FDA Label / DailyMed Record for GIAPREZA (Angiotensin II); Angiotensin II for the Treatment of Vasodilatory Shock (ATHOS-3); Angiotensin II in Catecholamine-Refractory Shock: A Systematic Review and Exploratory Analysis of the ATHOS-3 Trial
Supported
Native, endogenous Angiotensin II physiology and GIAPREZA's approved-product programme are evaluated and graded separately; GIAPREZA's FDA approval, efficacy data, and safety signals are product-specific and must not be generalized to native Angiotensin II physiology, and native Angiotensin II's small physiology-study evidence base must not be used to imply anything about GIAPREZA's own trial results.
Safety & Evidence Limitations
Considerations reported in the sources cited on this page — not a complete list of every possible risk, and not medical advice.
Higher-Priority Safety Consideration
GIAPREZA label (current Version 18): 12.9% vs. 5.1% in ATHOS-3, including DVT 4.3% vs. 0.0%; concurrent VTE prophylaxis recommended. This category-specific finding was originally reported by the ATHOS-3 investigators themselves (PMID 28528561), not first identified by the label. A 2025 exploratory reanalysis (PMID 40548153) separately reports a comparable AGGREGATE serious-adverse-event rate (~52.6% vs 56.5%) restating ATHOS-3's own top-line framing; that aggregate statement does not analyze the thromboembolic/DVT category specifically and does not contradict the label's category-specific finding, which controls for product-safety purposes.Safety Consideration
ATHOS-3's primary 28-day mortality result was not statistically significant (HR 0.78, P=0.12); post-hoc subgroup signals are not confirmatory.Safety Consideration
GIAPREZA's approval is scoped to septic/distributive shock refractory to fluids/high-dose vasopressors, not general hypotension.Safety Consideration
Native Angiotensin II's own small physiology-study base must not be conflated with GIAPREZA's much larger, product-specific ATHOS-3 dataset in either direction.
Research Areas Being Studied
Research areas discussed on this page reflect the Renal / Fluid-Balance Signaling category and the sources cited below.
Findings Reported in Studies
Educational summary only — reported in cited studies, not a claim of proven benefit.
- Angiotensin II for the Treatment of Vasodilatory Shock (ATHOS-3) (2017):
- Effect of ACE inhibition on pressor, renal vascular, and adrenal responses to infusion of angiotensin I in normal subjects eating a low-salt diet (2000):
- Dissociation between the renal effects of angiotensin I and II in sodium-restricted normal subjects (1998):
- Pressor doses of angiotensin II increase insulin-mediated glucose uptake in normotensive men (1993):
- Dose-response study of the redistribution of intravascular volume by angiotensin II in man (1992):
- Effect of a pressor infusion of angiotensin II on sympathetic activity and heart rate in normal humans (1991):
Study Tables by Evidence Type
Human Studies & Clinical Data
| Title | Year | Population / Model | Dose / Duration / Finding | Safety Notes | Source |
|---|---|---|---|---|---|
| Angiotensin II for the Treatment of Vasodilatory Shock (ATHOS-3) | 2017 | 344 patients randomized (172 angiotensin II, 172 placebo); 321 (163 angiotensin II, 158 placebo) analyzed in the modified intention-to-treat primary analysis; septic/distributive shock refractory to fluids and high-dose vasopressors, 75 ICUs in 9 countries | Primary MAP-response endpoint met decisively: 69.9% (angiotensin II) vs 23.4% (placebo) achieved target blood pressure at hour 3, P<0.001, OR 7.95 (95% CI 4.76-13.3). Reduced concurrent background-catecholamine dosing; lower rate of new renal-replacement-therapy initiation (19.0% vs 32.4%). | Overall 28-day mortality was NOT statistically significant: 75/163 (46.0%) angiotensin II vs 85/158 (53.8%) placebo, HR 0.78 (95% CI 0.57-1.07), P=0.12. The trial's own reporting separately identified a distinct thromboembolic-event category imbalance (~13% vs ~5%), separate from its broader serious-adverse-event comparison. | |
| Effect of ACE inhibition on pressor, renal vascular, and adrenal responses to infusion of angiotensin I in normal subjects eating a low-salt diet | 2000 | 10 normotensive healthy men, low-salt diet, studied before and during ACE inhibition with enalapril; Angiotensin I infused at 3, 10, and 30 ng/kg/min | ACE inhibition abolished the pressor/aldosterone response to low/mid-dose Angiotensin I; only the highest dose (30 ng/kg/min) still raised plasma Angiotensin II and produced a pressor/aldosterone response, tracking the residual Angiotensin II formed — i.e., Angiotensin I's measured effects are mediated entirely through ACE-dependent conversion to Angiotensin II. | ||
| Dissociation between the renal effects of angiotensin I and II in sodium-restricted normal subjects | 1998 | Sodium-restricted normal human subjects; Angiotensin I and Angiotensin II separately infused and directly compared | Angiotensin I and Angiotensin II produce dissociable renal effects under sodium restriction — direct evidence that Angiotensin I's renal actions are not a simple proxy for Angiotensin II's. | ||
| Pressor doses of angiotensin II increase insulin-mediated glucose uptake in normotensive men | 1993 | N=14 normotensive men; 3-hour hyperinsulinemic-euglycemic clamp, angiotensin II infusion raising BP by 20/15 mmHg | Angiotensin II co-infusion increased whole-body glucose uptake by 15% and glucose oxidation by 25% over insulin alone — a secondary/tertiary metabolic finding, not weighted as core cardiovascular/renal evidence. | ||
| Dose-response study of the redistribution of intravascular volume by angiotensin II in man | 1992 | N=8 normal male subjects; angiotensin II 1/3/10 ng/kg/min vs. placebo | Dose-dependent rise in total peripheral resistance, progressive fall in cardiac output, and a stepwise fall in renal blood flow with increasing angiotensin II infusion rate. | ||
| Effect of a pressor infusion of angiotensin II on sympathetic activity and heart rate in normal humans | 1991 | N=6 healthy volunteers; angiotensin II 5 ng/kg/min vs. phenylephrine vs. vehicle | Both angiotensin II and phenylephrine significantly raised mean arterial pressure (angiotensin II: 88±9.6 to 103±14 mmHg, P<0.001); heart rate fell only with phenylephrine, not angiotensin II; plasma norepinephrine/spillover was unaffected by either infusion. |
Animal / Cell / Preclinical Data
No Animal / Cell / Preclinical Data Listed Yet
This section will be updated as sources are added.
Regulatory Documents & Official Trial Registries
| Title | Year | Population / Model | Dose / Duration / Finding | Safety Notes | Source |
|---|---|---|---|---|---|
| FDA Label / DailyMed Record for GIAPREZA (Angiotensin II) | GIAPREZA is a sterile aqueous solution of chemically synthesized human-sequence Angiotensin II acetate (NOT recombinant), exact 8-residue native sequence (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe), FDA-approved (NDA 209360, initial approval 2017) to increase blood pressure in adults with septic or other distributive shock. | Current label (Version 18, revised July 22, 2026, independently re-fetched and reconfirmed this stage): Warnings and Precautions state a potential for venous and arterial thrombotic/thromboembolic events, recommending concurrent VTE prophylaxis. Adverse Reactions table: thromboembolic events 21/163 (12.9%) GIAPREZA vs 8/158 (5.1%) placebo, including deep vein thrombosis 7/163 (4.3%) vs 0/158 (0.0%) — figures unchanged from the version reviewed at Stage 2BR despite the intervening label revision. | No source link available |
Review Articles / Secondary Sources
| Title | Year | Population / Model | Dose / Duration / Finding | Safety Notes | Source |
|---|---|---|---|---|---|
| Angiotensin II in Catecholamine-Refractory Shock: A Systematic Review and Exploratory Analysis of the ATHOS-3 Trial | 2025 | Reports an aggregate serious-adverse-event rate comparable between groups (approximately 52.6% vs 56.5%) and states overall adverse events, including thromboembolic/ischemic complications, did not differ significantly between groups. |
Anecdotal Reported Patterns — Not Medical Advice
Anecdotal Reported Patterns — Not Medical Advice
Reported dosing patterns are included for educational context only. They are self-reported, unverified, not medical advice, and not instructions for human use. Community-submitted patterns are not yet available in this Phase 1 prototype; this section is a placeholder reserved for moderated, aggregated community data.
Lab Markers to Discuss With a Clinician
Educational topics only — not self-monitoring instructions.
FAQ
Disclaimer
Educational information only. This page summarizes published physiology research and official FDA regulatory information about Angiotensin II and Giapreza and does not provide medical advice, an individualized treatment recommendation, or dosing instructions.
Educational use only. This content is provided for informational and research-summary purposes only. It is not medical advice, not a treatment recommendation, not a dosing guide, and not a substitute for care from a licensed medical professional. Nothing here is intended to diagnose, treat, cure, prevent, or mitigate disease. Reported dosing patterns, when shown elsewhere on the site, must be labeled either as Study / Trial Dosing or Anecdotal Reported Patterns — Not Medical Advice. Community reports are self-reported, unverified, and not scientific proof.
Community-reported experiences, once enabled, must be displayed only as moderated, anonymized, or aggregated data. They are anecdotal, self-reported, unverified, and should never be presented as proof of safety, efficacy, or expected results.
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