Vasopressin — Diabetes insipidus, enuresis
- Class
- Posterior pituitary neurohormone (V1a / V1b / V2 receptor agonist)
- Status
- FDA-approved prescription drug (Pitressin, Vasostrict and generics); hospital and ICU-restricted use
- Best-supported effect
- Antidiuretic replacement in central diabetes insipidus (human label) and catecholamine-sparing pressor support in vasodilatory/septic shock (human RCT and guideline-supported)
- Main caveat
- Mortality benefit in septic shock has not been demonstrated in landmark RCTs; nonselective V1a activity makes use outside continuous hemodynamic monitoring unsafe
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
A chemistry service or a researcher ordered the sequence, it was manufactured, and mass spectrometry confirmed the right molecule was produced.
A binding or activity measurement confirmed that it actually does what the computer predicted — or didn't.
Snapshot
Class: Posterior pituitary neurohormone (V1a / V1b / V2 receptor agonist)
Evidence tier: Approved drug
Status: FDA-approved prescription drug (Pitressin, Vasostrict and generics); hospital and ICU-restricted use
Best-supported effect: Antidiuretic replacement in central diabetes insipidus (human label) and catecholamine-sparing pressor support in vasodilatory/septic shock (human RCT and guideline-supported)
Main caveat: Mortality benefit in septic shock has not been demonstrated in landmark RCTs; nonselective V1a activity makes use outside continuous hemodynamic monitoring unsafe
What this is
Arginine vasopressin (AVP), also called antidiuretic hormone (ADH), is the endogenous nine-amino-acid cyclic nonapeptide produced in hypothalamic supraoptic and paraventricular nuclei and released from the posterior pituitary. It is the body's principal regulator of water reabsorption and a backup pressor hormone activated when blood pressure falls.
Synthetic vasopressin is FDA-approved as Pitressin (and as Vasostrict and generic equivalents) for central diabetes insipidus and for postoperative abdominal distension, and is widely used in vasodilatory/septic shock as a catecholamine-sparing adjunct to norepinephrine. The V2-selective analogue desmopressin and the V1-selective analogue terlipressin are derivatives of the native sequence and have separate regulatory and clinical profiles. Native vasopressin is, in practical terms, a hospital and ICU drug — not a wellness or self-administered peptide.
Evidence map
| Evidence layer | Grade | What it supports |
|---|---|---|
| Human | Approved / Phase III | FDA label use in central diabetes insipidus; landmark RCTs (VASST 2008, VANISH 2016) and individual-patient-data meta-analysis in vasodilatory/septic shock; meta-analysis support in post-surgical vasoplegic shock |
| Animal | Comprehensive | V1a / V1b / V2 receptor pharmacology, osmoregulation, baroreflex, and HPA-axis interactions characterized across multiple species |
| In vitro | Strong | V1a (Gq / PLC), V1b (Gq), and V2 (Gs / cAMP) receptor signaling pathways mapped in cell systems |
| Computational | None identified | No structure prediction or docking data identifieds available literature |
| Mechanism | Strong | Three-receptor mechanism (V1a vasoconstriction, V2 aquaporin-2 trafficking, V1b ACTH release) is well established; relative-vasopressin-deficiency rationale in late septic shock grounded in serial human hormone measurements |
Claim check
| Claim | Verdict | Evidence layer | Confidence |
|---|---|---|---|
| Replaces missing hormone in central diabetes insipidus (inpatient setting) | Supported (human, FDA label) | Human label | High |
| Adjunctive catecholamine-sparing pressor in vasodilatory/septic shock when norepinephrine is insufficient | Supported (human, guideline-supported off-label) | Human RCT and guideline | High — guideline-supported; trials did not show mortality benefit |
| Reduces overall mortality in septic shock | Contradicted / not established | Human RCT | High |
| Reduces renal replacement therapy requirement in septic shock | Partially supported | Human individual-patient-data meta-analysis | Medium — meta-analytic signal; not a primary RCT mortality endpoint |
| Improves outcomes in cardiac arrest resuscitation | Contradicted / not established | Human RCT and meta-analysis | High — meta-analyses and Cochrane review found no consistent benefit |
| Equivalent to desmopressin for ambulatory diabetes insipidus or bedwetting | Contradicted | Human label and pharmacology | High — V1a pressor activity makes native AVP unsuitable for ambulatory use; desmopressin is the V2-selective analogue developed for this role |
| Useful as a behavioral or "social bonding" peptide in humans | Not established | Human and animal mechanism | Low — animal V1a literature exists; human translation as a behavioral therapeutic is not established |
Exposure studied
This section reports exposure used in labels and human studies. It is not a personalized protocol.
| Context | Population | Exposure studied | Duration | Endpoint | Evidence strength | Limitation |
|---|---|---|---|---|---|---|
| FDA label (Pitressin / Vasostrict) | Adults with central diabetes insipidus (inpatient) | IM or subcutaneous injection per label; continuous IV infusion in inpatient settings per label | Per inpatient course | Urine output / urine osmolality / serum sodium | Approved label | Hospital-restricted; not for ambulatory chronic use |
| FDA label (Pitressin) | Adults with postoperative abdominal distension | Per label | Per label | Postoperative abdominal distension | Approved label | Hospital-restricted |
| Surviving Sepsis Campaign guidance / VASST trial | Adults with septic shock receiving norepinephrine | Continuous IV infusion at low fixed rate (typically 0.03 U/min) added to norepinephrine | Hours to several days, until weaned | 28-day mortality (primary, negative); MAP support; renal replacement therapy requirement | Phase III RCT plus IPD meta-analysis | Mortality benefit not demonstrated; ischemic risk rises at higher rates |
| VANISH trial | Adults with septic shock | Early vasopressin vs norepinephrine | Trial duration | Kidney failure-free days | Phase III RCT | Did not show mortality benefit; early-initiation strategy not superior |
| Vasoplegic shock in surgical patients | Adults with post-cardiopulmonary-bypass vasoplegia | Infusion regimens similar to septic shock; protocols vary by institution | Hours to days | MAP / pressor support / outcomes | Systematic review and meta-analysis | Heterogeneous protocols; off-label institutional use |
available literature describes adjunctive use in cardiac arrest resuscitation, but meta-analytic evidence does not support routine inclusion and most current advanced cardiac life support algorithms have removed vasopressin in favor of epinephrine alone.
Safety signals
| Signal | Evidence context | Notes |
|---|---|---|
| Skin blanching / pallor from peripheral vasoconstriction | Label / human use | V1a-mediated |
| Digital ischemia | Label / human use | Risk rises above 0.03 U/min and with peripheral vascular disease or Raynaud's phenomenon |
| Mesenteric ischemia and abdominal cramps | Label / human use | V1a-mediated splanchnic vasoconstriction; risk rises at higher infusion rates |
| Coronary vasoconstriction | Label / human use | Can precipitate ischemia in susceptible patients |
| Bradycardia | Label / human use | Reported at therapeutic pressor doses |
| Hyponatremia | Label / human use | With prolonged or higher-dose antidiuretic exposure; SIADH worsens free-water retention |
| Infusion-site reactions and extravasation necrosis | Label / human use | Central venous administration is strongly preferred over peripheral |
| Long-term neurocognitive and social outcomes after ICU exposure | Label limitation | Not characterized in human follow-up; animal V1a central-effect literature has not translated into well-defined human outcomes |
Label safety exclusions (from FDA-labeled cautions and contraindications described in source):
- Known hypersensitivity to vasopressin, chlorobutanol, or other formulation excipients
- Chronic nephritis with nitrogen retention (unreliable antidiuretic response; fluid-overload risk)
- Coronary artery disease with unstable angina or recent myocardial infarction (V1a coronary vasoconstriction risk)
- Severe peripheral vascular disease or Raynaud's phenomenon (digital ischemia and necrosis risk)
- Documented mesenteric vascular disease or mesenteric ischemia (splanchnic vasoconstriction risk)
- Hyponatremia or history of SIADH (free-water retention; seizure and cerebral edema risk)
- Pregnancy, except where clearly indicated and alternatives unavailable (uterine contraction via oxytocin-receptor cross-reactivity)
- Older extract-based preparations: hypersensitivity to beef- or pork-derived peptides (largely historical; modern formulations are synthetic)
Drug interaction signals from label / source: Concomitant catecholamines (norepinephrine, epinephrine) and other pressors (phenylephrine, angiotensin II) interact additively; in septic shock this combination is intentional and synergistic, and monitoring intensity rather than pharmacologic antagonism. Controlled interaction data beyond published research-described pressor combinations are not individually extracted.
Regulatory status
| Region / body | Status | Notes |
|---|---|---|
| US (FDA) | Approved prescription drug | Pitressin, Vasostrict, and generics; labeled for central diabetes insipidus and postoperative abdominal distension; widely used off-label and consistent with professional guidelines for septic and vasodilatory shock; not a controlled substance; dispensed to hospitals and healthcare institutions, not retail pharmacies |
| International | Approved across major markets for similar indications | Source-bundle description; specific regional label details not separately extracted in this card |
| WADA | Not specifically named on the WADA Prohibited List | Source-bundle reported; current list status not independently refreshed in this card. V2-mediated antidiuretic activity is potentially relevant to the S5 Diuretics and Masking Agents category; desmopressin (separate analogue) is explicitly prohibited per source |
The V1-selective analogue terlipressin (Terlivaz) received FDA approval in September 2022 for hepatorenal syndrome-1 on the basis of the CONFIRM trial; the V2-selective analogue desmopressin has its own regulatory profile. Both are separate molecules and are not used as evidence for native vasopressin's profile in this card.
Clinical trials
| Trial / source | Phase | Population | Endpoint | Status / result |
|---|---|---|---|---|
| VASST (Russell et al., NEJM 2008;) | Phase III RCT | Adults with septic shock | 28-day all-cause mortality | Completed / published; no overall mortality benefit; signal for benefit in less-severe shock |
| VANISH (Gordon et al., JAMA 2016;) | Phase III RCT | Adults with septic shock | Kidney failure-free days (early vasopressin vs norepinephrine) | Completed / published; did not show mortality benefit |
| CONFIRM | Phase III RCT | Adults with type 1 hepatorenal syndrome | Verified hepatorenal syndrome reversal | Completed / published; supported FDA approval of terlipressin (Terlivaz, 2022) — analogue, not native vasopressin |
| Copeptin diagnostic RCT | RCT | Patients undergoing diagnostic workup for diabetes insipidus | Diagnostic accuracy of copeptin-based approach | Completed / published; supports copeptin as surrogate for AVP measurement |
| Arginine or hypertonic saline-stimulated copeptin RCT | RCT | Patients undergoing diagnostic workup for AVP deficiency | Diagnostic accuracy | Completed / published; supports stimulated-copeptin testing for AVP deficiency |
Additional human evidence is summarized through meta-analyses and reviews cited in References (vasoplegic shock, septic shock IPD meta-analysis, cardiac-arrest meta-analysis, terlipressin in hepatorenal syndrome). Detailed trial rows beyond those above are not individually extracted.
Mechanism
Vasopressin acts through three G-protein-coupled receptors:
- V1a receptor (Gq / PLC / IP3 / DAG) on vascular smooth muscle mediates vasoconstriction — the clinical pressor effect — and contributes to platelet aggregation and hepatic glycogenolysis.
- V2 receptor (Gs / cAMP / PKA) on the basolateral membrane of renal collecting-duct principal cells drives trafficking of aquaporin-2 water channels to the apical membrane, increasing water reabsorption and concentrating urine.
- V1b / V3 receptor (Gq) on anterior pituitary corticotrophs drives ACTH release as part of the stress axis, particularly during sustained or chronic stress.
Endogenous release is controlled by plasma osmolality (detected by hypothalamic osmoreceptors; the dominant physiological driver under normal conditions) and by effective circulating volume or arterial pressure (detected by cardiopulmonary and arterial baroreceptors; a higher-threshold but more powerful stimulus). Approximately a 1% rise in plasma osmolality produces measurable AVP release; a blood pressure drop of more than 10–20% produces high-amplitude release that can reach pressor concentrations.
The therapeutic rationale for low-dose vasopressin in late septic shock rests on the relative-vasopressin-deficiency hypothesis articulated by Landry and Oliver: endogenous AVP stores are mobilized early by baroreflex activation but become depleted after hours to days of sustained shock, removing a physiologic backstop against vasodilation. Vasopressin's V1a-Gq pathway is non-catecholamine and is not subject to adrenergic receptor desensitization, which is the basis for using it as a catecholamine-sparing adjunct rather than a stand-alone pressor.
Vasopressin and oxytocin are close structural cousins — both are nine-amino-acid cyclic peptides differing only at positions 3 (Phe vs Ile) and 8 (Arg vs Leu) — which accounts for cross-reactivity at each other's receptors, including vasopressin's potential uterotonic activity via oxytocin-receptor cross-reactivity in pregnancy.
Chemistry
| Field | Value |
|---|---|
| Amino-acid sequence | Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH2 |
| Length | 9 amino acids |
| Topology | Cyclic (disulfide bridge between Cys1 and Cys6); C-terminal amidation (Gly-NH2) |
| Modifications | Intramolecular disulfide bond between the two cysteine residues; C-terminal amide |
| Sequence confidence | Verified (consistent with source) |
| Native source | Synthesized in magnocellular and parvocellular neurons of the hypothalamic supraoptic and paraventricular nuclei; released from the posterior pituitary |
| Plasma half-life | Approximately 10–20 minutes (per source narrative) |
| Pharmaceutical formulations | Pitressin, Vasostrict, and generic synthetic preparations; older extract-based preparations are largely historical |
Related synthetic analogues described in source: desmopressin (1-deamino-8-D-arginine vasopressin; V2-selective; deaminated position 1, D-Arg at position 8) and terlipressin (triglycyl-lysine vasopressin; V1-selective prodrug). These are distinct molecules with separate cards or directory entries and are not interchangeable with native vasopressin.
Open questions
- Optimal timing of vasopressin initiation in septic shock: Whether to start at low norepinephrine doses (early) or reserve for refractory shock (late) is not resolved by current trial evidence; the VANISH trial's early-initiation approach did not show mortality benefit. Gap type: human / comparative. Priority: high.
- Vasopressin responder subgroups: The VASST signal for benefit in less-severe shock and the meta-analytic reduction in renal replacement therapy requirement suggest heterogeneity of treatment effect that is not yet characterized by clinical or biomarker features. Gap type: human / comparative. Priority: high.
- Dose ceiling and upward titration: Whether modestly higher infusion rates (up to 0.067 U/min in some reports) are safe and beneficial in refractory shock remains controversial; most guidance caps infusions to limit ischemic risk. Gap type: human / safety. Priority: medium.
- Copeptin as a real-time shock biomarker: Established as a diagnostic surrogate for AVP deficiency, but its utility to guide vasopressin dosing or predict response in shock is only beginning to be studied. Gap type: human / mechanism. Priority: medium.
- Positioning of V1a-selective and V1a/V2 dual agonists: Terlipressin has an established hepatorenal syndrome role, but its positioning vs native vasopressin in septic shock is still being defined. Gap type: comparative. Priority: medium.
- Long-term neurocognitive and social outcomes after ICU vasopressin exposure: The animal V1a central-effect literature (social behavior, aggression, bonding) has not translated into well-characterized human outcomes after ICU exposure. Gap type: human / safety / duration. Priority: medium.
- Pediatric vasopressin use in shock: Most trial evidence is adult; optimal dosing, indication selection, and outcomes in pediatric septic shock are less well defined. Gap type: human. Priority: medium.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.934156060218811 | boltz-2 |
| ranking score | 0.7782688140869141 | boltz-2 |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 1.025 | global PDE — lower = better |
| disorder | NaN | fraction disordered |
▸3-letter notation
▸recipeboltz-2 1.0
| parameter | value |
|---|---|
| model | boltz-2 1.0 |
| weights | — |
| hardware | nvidia_nim_api |
| mlx version | — |
| python | — |
| random seed | — |
| msa strategy | none |
| diffusion samples | 1 |
| runtime | — |
| predicted by | mlx@peptide |
| predicted at | 2026-04-24 |
▸ lineage 1 parent
▸citationbibtex
@peptide{pep04423,
sequence = {CYFQNCPRG},
target = {avpr2},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}