Vasopressors increase blood pressure by activating G protein-coupled receptors (GPCRs) on vascular smooth muscle and cardiac cells. The result is an increase in systemic vascular resistance (SVR), cardiac output (CO), or both, which raises mean arterial pressure (MAP).
The signaling pathway is easiest to understand in four steps:
Step 1: Vasopressor binds to a cell surface receptor
Most vasopressors are catecholamines (or act similarly) and bind to adrenergic receptors, which are GPCRs.
| Vasopressor | Primary receptor | G Protein |
|---|---|---|
| Norepinephrine | α1, β1 | Gq, Gs |
| Epinephrine | α1, β1, β2 | Gq, Gs |
| Phenylephrine | α1 | Gq |
| Dopamine | D1, β1, α1 | Gs, Gq |
| Vasopressin | V1 | Gq |
| Dobutamine | β1 | Gs |
Step 2: The receptor activates a G protein
A GPCR spans the membrane seven times.
When norepinephrine binds:
- Receptor changes shape.
- Attached G protein exchanges GDP for GTP.
- The α-subunit separates.
- The activated α-subunit activates intracellular enzymes.
Different receptors activate different G proteins.
α1 Adrenergic Receptors → Gq Pathway (Most Important for Raising BP)
This is the mechanism responsible for vasoconstriction.
Norepinephrine binds α1 receptor
↓
Gq protein activated
↓
Activates phospholipase C (PLC)
↓
PLC splits PIP₂ into:
- IP₃
- DAG
IP₃ Pathway
IP₃ diffuses to the sarcoplasmic reticulum.
It binds IP₃ receptors.
↓
Calcium channels open.
↓
Intracellular calcium rises dramatically.
Calcium causes contraction
Calcium binds calmodulin
↓
Activates myosin light chain kinase (MLCK)
↓
MLCK phosphorylates myosin
↓
Actin and myosin interact
↓
Smooth muscle contracts
↓
Arteriole constricts
↓
SVR increases
↓
MAP increases
Summary
Norepinephrine
↓
α1 receptor
↓
Gq protein
↓
PLC
↓
PIP2
↓ ↓
IP3 DAG
↓
Ca2+ release
↓
Calmodulin
↓
MLCK
↓
Smooth muscle contraction
↓
Vasoconstriction
↓
↑ SVR
↓
↑ MAP
β1 Adrenergic Receptors → Gs Pathway
This pathway primarily affects the heart, increasing contractility and heart rate.
Norepinephrine or epinephrine binds β1 receptor
↓
Gs protein activated
↓
Activates adenylate cyclase
↓
ATP converted into cAMP
↓
Protein kinase A (PKA) activated
↓
PKA phosphorylates calcium channels
↓
More calcium enters cardiac muscle
↓
More calcium released from the sarcoplasmic reticulum
↓
Greater actin-myosin interaction
↓
Stronger contraction
Effects:
- Increased contractility (positive inotropy)
- Increased heart rate (positive chronotropy)
- Increased conduction velocity (positive dromotropy)
This increases cardiac output, since:
CO = HR × Stroke Volume
An increase in cardiac output raises blood pressure.
β2 Adrenergic Receptors → Gs Pathway
β2 receptors also activate Gs and increase cAMP, but in vascular smooth muscle, cAMP has the opposite effect.
PKA inhibits MLCK rather than activating contraction.
Result:
- Smooth muscle relaxation
- Vasodilation
- Decreased SVR
This is why epinephrine at low doses can lower diastolic blood pressure despite increasing heart rate.
Vasopressin (V1 Receptor)
Unlike catecholamines, vasopressin does not use adrenergic receptors.
It binds the V1 receptor on vascular smooth muscle.
V1 receptor
↓
Gq protein
↓
PLC
↓
IP₃
↓
Calcium release
↓
MLCK activation
↓
Powerful vasoconstriction
Thus, vasopressin converges on the same calcium-dependent contraction pathway as α1 stimulation, even though it uses a different receptor.
Phenylephrine
Phenylephrine is essentially a pure α1 agonist.
Mechanism:
Phenylephrine
↓
α1 receptor
↓
Gq
↓
PLC
↓
IP3
↓
↑ Ca2+
↓
MLCK
↓
Vasoconstriction
↓
↑ SVR
↓
↑ MAP
Since it has virtually no β1 activity:
- SVR increases
- Heart rate often decreases due to the baroreceptor reflex
- Cardiac output may fall slightly
Norepinephrine
Norepinephrine stimulates both α1 and β1 receptors.
α1 effects
- Vasoconstriction
- Increased SVR
β1 effects
- Increased contractility
- Mild increase in heart rate (often blunted by reflex vagal activation)
Overall:
- Large increase in MAP
- Increased coronary perfusion
- Improved cerebral perfusion
- Increased organ perfusion pressure
This is why norepinephrine is the first-line vasopressor in septic shock.
Epinephrine
Epinephrine’s effects depend on the dose.
Low dose
- β1 predominates
- β2 predominates
- Increased cardiac output
- Vasodilation in skeletal muscle
High dose
- α1 predominates
- Strong vasoconstriction
- Increased SVR
- Increased MAP
Putting It All Together
Blood pressure is determined by:
MAP ≈ CO × SVR
Vasopressors increase MAP by altering one or both variables:
| Drug | G protein pathway | Main effect | MAP mechanism |
|---|---|---|---|
| Norepinephrine | α1 → Gq; β1 → Gs | Vasoconstriction + increased contractility | ↑ SVR + ↑ CO |
| Phenylephrine | α1 → Gq | Vasoconstriction | ↑ SVR |
| Epinephrine | α1 → Gq; β1/β2 → Gs | Increased CO, dose-dependent vasoconstriction | ↑ CO ± ↑ SVR |
| Vasopressin | V1 → Gq | Vasoconstriction | ↑ SVR |
| Dobutamine | β1 → Gs | Increased contractility | ↑ CO |
| Dopamine | Dose-dependent (D1, β1, α1) | Renal vasodilation at low doses (historically described), increased contractility at intermediate doses, vasoconstriction at high doses | Variable |
Clinical takeaway
From an ICU perspective, most vasopressors work by exploiting one of two intracellular signaling systems:
- Gq → PLC → IP₃ → Ca²⁺ → MLCK → smooth muscle contraction → vasoconstriction → increased SVR
- Gs → adenylate cyclase → cAMP → PKA → increased cardiac Ca²⁺ handling → stronger and/or faster cardiac contractions → increased cardiac output
Because MAP = CO × SVR, stimulating either pathway—or both, as norepinephrine does—raises arterial blood pressure and helps restore perfusion to vital organs during shock.