This is a mechanism module, not a specific disease. Do NOT create an "AT1 Receptor Blockade" Disease entry. Disorder entries reference individual nodes via conforms_to, for example "at1_receptor_blockade#Angiotensin II Type 1 Receptor Antagonist Occupancy".
Scope, and three things this module deliberately does not claim. First, an ACE inhibitor is not an AT1 blocker: it acts upstream by reducing angiotensin II generation and converges on the same effector arms without ever occupying the receptor, so an entry whose only RAS drug is an ACE inhibitor should conform at the central effector rather than at the trigger. Second, losartan is used in Marfan syndrome and the Loeys-Dietz spectrum for attenuation of TGF-beta signalling in the aortic wall, which is a different downstream claim from anything modelled here; an aortopathy entry should not conform to this module on the strength of carrying losartan. Third, the Gq and phospholipase C step between receptor occupancy and the haemodynamic arms is real but is not modelled as its own node: the sources cited here establish receptor occupancy and the downstream effects without a citable step in between, and a curator who finds one should add the node rather than inferring it.
The two arms the module keeps apart are the point of its shape. Lower arterial pressure and slowed renal progression both follow from the same receptor action, but RENAAL reports the renal benefit as exceeding what the blood-pressure change accounts for, so collapsing them into one outcome node would assert that the kidney protection is a pressure effect.
Within-class differences are recorded on the trigger node and are not modelled as separate nodes: the agents differ severalfold in receptor affinity and in how slowly they leave the receptor, and an entry that depends on that distinction should say so in its own prose.
Sparsentan, a dual endothelin type A and AT1 antagonist used in IgA nephropathy and focal segmental glomerulosclerosis, engages this module's trigger with a second target this module does not carry. An entry curating it should conform here for the AT1 half and describe the endothelin half separately.
Angiotensin II Type 1 Receptor Antagonist Occupancy
trigger
An AT1-selective antagonist occupies AGTR1 and prevents angiotensin II from activating it. The selectivity is the distinctive feature: AT2 receptors are left free to be stimulated by the angiotensin II that accumulates, which is what separates this drug class mechanistically from inhibition of angiotensin II generation. The agents are not interchangeable at the receptor - they differ severalfold in binding affinity and in dissociation rate, with candesartan at one end and losartan at the other.
Used by disorders
Heart Failure
as AT1 Receptor Blockade (Angiotensin Receptor Blocker Target)
IgA Nephropathy
as AT1 Receptor Blockade (Angiotensin Receptor Blocker Target)
Downstream
-
Loss of AT1-Mediated Vasoconstrictor and Mitogenic Signalling
Occupancy of the receptor removes the signal it would otherwise transduce.
-
Fetal Renal Tubular Dysgenesis and Hypocalvaria
In a pregnancy exposed in the second or third trimester, the same receptor blockade acts on a kidney that needs angiotensin II signalling to develop. Attached to receptor occupancy rather than below the haemodynamic arms because the fetal injury is developmental, not a consequence of the adult pressure response.
Show evidence (2 references)
"Because all major deleterious effects of angiotensin II are produced via binding to AT1-receptors, selective blockade of this receptor subtype should confer haemodynamic benefits, while allowing stimulation of the potentially beneficial effects mediated by AT2-receptors."
Sources this node's distinctive claim - that the antagonism is subtype-selective and leaves AT2 signalling available. Note the quoted sentence states the rationale for the class ("should confer"), not a measured outcome; the outcome arms below carry their own evidence.
"Candesartan is also released from the receptor more slowly than other available AT1-receptor blockers, with a half-life of approximately 152 min for the receptor-blocker complex, compared with 31 min for EXP-3 174, 17 min for irbesartan and 5 min for losartan."
Sources the within-class heterogeneity the description records, which is why the module treats receptor occupancy as one node rather than asserting that every agent occupies the receptor equivalently.
Reduced Arteriolar Vasoconstriction
effector
Peripheral arteriolar smooth muscle loses the dominant vasoconstrictor input, and resistance falls. This is the arm that acts fastest and the one a hypertension entry will usually have modelled already, often as a vascular-resistance node with no receptor above it.
Downstream
-
Lower Arterial Blood Pressure
Falling systemic vascular resistance lowers arterial pressure.
Show evidence (1 reference)
"a potent vasopressor and the primary effector of renin-induced hypertension"
Establishes that angiotensin II is the dominant vasoconstrictor input this arm removes. INDIRECT for the same reason as the node above - the source describes the agonist.
Reduced Aldosterone-Driven Sodium Retention
effector
Angiotensin II is the principal stimulus to adrenal aldosterone release, and aldosterone in turn drives distal tubular sodium reabsorption. Blockade withdraws that stimulus, so sodium and water retention fall and intravascular volume contracts. The arm is listed separately from vasoconstriction because its time course is slower and because it is the arm that produces the hyperkalaemia below.
Downstream
-
Lower Arterial Blood Pressure
Volume contraction contributes to the pressure fall.
Show evidence (1 reference)
"Angiotensin II stimulates the adrenal cortical release of aldosterone, which promotes renal tubular sodium reabsorption, resulting in volume expansion."
Sources the adrenal-to-tubule sequence this arm withdraws. INDIRECT because the source states the agonist pathway, not the antagonist's effect on it.
Reduced Intraglomerular Pressure and Proteinuria
effector
Blockade lowers filtration pressure across the glomerular capillary, and the measurable consequence is a fall in protein excretion - about a third in the type 2 diabetic nephropathy trial. This arm is the reason the module's renal consequence is kept separate from its pressure consequence. The node is bound at the efferent arteriole because that is where the standard account places the pressure change, but note that the cited evidence here measures the protein excretion rather than the arteriolar step: a source for the preferential efferent constriction would strengthen the location binding.
Downstream
-
Slowed Progression of Chronic Kidney Disease
Lower filtration pressure and less protein traffic slow nephron loss.
Show evidence (1 reference)
"The level of proteinuria declined by 35 percent with losartan (P<0.001 for the comparison with placebo)."
Measures this arm's output directly in a randomised trial of an AT1 blocker.
Lower Arterial Blood Pressure
consequence
The haemodynamic consequence the hypertension indication rests on, reached by the vasoconstrictor and volume arms together. The magnitude available from placebo-controlled trials is a class-agnostic one and the module does not assert an AT1-blocker-specific figure.
Show evidence (2 references)
"All of these mechanisms coalesce to increase arterial pressure by way of arteriolar constriction, enhanced cardiac output, and the retention of sodium and water."
Sources the convergence of the two arms above onto arterial pressure. INDIRECT - the source states how the agonist raises pressure, from which the antagonist's effect follows.
"On average, monotherapy at standard dose reduced systolic blood pressure by 8·7 mm Hg (95% CI 8·2-9·2), and each doubling in dose conferred an additional 1·5 mm Hg (1·2-1·7) reduction."
Bounds the magnitude of this node. Graded INDIRECT because the figure is pooled across the five major antihypertensive classes rather than specific to angiotensin receptor blockers; the same analysis reports considerable variation between and within classes, so it is a scale for this node, not an AT1-blocker estimate.
Slowed Progression of Chronic Kidney Disease
consequence
The renal outcome, and the one the module separates from blood pressure on the strength of the trial's own reading: the benefit was reported as larger than the pressure change accounts for. Note what the same trial did not show - no effect on death - which is why this node claims renal progression and not survival.
Show evidence (2 references)
"Losartan reduced the incidence of a doubling of the serum creatinine concentration (risk reduction, 25 percent; P=0.006) and end-stage renal disease (risk reduction, 28 percent; P=0.002) but had no effect on the rate of death."
Sources this node's claim and its limit in one sentence - renal progression slowed, mortality unchanged.
"The benefit exceeded that attributable to changes in blood pressure."
The reason this node is not drawn below Lower Arterial Blood Pressure. The trial reports the renal benefit as larger than the pressure change explains, so the module routes it through the intraglomerular arm instead.
Hyperkalaemia on Renin-Angiotensin System Blockade
adverse effect
The class's characteristic dose-limiting laboratory adverse effect, and the usual reason the drug is stopped: with aldosterone drive withdrawn, distal potassium secretion falls. It is recorded here as an arm of the same signal that produces the therapeutic sodium effect, not as an unrelated toxicity. Stopping the drug for it carries its own risk, which is why the node is a dose-limiting effect rather than a reason to discontinue.
Show evidence (2 references)
"Renin-angiotensin-aldosterone system (RAAS) inhibitors are evidence-based therapies that slow the progression of chronic kidney disease (CKD) but can cause hyperkalemia."
Sources the adverse effect. The sentence sits in the paper's rationale rather than among its own results, hence BACKGROUND; it reports the human clinical fact, hence HUMAN_CLINICAL.
"RAAS inhibitor discontinuation is associated with higher mortality and CV events compared with continuation among patients with hyperkalemia and CKD."
Bounds the node. The adverse effect is real, but this cohort's own finding is that stopping the drug because of it is associated with worse outcomes - which is why the node is framed as dose-limiting rather than as grounds for withdrawal.
Fetal Renal Tubular Dysgenesis and Hypocalvaria
adverse effect
Angiotensin II signalling through AT1 is required for normal kidney development, so blockade in the second or third trimester produces an acquired phenocopy of genetic renal tubular dysgenesis, with reduced proximal tubules and defective skull ossification. This is the arm that makes the class contraindicated in pregnancy, and it is developmental rather than haemodynamic, which is why it hangs off receptor occupancy.
Show evidence (2 references)
"AA fetopathy phenotype is similar to renal tubular dysgenesis including reduced proximal convoluted tubules (PCTs)."
Sources the fetal phenotype, quantified against the genetic form of renal tubular dysgenesis.
"Among other AA fetopathy findings, 1 case demonstrated unilateral renal vein thrombosis and 4 had hypocalvaria."
Sources the second half of this node's name. The skull ossification defect was previously asserted in the node name with only the tubular half cited.
Angiotensin II Receptor Blocker Therapy
Platform:
Small molecule
The AT1-selective antagonists used across hypertension, heart failure, diabetic and non-diabetic proteinuric kidney disease. Listed as one treatment because they share the receptor action; the agents differ in affinity and dissociation rate, as the trigger node records.
Angiotensin Receptor-Neprilysin Inhibitor Therapy
Platform:
Small molecule
Sacubitril/valsartan, in which the valsartan component engages this module's trigger while the sacubitril component inhibits neprilysin and raises natriuretic peptide concentrations. Only the AT1 half is modelled here; the neprilysin arm is out of scope and an entry curating this drug should describe it separately.