Angiotensin Receptors

Different receptors/binding sites have been identified for the biologically active angiotensin (Ang) peptides, i.e. Ang II (1-8), Ang III (2-8), Ang IV (3-8) and Ang (1-7), based on the availability of selective agonists and antagonists, signal transduction mechanisms and structure of the receptor proteins. The primary receptors for Ang II (and Ang III) are designated AT₁ and AT₂. AT₁ receptors exhibit high affinity for the biphenyltetrazole class of non-peptide antagonists. These clinically used angiotensin receptor blockers (ARB’s) are generically known as sartans. Tetrahydroimidazolepyridines behave as selective non-peptide AT₂ receptor antagonists. The octapeptide Ang II receptor antagonist, saralasin, [Sar¹,Ala⁸]-Ang II and other 8 position aliphatic amino acid substituted Ang II analogs, do not discriminate between AT₁ and AT₂ receptors. On the other hand, the antagonist [Sar¹,Gly⁸] Ang II shows moderate selectivity for the AT₁ receptor. The peptides CGP42112A and p-aminophenylalanine⁶ Ang II bind selectively to the AT₂ receptor, and exhibit agonist activity.

The sequence identity between the AT₁ (359 aa) and AT₂ (363 aa) receptors is only 34%, but both receptors belong to the G protein-coupled receptor superfamily. In humans, the single gene encoding the AT₁ receptor protein is found on chromosome 3. Two subtypes, AT_1A and AT_1B, exhibiting a 94% overall sequence identity, are found in rodents. In the rat, the AT_1A and AT_1B receptor genes are located on chromosomes 17 and 2, respectively. In the mouse the genes are located on chromosomes 13 and 3, respectively. Upon stimulation, the AT₁ receptor couples via G protein- (predominantly G_q/11) dependent and independent mechanisms, modulating several intracellular signaling mechanisms involving phospholipases C, D and A₂, adenylyl cyclase, Erk MAP kinase, c-Jun N-Terminal kinase (JNK) and the Jak/STAT pathway, some of which involve transactivation of the EGF receptor. Mouse, rat and human AT₂ receptor genes have been mapped to the X-chromosome and no subtypes or splice variants have been described. The AT₂ receptor also couples via G protein- (G_i) dependent and independent mechanisms. These include activating tyrosine phosphatases (MKP1 and SHP-1) and serine/threonine phosphatases to decrease in MAP kinase activity, activation of PLA₂, opening of delayed-rectifier potassium channels and closing of T-type calcium channels, and stimulation of ceramide production.

The predominant role of the AT₁ receptor in mediating the pathophysiological actions of Ang II underlies the effectiveness of AT₁ receptor antagonists to lower arterial blood pressure, reduce cardiac pre- and afterload, inhibit sympathetic activity, promote salt and water excretion, and prevent cardiovascular hypertrophy, cardiac failure and atherosclerosis mediated by activation of the renin-angiotensin system. The functional role(s) of the AT₂ receptor remain(s) incompletely understood, but reports indicate vasodilatory, natriuretic, antiproliferative/antihypertrophic, apoptotic, cardioprotective and possibly cerebroprotective actions of Ang II via this site. A consistent theme is that stimulation of AT₂ receptors produces opposite effects to those mediated by AT₁ receptors. Since AT₁ receptors exert feedback inhibition on Ang II formation, selective AT₁ receptor blockade will increase circulating Ang II in the bloodstream leading to increased AT₂ receptor stimulation, which (via a vasodilatory action) may contribute to the beneficial actions of ARBs.

The 3-8 hexapeptide Ang IV binds to a site that is distinct from the AT₁ and AT₂ receptors , designated as the AT₄ receptor. This site has high affinity for Ang IV and the structurally unrelated decapeptide LVV-Hemorphin-7 (LVV-H7), and much lower affinity for Ang II and AT₁/AT₂ receptor-selective ligands. The AT₄ receptor has been identified as the transmembrane enzyme insulin-regulated membrane aminopeptidase (IRAP), and Ang IV, LVV-H7 and other AT₄ receptor-selective ligands inhibit IRAP catalytic activity. The major described function of Ang IV is facilitation of memory retention and retrieval.

Ang (1-7) can be formed directly from Ang I by the action of neutral- or prolyl-endopeptidases, or from Ang II via angiotensin converting enzyme-2 (ACE-2). The major described actions of Ang (1-7) are vasodilation, via stimulation of nitric oxide, prostaglandins and potentiation of bradykinin actions, and antidiuresis. These effects are abolished by the specific Ang (1-7) antagonist [D-Ala⁷]-Ang (1-7), which has little effect at AT₁ or AT₂ receptors. While an Ang (1-7) receptor has not been cloned, evidence indicates that it is an endogenous ligand for the G protein coupled receptor Mas.

The Table below contains accepted modulators and additional information. For a list of additional products, see the Materials section below.

Footnotes

a) Further subtypes of rat and mouse AT₁ receptors, designated AT_1A and AT_1B, have been cloned and sequenced. In the human, only one AT₁ receptor gene has been identified.

b) “Atypical” AT receptors: 362/363 aa (amphibian), 359 aa (chicken), 359 aa (turkey) and 359 aa ( gerbil) have also been cloned.

Abbreviations

BIBR277: 4'-[(1,4'-Dimethyl-2'-propyl[2,6'-bi-1H-benzimidazol]-1'-yl)methyl]-[1,1'-biphenyl]-2-carboxylic acid
CGP42112A: Nicotinic acid-Tyr-N-benzoxyl-carbonyl-Arg-Lys-His-Pro-Ile-OH
CGP48933: N-(1-Oxopentyl)-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-L-valine
CS-866: 4-(1-Hydroxy-1-methylethyl)-2-propyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester
E3174: 2-Butyl-4-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-carboxylic acid
EXP801: 2-(Diphenylacetyl)-6-phenyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
L-158,809: 5,7-Dimethyl-2-ethyl-3-[[2'-(1H-tetrazol-5-yl)-[1,1']-biphenyl-4-yl]methyl]-3H-imidazo[4,5-b]pyridine
L-159,686: 1,4-Bis-diphenylcarbamoyl-piperazine-2-carboxylic acid
L-161,638: 2-Ethyl-6-[N-benzyl-N-(2-thienoyl)amino-3-[[2’-(1H-tetrazol-5-yl)-[1,1’]-biphenyl-4-yl]methyl]quinazolin-4-(3H)-one
L-162,313: 5,7-Dimethyl-2-ethyl-3-[[4-[2(n-butyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazo[4,5,6]pyridine
L-163,491: 5,7-Dimethyl-2-ethyl-3-[[2'-([butyloxycarbonyl)aminosulfonyl]-5'-(3-methyoxybenzyl)-[1,1'-biphenyl]-4-yl]methyl]-3H-imidazo[4,5-b]pyridine
PD 123,177: S(+)-1-[(4-Amino-3-methylphenyl)methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo-(4,5-c]pyridine-6-carboxylic acid
PD 123,319: S(+)-1-[[4-Dimethylamino)-3-methylphenyl]methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo-[4,5-c]pyridine-6-carboxylic acid
PD 126,055: 2-(Diphenylacetyl)-5-benzyloxy-6-methoxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid
SKF 108566: (aE)-a-[[2-Butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene]-2-thiophenepropanoic acid
SR 47436: 2-Butyl-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one
TCV 116: 2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid 1-[[(cyclohexyloxy)carbonyl]oxy]ethyl ester