AT(1) RECEPTOR CHARACTERISTICS OF ANGIOTENSIN ANALOG BINDING IN HUMAN SYNOVIUM

1 Angiotensin II (AII) reduces blood flow, modulates vascular remodelling and is a growth factor. Human inflammatory arthritides are characterized by synovial hypoperfusion, hypoxia and proliferation. We aimed to localize and characterize receptors for AII in human synovium. 2 We used quantitative in vitro receptor autoradiography with [I-125]-(Sar(1), Ile(8))AII and [I-125]-AII on human synovium from patients with chondromalacia patellae, osteoarthritis and rheumatoid arthritis. 3 [I-125]-(Sar(1), Ile(8))AII and [I-125]-AII bound to similar sites on synovial blood vessels, lining cells and stroma. Binding to microvessels (<100 mu m diameter) was more dense than to arteriolar media, and vascular binding was more dense than that to lining cells and stroma. 4 Microvessels and arterioles which displayed angiotensin converting enzyme-like immunoreactivity also displayed specific binding of [I-125]-(Sar(1), Ile(8))AII. 5 Specific binding of [I-125]-(Sar(1), Ile(8))AII to each structure was completely inhibited by 10 mu M dithiothreitol and was inhibited by unlabelled ligands with the rank order of potency (Sar(1), Ile(8))AII > AII > losartan = SKF108566 much greater than PD123319 indicating an AT(1) subclass of angiotensin receptor. 6 GTP gamma S (1 mu M) abolished specific binding of [I-125]-AII and abolished the high affinity component of the binding inhibition curve for AII against [I-125]-(Sar(1), Ile(8))AII, indicating G protein coupling. 7 The distribution of [I-125]-(Sar(1), Ile(8))AII binding sites was similar in all disease groups and no significant differences in binding densities, affinities or specificities were observed between disease groups. 8 Locally generated AII may act on synovial AT(1) receptors to modulate synovial perfusion and growth. Specific AT(1) receptor antagonists should help elucidate the role of angiotensins in human arthritis.