PHARMACOLOGY OF XR510, A POTENT ORALLY-ACTIVE NONPEPTIDE ANGIOTENSIN-II AT(1) RECEPTOR ANTAGONIST WITH HIGH-AFFINITY FOR THE AT(2) RECEPTORSUBTYPE

The angiotensin II (Ang II) type 1 receptor (AT(1)) mediates all known physiological effects of ANG II, whereas functions of the type 2 (AT( 2)) receptor are not clear. Should undesirable AT(2) effects be identi fied, it may be advantageous to combine antagonism of AT(1) and AT(2) receptors. XR510 was shown to inhibit the specific binding of [I-125]S ar(1),Ile(8)-Ang II for AT(1) and AT(2) subtype binding sites in rat a drenal membranes with IC50 of 0.26 and 0.28 nM, respectively, and in h uman tissues with subnanomolar binding affinity. In isolated rabbit ao rta, XR510 exerted insurmountable Ang II antagonism with a K-b value o f 4 nM. In conscious renal hypertensive rats, XR510 decreased blood pr essure (BP) with intravenous (i.v.) and oral (p.o.) ED(30) of 0.08 and 0.27 mg/kg, respectively. In spontaneously hypertensive rats (SHR), r epeated daily oral dosing of XR510, losartan, and enalapril at 30 mg/k g/day decreased BP similarly. In conscious furosemide-treated dogs, XR 510, given either intravenously or orally, decreased BP. These results suggest that XR510 is an orally active and selective Ang II receptor antagonist with equal binding affinities for AT(1) and AT(2) receptor binding sites.