EFFECTS OF ANGIOTENSIN RECEPTOR SUBTYPE INHIBITORS ON PLASMA ANGIOTENSIN CLEARANCE

The aim of this study was to determine whether angiotensin receptor su btypes play a role in angiotensin clearance from plasma. Angiotensin m etabolic clearance rate was measured in rats by the constant infusion method. Increasing doses of angiotensin II were infused for 15 minutes , and blood was sampled for angiotensin II. The type 1 angiotensin II receptor antagonist losartan decreased the apparent metabolic clearanc e rate by >50% at low-dose infusion, suggesting that type 1 angiotensi n II receptors are involved in angiotensin II clearance from plasma. A t higher angiotensin infusion rates, the metabolic clearance rate of a ngiotensin was unaffected. To dissect the contribution of renin-genera ted angiotensin, additional experiments were performed in nephrectomiz ed rats. In anephric rats, angiotensin clearance was unaffected by typ e 1 angiotensin II receptor inhibition. In contrast, the type 2 angiot ensin II receptor ligand PD123319 in intact rats caused a >50% increas e in metabolic clearance rate of angiotensin at higher infusion rates (P<.05). In anephric rats, the type 2 angiotensin II receptor ligand a lone or combined with type 1 receptor inhibition was without effect on the metabolic clearance rate or the T-1/2 for angiotensin disappearan ce. These data argue against a role for type 1 or 2 angiotensin II rec eptors as clearance receptors. Increased clearance of angiotensin by t ype 2 receptor blockade in the presence but not the absence of kidneys suggests an alternative renal mechanism by which selective type 2 lig ands may alter angiotensin effects.