Action of AT1 receptor antagonists on angiotensin II-induced tone in human isolated subcutaneous resistance arteries

1 Human isolated subcutaneous arteries were studied under isometric conditions in a myograph. 2 Addition of angiotensin II (AII) induced a concentration-dependent increase in tone in isolated arteries. The active metabolite of candesartan (CV 11974), losartan and the active metabolite of losartan, E-3174 antagonized AII-induced tone in a non-competitive manner, but the AT(2) selective antagonist, PD123319, was without effect on responses to AII. The effects of candesartan, losartan and E-3174 were analysed using a classical model of non-competitive antagonism and a two-state receptor model. 3 Mechanical removal of the endothelium; pre-incubation with N-omega-nitro-L-arginine methyl eater hydrochloride (L-NAME); pre-incubation with indomethacin, a cyclo-oxygenase inhibitor; or preincubation with BQ 485, an endothelin antagonist; had no significant effect on contractions induced by AII. 4 Our results suggest AII contracts human isolated resistance arteries by an action on AT(1) receptors and does not involve release of endothelial factors. Use of a two-state receptor model successfully described the action of the AT(1) antagonists without sacrificing assumptions regarding the competitive nature of binding of these antagonists.