Mechanistic differences of various AT(1)-receptor blockers in isolated vessels of different origin

The functional inhibitory characteristics of the angiotensin II type 1 rece ptor blockers (ARB) candesartan; irbesartan; and losartan and its active me tabolite EXP 3174 (EXP) were studied in rabbit aortic strips and rat portal vein preparations in vitro. Moreover, plasma-protein binding was determine d, and the binding was high (>98.5%) for all ARBs. These values were needed to relate the concentrations of the ARBs used in vitro to the nonprotein b ound concentrations in clinical use. In both vascular preparations, candesa rtan caused a marked decrease in the maximal contractile response of the an giotensin II (Ang II) concentration-response curve. Losartan, EXP, and irbe sartan caused a rightward parallel shift without any major effects on the m aximal response to Ang II. The inhibitory effect of candesartan developed s lowly (maximal effect after >30 minutes) and lasted >2 hours despite repeat ed washing of the vessels. The effect of losartan, irbesartan, and EXP had a faster onset, and most of the inhibitory effect disappeared after washing . The duration of the inhibitory effects of the ARBs were not related to li pophilicity of the compounds. Cooling of the rat portal vein preparations t o 4 degrees C before administration of candesartan prevented the persistent inhibition of Ang II response seen at 37 degrees C. For the other ARBs stu died, the magnitude of inhibition and the speed of recovery of the Ang II r esponse were independent of the incubation temperature before washing. In a ddition, when candesartan was given to conscious rats, the inhibitory effec t on Ang II-induced blood pressure responses persisted during the 24-hour p eriod despite nondetectable plasma concentrations of candesartan at 24 hour s. It is concluded that functional inhibitory characteristics of candesarta n differ from those of the other ARBs tested. At clinically relevant concen trations, candesartan is an insurmountable and long-lasting antagonist of t he vascular contractile responses to Ang II.