Inhibitory effect of KT3-671, a non-peptide angiotensin subtype 1 receptor antagonist, on sympathetic neurotransmission in isolated rabbit aorta

Abstract

Effect of KT3-671 on the sympathetic neurotransmission in isolated rabbit aorta was studied and compared with those of losartan and its active metabolite, EXP3174. Angiotensin (Ang) II (30 n m) produced approximately 1.7-fold increase in the transmural nerve stimulation (TNS)-evoked tritium overflow in the aorta preloaded with [(3)H]noradrenaline. KT3-671 (1 microm) by itself did not alter the TNS-evoked tritium overflow but it (0.1-1 microm) concentration-dependently inhibited the enhancing effect of Ang II on the TNS-evoked tritium overflow. Both losartan (1 and 3 microm) and EXP3174 (0.03-0.3 microm) also inhibited the Ang II effect. KT3-671 was approximately 8.6 and 0.3 times more potent than losartan and EXP3174, respectively, in inhibiting the Ang II response. This is consistent with the previous results showing the relative potency of the three antagonists to block AT(1)receptors. None of Ang II, KT3-671, losartan and EXP3174 affected significantly the spontaneous tritium outflow. These results suggest that KT3-671 as well as losartan and EXP3174 may inhibit vascular sympathetic neurotransmission by blocking presynaptic Ang II subtype 1 receptors, which appears to contribute partly to its antihypertensive action. 2000 Academic Press@p$hr