Robertson M J, Wragg A, Clark K L
Department of Cardiovascular and Respiratory Pharmacology, Glaxo Group Research, Ware, Herts., UK.
Regul Pept. 1994 Feb 24;50(2):137-45. doi: 10.1016/0167-0115(94)90029-9.
In rabbit aortic strip preparations, angiotensin II (AII) concentration-contractile response curves (0.3-100 nM) were highly reproducible. However, tachyphylaxis to the contractile response elicited by AII could be induced by repeated exposure to a supramaximal concentration (10 microM) of the peptide. In contrast, a correspondingly supramaximal concentration of the alpha 1-adrenoceptor agonist, phenylephrine (1 mM), did not cause the tissue to become tachyphylactic to phenylephrine. Furthermore, phenylephrine responses were unaffected in tissues previously made tachyphylactic to AII. When the non-peptide, competitive angiotensin AT1 receptor antagonist, losartan (300 nM), was administered before each supramaximal AII challenge, tachyphylaxis did not subsequently occur. Additionally, in tissues made tachyphylactic to AII, subsequent incubation with losartan (300 nM) reversed the AII tachyphylaxis. Thus, losartan may prevent the loss of contractility by preventing AII from interacting with its receptor in a manner which induces tachyphylaxis. However, since losartan can also completely reverse the loss of contractility, it appears capable of restoring the AT1 receptor to a state which allows subsequently administered AII to fully activate the contractile pathway.
在兔主动脉条制备物中，血管紧张素II（AII）浓度-收缩反应曲线（0.3 - 100 nM）具有高度可重复性。然而，通过重复暴露于该肽的超最大浓度（10 μM）可诱导对AII引起的收缩反应产生快速耐受性。相比之下，α1 - 肾上腺素能受体激动剂去氧肾上腺素（1 mM）的相应超最大浓度并未使组织对去氧肾上腺素产生快速耐受性。此外，在先前已对AII产生快速耐受性的组织中，去氧肾上腺素反应不受影响。当在每次超最大AII刺激前给予非肽类竞争性血管紧张素AT1受体拮抗剂氯沙坦（300 nM）时，随后并未出现快速耐受性。此外，在对AII产生快速耐受性的组织中，随后用氯沙坦（300 nM）孵育可逆转AII快速耐受性。因此，氯沙坦可能通过阻止AII以诱导快速耐受性的方式与其受体相互作用来防止收缩力丧失。然而，由于氯沙坦也能完全逆转收缩力丧失，它似乎能够将AT1受体恢复到一种状态，使随后给予的AII能够充分激活收缩途径。
