Structure–desensitization relationships of angiotensin analogues in the rat isolated uterus

Abstract

The desensitizing potencies of angiotensin II (ANG II) analogues modified at positions 1, 2, 4, 7, and 8 have been examined in the rat isolated uterus assay by determining the time of recovery of the half-maximal concentration (EC₅₀) response to angiotensin II after treatment of the tissues with a high dose (10⁻⁵ M) of each analogue for 2 min. The magnitude of the desensitization effect was substituent dependent in the following manner: position 1, sarcosine (Sar) > Asp > des-Asp; position 2, Arg > Sar; position 4, Tyr > Tyr(Me) ~ Phe; position 7, 3,4-dehydroproline (Dpr) > Pro > thioproline (Tpr) > Sar; position 8, Ile > D-Trp > Ala > Phe. The "additivity" rule applied to these structure–desensitization relationships and the most potent desensitizer, requiring 3 h for reestablishment of the EC₅₀ response, was [Sar¹,Dpr⁷,Ile⁸]-ANG II. The desensitizing potencies of these analogues did not correlate with agonist or antagonist activities and demonstrated that the angiotensin-mediated tissue desensitization process has unique structural determinants. Methylation or elimination of the tyrosine hydroxyl group of strong desensitizers virtually eliminated the desensitization effect, implicating the phenoxyl moiety in the mechanism of desensitization. The initial phase of recovery of angiotensin responsiveness after desensitization by several analogues appeared to obey first-order kinetics. The results are discussed in the contexts of both one- and two-site receptor models.