Tachyphylaxis to angiotensin II and [Phe4]-angiotensin II in the rat mesentery in vivo.

The existence of tachyphylaxis to angiotensin II (Ang II) in vivo is not unequivocally established, and the hydroxyl group of the Tyr4 residue of Ang II has been suggested as a determinant of tachyphylaxis. In view of these observations, we conducted a series of experiments to assess and compare the ability of Ang II and [Phe4]-Ang II to induce tachyphylaxis in vivo. All experiments were performed in the autoperfused rat mesenteric vascular bed. The tachyphylaxis to intramesenteric (IMA) infusions of Ang II was minimal, and after 120 min of continuous infusion (33 pmol/min), Ang II retained most of its vasoconstrictor activity (67.7 +/- 6.6% of the initial response). Also most of the agonist activity was retained even when Ang II was administered continuously in a dose-increasing manner (1-33 pmol/min). Continuous IMA infusions of single doses of [Phe4]-Ang II caused an initial full response that rapidly declined, and after 120 min retained only 18.2 +/- 9.2% of the initial response. Single continuous IMA infusion of [Phe4]-Ang II induced greater vasoconstrictor responses compared with vascular responses to the same doses delivered after the infusion of smaller doses. This difference was significant (P < .001, unpaired Student's t test) for all doses (10, 100, 330 and 1000 pmol/min) of [Phe4]-Ang II. In conclusion, although the development of tachyphylaxis to Ang II in vivo is minimal, tachyphylaxis to [Phe4]-Ang II does occur (at least in rat mesenteric vascular bed). Thus, omission of the hydroxyl group in position 4 dramatically increases the tachyphylactic potential, while preserving full agonist activity. These results suggest that the hydroxyl group of Tyr4 may protect the Ang II receptor from changes that induce tachyphylaxis.