TACHYPHYLAXIS TO ANGIOTENSIN-II AND [PHE(4)]-ANGIOTENSIN-II IN THE RAT MESENTERY IN-VIVO

The existence of tachyphylaxis to angiotensin II (Ang II) in vivo is n ot unequivocally established, and the hydroxyl group of the Ty(4) resi due of Ang II has been suggested as a determinant of tachyphylaxis. In view of these observations, we conducted a series of experiments to a ssess and compare the ability of Ang II and [Phe(4)]-Ang II to induce tachyphylaxis in vivo. All experiments were performed in the autoperfu sed 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 a ctivity (67.7 +/- 6.6% of the initial response). Also most of the agon ist activity was retained even when Ang II was administered continuous ly in a dose-increasing manner (1-33 pmol/min). Continuous IMA infusio ns of single doses of [Phe(4)]-Ang II caused an initial full response that rapidly declined, and after 120 min retained only 18.2 +/- 9.2% o f the initial response. Single continuous IMA infusion of [Phe(4)]-Ang II induced greater vasoconstrictor responses compared with vascular r esponses to the same doses delivered after the infusion of smaller dos es. This difference was significant (P <.001, unpaired Student's t tes t) for all doses (10, 100, 330 and 1000 pmol/min) of [Phe(4)]Ang II. I n conclusion, although the development of tachyphylaxis to Ang II in v ivo is minimal, tachyphylaxis to [Phe(4)]-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, whi le preserving full agonist activity. These results suggest that the hy droxyl group of Tyr(4) may protect the Ang II receptor from changes th at induce tachyphylaxis.