Changes in residues 1 and 4 of angiotensin II affect differently its agonist and tachyphylactic properties.

Two series of angiotensin II analogues with modifications at positions 1 or 4 of the peptide chain were studied with respect to their tachyphylactic properties and to the kinetics of relaxation of the guinea-pig ileum after a contractile response to maximally effective concentrations. Tachyphylaxis was measured by the decrease in response amplitude after three successive treatments ("tachyphylactic index") and the relaxation rate was evaluated by the time taken for the tonus to reach half of its value at the moment of agonist washout ("half relaxation time"). A correlation between tachyphylactic index and half relaxation time was found for the series of position 1 analogues, but not for the position 4 analogues. For the two series, the half relaxation times of the tachyphylactic analogues decreased from the first to the third of a series of successive treatments. Bulky substituents at position 1, which did not greatly affect the agonist activity, suppressed the tachyphylactic property. The results provide evidence that the agonist and tachyphylactic properties of angiotensin II are due to its interaction, respectively, with an agonist site and a "tachyphylaxis" site on the receptor and that the structural requirements for binding to the two sites are different.