I Indomethacin had an equal inhibitory effect on the response of the guinea-pig isolated ileum to angiotensin II (angiotensin), bradykinin, histamine and acetylcholine. This effect did not seem to result from inhibition of prostaglandin synthesis, as it did not depend on the time of treatment with indomethacin. 2 Prostaglandin E2 (prostaglandin) potentiated the responses of the guinea-pig ileum to angiotensin, bradykinin, histamine and acetylcholine without significant differences in the effects observed.3 In the rabbit isolated mesenteric and coeliac arteries, indomethacin had an equal potentiating effect on the responses to angiotensin and to adrenaline. In these organs pre-incubation with indomethacin was necessary for the effect to be observed, and this effect lasted for 2 h or more after that drug was removed from the medium. 4 No cross-tachyphylaxis between angiotensin and adrenaline was observed in the rabbit mesenteric and coeliac arteries.5 It is concluded that the effects of indomethacin and prostaglandin on the response of the guinea-pig ileum to the four agonists result from an action on the smooth muscle contractile mechanism per se rather than from an inhibitory action on the release of endogenous prostaglandin produced by the four agonists. 6 The results with the rabbit isolated arteries indicate that tachyphylaxis to angiotensin in these organs is not caused by prostaglandin release.

Tachyphylaxis to [Ile5]angiotensin II (angiotensin) in the isolated guinea pig ileum was found to be more severe when the Ca2+ concentration or the temperature of the medium were lowered, or when glucose was absent. Incubation with indomethacin or prostaglandin E2 did not affect the onset of tachyphylaxis or recovery from the tachyphylactic state. The angiotensin dose-response curves of tachyphylactic organs were shifted to the right, and the maximum responses were depressed in proportion to the conditioning doses of the hormone. The recovery from tachyphylaxis followed zero-order kinetics and was not affected by Ca2+ concentration or pH. The temperature dependence of the rate of recovery yielded a value of 14.6 kcal/mol for the activation energy in the physiological temperature range. It is concluded that tachyphylaxis results from the tight binding of angiotensin to superficial calcium-binding sites in the smooth muscle cell membrane. Recovery from tachyphylaxis appears to involve displacement of angiotensin by calcium in a process that is dependent on active transport.

Chl-des-Asp^Val^angiotensins I were synthesized by the solid-phase method and shown to be specific reversible antagonists of angiotensin I and II on the rat's blood pressure, the isolated guinea pig ileum, rat uterus, and rabbit aortic strip. The inhibition was of the competitive type, although lowering of the maximum response to the agonists was observed at high antagonist concentrations in the ileum and the uterus but not in the aorta preparations. pA2 values were calculated and were the same for the two agonists in each of the smooth muscle organs. pA2 values were of the same order of magnitude as pD2 values for angiotensin II. The evidence favors the hypotheses that angiotensins I and II act on the same receptor and that the C-terminal residue of angiotensin II is important for intrinsic activity rather than for binding to the receptor.After the discovery that [Ala8]angiotensin II was a competitive antagonist of angiotensin II,2 several other analogs, in which the phenylanine in position 8 of the peptide chain was replaced by other residues, were also shown to be angiotensin antagonists.3"10 Since all of these have been octapeptides described as angiotensin II inhibitors, it was thought

The belief that the smooth muscle contracting activity of angiotensin II (angiotensin) in the guinea pig ileum is partly mediated by release of acetylcholine was reexamined, with the following results. 1. Atropine did not reduce the maximum contraction produced by angiotensin, although it caused a shift to the right of the log dose-response curve (dose ratio = 2.2). A similar shift was observed with histamine, bradykinin and BaCl2. 2. A moderate potentiation of angiotensin by eserine was also observed, which was similarly found for the other agonists. 3. A previous report that atropine blocks the fast (phasic) component of the isometric response of the ileum to angiotensin was not confirmed. The disappearance of the phasic component was found to be due to a tachyphylactic change in the response. 4. Depolarization by high doses of nicotine, and inhibition of acetylcholine synthesis by hemicholinium, did not affect the response to angiotensin. 5. Ilei in which the intramural ganglia had been destroyed by incubation at 4 degrees 48-56 h responed maximally to angiotensin, without loss of the phasic component of the response. It is concluded that the available evidence does not support the participation of a cholinergic mechanism in the effect of angiotensin upon the guinea pig ileum.

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