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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.

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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

An alkylating analogue of angiotensin II (AII) containing a nitrogen mustard group (p-[N, N-bis(2-chloroethyl) aminojphenylbutyryl at the N-terminus ([Chi¹]-All) was shown to be an irreversible specific inhibitor of the action of AII on the isolated rat uterus. The inhibition was observed when the Ca⁺⁺ concentration in the medium was 0.18 mM, and was more intense in calcium-free medium. It was not observed in the presence of 1 mM Ca⁺⁺. It is concluded that a site near (but not on) the AII receptor is alkylated by [Chi¹ ]-AII, and the properties of this site suggest that it is the same one involved in the phenomenon of tachyphylaxis.

The response of plasma aldosterone (PA) to ACTH administration (250 µg α^1-24 ACTH i.m.) before and during treatment with spironolactone (Sp, 75-100 mg/day) for at least 8 months was studied in 11 patients with essential hypertension. These responses were compared with those before and during prolonged treatment with hydrochlorothiazide (Th, 50-75 mg/day), with or without potassium supplement, in 14 hypertensives. PA and plasma cortisol (PC) were determined by radioimmunoassay in which Sp showed minimal cross-reactivity. Both Sp and Th treatments caused similar increases in plasma renin activity accompanied by nearly identical decreases in blood pressure and body weight. PA was also increased by both treatments, but to a significantly greater extent in the Sp-treated group. Serum potassium concentration was increased only by Sp treatment. The response of PA, but not of PC, to acute ACTH stimulation was blunted in the Sp-treated group. That is, the maximal increment of PA above the baseline level was significantly lower during Sp treatment than either before Sp treatment or during Th treatment. These results demonstrate that long-term treatment with Sp can inhibit aldosterone production by acute ACTH stimulation in patients with essential hypertension.

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