SUMMARY We made separate measurements of angiotensin II (A II) and of its immunoreactire metabolites (2-8 heptapeptide, 3-8 bexapeptide, and 4-8 pentapeptide) in arterial and venous plasma from subjects with widely different plasma levels of the peptides. A II and its three metabolites were extracted from blood, separated by paper chromatography, and measured by radioimmunoassay using an A II antisemm which had a 100% cross-reaction with each metabolite. In contrast to results of previous studies, A II was found to predominate in both arterial (60-100%) and venous (55-100%) blood. The biologically active 2-8 beptapeptide metabolite accounted for only 10% of the activity in arterial plasma. Radioimmunoassay of venous plasma extracts using an A II antisemm which had a low cross-reaction with the 3-8 hexapeptide and the 4-8 pentapeptide confirmed the results obtained using the antisemm which had a 100% cross-reaction with the metabolites. We conclude that radioimmunoassay methods for measuring A II in venous blood may be more accurate and relevant than has previously been recognized. The small difference between A II concentrations in arterial and venous plasma suggests further that there may be significant conversion of angiotensin I (A I) to A II in the limb vasculature.THE PRESSOR octapeptide, angiotensin II (A II), coexists in blood with its major metabolites, the C-terminal 2-8 heptapeptide, 3-8 hexapeptide, and 4-8 pentapeptide. Compared to A II, the heptapeptide has only weak pressor activity in the rat, whereas the remaining metabolites have none.1 ' * In contrast, the heptapeptide is equally as potent as A II in stimulating aldosterone secretion in the sheep' and in the conscious rat,'1 and more potent as a stimulus to aldosterone biosynthesis in vitro using rabbit capsular adrenal tissue. 5 The aldosterone-stimulating properties of the remaining metabolites are weak.*-* Antisera raised against A II usually cross-react with the C-terminal heptapeptide and hexapeptide metabolites'-' and sometimes also with the pentapeptide metabolite.' Radioimmunoassays of A II thus measure not only A II but also these immunoreactive metabolites. A II can be separated from metabolites by chromatography of blood extracts before immunoassay. Cain et al.*"" used this approach and found that A II comprised 85% of the immunoreactive material in human arterial blood, but only 28% of that in venous blood. In venous blood, they found the major immunoreactive substance to be the hexapeptide, although the concentrations of hepta-and pentapeptides were not determined.Our present paper describes a method for determining the relative proportions of A II and the three major peptide metabolites in arterial and venous blood, and the results obtained in a group of subjects with a wide range of circulating levels of renin and A II. Further, because the analogue of A II, l-Asp(NH,)-5-Val-angiotensin II, often used in investigations of the renin-angiotensin system, is degraded, in plasma at least, by a different enzyme from that which catalyze...

1 Three normal subjects were infused with Sarl -ala8 -angiotensin II (Saralasin, P1 13) whilst on a high sodium (200 mEq + normal diet) and a low sodium (10 mEq diet) intake. 2 On the high sodium intake when angiotensin II and plasma renin activity (PRA) were suppressed, P113 infusion (5-10 ,ug kg-' min-') caused a slight rise in BP and a marked drop in urine flow and sodium excretion, with a fall in glomerular filtration rate, and effective renal plasma flow. 3 On the low sodium intake, when angiotensin II and PRA were increased, P113 infusion (5-10 jig kg-' min-) caused no change in blood pressure, urine flow or sodium excretion. However, when PI 13 was infused at an incremental rate starting at 0.25 ,ug kg-' min-1 there was a fall in standing BP, which was maximal at an infusion rate of 1 ,ug kg-1 min-', and this fall in standing BP was largely abolished as the rate of infusion was increased to 10 Mg kg-1 min-. 4 These results show firstly that angiotensin II is involved in maintaining standing blood pressure during dietary sodium depletion in normal man and secondly that P113 does have agonist as well as antagonist activity in normal man, the effect depending on the level of angiotensin II and sodium intake. When looking for angiotensin II mediated hypertension it may be important to use an incremental rate of infusion of P1 13 as the agonist activity of larger doses may mask its hypotensive action.

SUMMARY Sodium depletion was induced in dogs to raise plasma renln activity (PRA) from 1.11 to 26.48 ng/ml/hr. Little overall change in blood pressure (BP) occurred, but cardiac output (CO) and central venous pressure fell, while total peripheral resistance and heart rate (HR) increased.A nonapeptide converting enzyme inhibitor (CEI) produced a fall in BP which was linearly related to log. PRA; the intercept with PRA was at 1.05 ng/ml/hr, dose to the average value for dogs on a normal diet. The fall in BP with this agent was not accompanied by an increase in HR or CO.When Sar'-Ala' angiotensin II was used to antagonize the action of angiotensin, the fall in BP was also linearly related to log. PRA. However, for a given level of PRA this fall in BP was less than that achieved with CEI and the intercept of BP fall with PRA was 2.6 ng/ml/hr. Again with this agent there was little change in HR or CO as BP was reduced.Thus, both antagonists lowered peripheral resistance without exciting the bomeostatic reflexes indicating that, as PRA rose above the normal resting level, the angiotensin generated had both a direct and indirect effect in maintaining BP.

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