Agonist and antagonist effects of Sar1‐ala8‐angiotensin II in salt‐ loaded and salt‐depleted normal man.

Abstract

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.

Pharmacokinetic and pharmacodynamic studies of infusions with [Sar1, Val5, Ala8] angiotensin II (saralasin)

“…Similar results have been described by other investigators [10,17]. MacGregor and Dawes [14] did not see a reduction of blood pressure in resting normotensive subjects on a low sodium diet of 10 inEq per day. Also pretreatment with 80 mg furosemide did not result in blood pressure decreases in normotensive and hypertensive subjects with normal plasma renin activity [2,15,20].…”

Interferences with the Renin-Angiotensin System and Their Effects on High Blood Pressure

“…In sodium-depleted patients pretreated with diuretics or vasodilating drugs, severe hypotensive effects and fainting can be induced by the administration of AIl antagonists. In contrast, when the same individuals were sodium loaded, the effect of saralasin was reversed, inducing a pressor response (MACGREGOR and DAWES, 1976;GLESS et aI., 1977) (Fig. 5).…”

“…Saralasin was not effective in animals made hypertensive by the infusion of norepinephrine, tyramine, or vasopressin (BRUNNER et al, 1971(BRUNNER et al, , 1972aGAVRAS et al, 1973;SWEET et al, 1973;NEEDLEMAN et al, 1976). In hypertension caused by overdosage of mineralocorticoid hormones such as desoxycorticosterone or positive sodium balance with suppressed PRA, a marked pressor effect of angiotensin antagonists was noted even at low doses, which indicates the partial agonistic activity of these compounds at the vascular smooth muscle receptor (GLESS et al, 1977;KEIM et al, 1976;MACGREGOR and DAWES, 1976;DIETZ et al, 1977).…”

“…The hypertensive as well as the acute hypotensive episodes (CASE et al, 1976a) may be dangerous, and blood pressure of patients should be monitored for several hours after the administration of saralasin. If saralasin is given in cumulative doses (MACGREGOR and DAWES, 1976;GLESS et al, 1977), starting at low levels of 0.01 fLgjkgjmin and increasing the doses to 0.1, 1.0, and 10 fLg/kgjmin, each doses being infused over a period of 15 to 20 min, unwanted blood pressure responses can be discovered early and dangerous adverse reactions avoided. The plasma levels of saralasin during the infusion of the antagonist are extremely high (Fig.…”

Angiotensin II Blockade in Normal Subjects and Essential Hypertensive Patients

“…In the first eight patients and three normal subjects, saralasin was infused on the fifth day of the high sodium intake and on the fifth day of the low sodium diet, at an infusion rate of 5 pg min-' kg-l for 30 min, and 10 pg min-kg-for 60 min. These three normal subjects and eight patients had a water diuresis induced with 5% glucose solution (MacGregor & Dawes, 1976) so that measurements of urine flow and sodium excretion could be made. Subsequently the same three normal subjects and a further seventeen patients were infused with saralasin on the fifth day of the low sodium diet only, an incremental rate of infusion being used: normal, 0.25, 0.5, 1.0, 2.5, 5.0, 10.0 pg min-l kg-l; hypertensive, 0.25, 1.25, 5.0, 10 pg min-' kg-'.…”