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Angiotensin converting enzyme plays a key role in the hormonal regulation of blood pressure. It is responsible for the production of the vasoconstrictor hormonal peptide angiotensin II as well as the destruction of the vasodilator peptide bradykinin. Recently, orally active specific inhibitors of angiotensin converting enzyme have become available. Captopril (SQ14225) blocks angiotensin I and potentiates bradykinin effects in vitro and in vivo. In man it leads to a fall in endogenous plasma angiotensin II, a rise in blood angiotensin I and renin, but no change in blood bradykinin can be detected. In sodium deplete normal subjects it lowers the blood pressure, but in sodium replete subjects it is without effect. Similarly, it will acutely lower blood pressure in renovascular and accelerated hypertension but not in essential hypertension. The acute hypotensive effect of captopril may therefore be due to inhibition of the renin-angiotensin system. However, in the long term, it is effective in lowering the blood pressure in patients with essential hypertension, especially when combined with a diuretic. This suggests that the long-term hypotensive effect differs from the short term effect, and involves mechanisms other than inhibition of the renin-angiotensin system. This may include local effects on blood vessels and the kidney and the kallikrein-kinin system.

Distinct and specific binding sites for 3H-angiotensin II (A II) AND 3H-angiotensin III (A III) have been demonstrated in Rat adrenal gland preparations. A III binding sites have the highest affinity (KD29C1-2.10(-10)M) for the 2-8 heptapeptide. This suggests the possibility of a separate and distinct physiological role for the 2-8 heptapeptide, mediated via such A III binding sites.

1. The acute effects of captopril on blood pressure, renin, angiotensin, bradykinin and catecholamines were examined in patients with essential (n = 10, Group 1), accelerated (n = 6, Group 2) and renal hypertension (n = 14, Group 3). 2. Blood pressure showed little change in Group 1, fell significantly in Group 2, with a marked fall in Group 3. Heart rate did not change. 3. The fall in blood pressure was positively correlated with pretreatment renin and angiotensin II. 4. Angiotension II fell, with reciprocal increases in renin and angiotensin I. No changes occurred in bradykinin or catecholamines. 5. The rise in renin after captopril was greatest in renovascular hypertension which may prove useful as a screening test for such patients.

The specific binding of angiotensin II and des-Asp1-angiotensin II ("angiotensin III") III") to rat adrenals was studied with the use of the tritiated peptides. The binding sites having maximal affinity for angiotensin II were characterized by an equilibrium dissociation constant of 3.3 to 5.2 X 10(-9) M. Angiotensin III was able to interact with these sites, and also with a class of sites with very high affinity, characterized by an equilibrium dissociation constant of 1 to 2 X 10(-10) M. These sites exhibited a greater affinity for the heptapeptide angiotensin III than for the octapeptide angiotensin II. These findings, together with the known potent aldosterone stimulating effect of angiotensin III and its presence in rat plasma, suggest that this heptapeptide could be the physiologically important steroidogenic angiotensin in this species.

3H-angiotensin binding sites have been studied in a particulate fraction prepared from rat adrenal glands. This binding is rapid and reversible, of high affinity (KD29 degrees C = 3-5 X 10(-9) M) and with demonstrable specificity for the angiotensin II octapeptide. The number of binding sites varies with endogenous angiotensin levels: nephrectomy is followed by an increase in number of binding sites. This increase can be prevented by chronic angiotensin II administration and, to a lesser extent, by administration of Sar1,Ala8-angiotensin II, a competitive antagonist of the hormone. No variation in the equilibrium dissociation constant accompanied these changes in binding capacity. The post-nephrectomy increase in capacity is time-dependent, with a lag period of 24-40 h. The observed changes in receptor concentration do not appear explicable on the basis of receptor occupancy. Accordingly, angiotensin II receptors in the rat adrenal appear to be dependent on circulating angiotensin levels as previously reported for rat uterus.

Angiotensin II receptors from rat adrenal cortex and myometrium were studied with the use of tritiated angiotensin under conditions where the sensitivity of the target organs for angiotensin II is modified. Sodium status was found to modulate the number of angiotensin receptors both in adrenal gland and uterus. In both target tissues low Na+ diet increases the number of receptors, while a high Na+ diet results in an increase in uterine receptors without modifying adrenal cortical receptors. However, a more markedly positive sodium balance, such as that observed in deoxycorticosterone acetate (DOCA) hypertension and in one-kidney Goldblatt hypertension, resulted in a reduction of the adrenocortical angiotensin II binding capacity. The endogenous angiotensin II level may also regulate the number of receptor sites as demonstrated by an increased number of receptors after suppression of circulating angiotensin II. It is proposed that the number of angiotensin II receptors is determined by the combined influences of sodium status and angiotensin II concentration. Some changes in the sensitivity of the target organ can be secondary to variations in the number of angiotensin receptors. However, others cannot be so explained and stem, therefore, from events occurring beyond the hormone-receptor interaction.