Possible Role of Vascular Angiotensin Converting Enzyme in the Genesis of Hypertension

This study was designed to evaluate changes in angiotensin converting enzyme (ACE) activity in 2-kidney, 1-clip renal hypertensive dogs. Blood pressure increased and remained elevated for eight months after partial clamping of the left renal artery. Plasma renin activity was increased for one month after surgery, but then returned to the pre-clamping level. SA-446, a potent ACE inhibitor, reduced blood pressure in 8 M-hypertensive dogs. Plasma ACE activities was not altered during the course of hypertension, but vascular ACE activities in the pulmonary and mesenteric arteries and the aorta were significantly increased in 8 M-hypertensive dogs. These results may indicate that ACE plays an important role in the maintenance of chronic phase of 2-kidney, 1-clip renal hypertension and that suppression of vascular ACE activities might be a mechanism underlying the hypotensive effect of ACE inhibitors.     

A Long-term Follow-up of Patients with Essential Hypertension Treated with Captopril

Abstract Seventy-four patients from four short-term studies of captopril in mild-moderate essential hypertension continued in a cooperative long-term efficacy and tolerance program. The duration of observation is 2–>4 years, the total treatment time being 2434 months. No development of resistance to therapy was observed. The total daily dose of captopril has been gradually decreased and in 20 patients changed from t.i.d. to b.i.d. regime. The drug has been well tolerated and only few and mild side-effects have been observed after the initial titration period. The drop-outs (n=19) were mostly due to non-medical causes (n=14). Except for one case of proteinuria, no laboratory abnormalities were detected and there were no signs of long-term toxicity.     

Lifetime Treatment with Captopril Improves Renal Function in Spontaneously Hypertensive Rats

Lifetime treatment with captopril prevents the development of hypertension in spontaneously hypertensive rats (SHR). This study tests the hypothesis that compared to untreated hypertensive SHR, captopril-treated SHR display similar diuretic and natriuretic responses to an isotonic saline infusion despite significantly lower arterial pressure. Eight-week-old, male SHR were instrumented with femoral arterial, venous, and bladder catheters. Forty-eight hours later, each rat was infused intravenously with an isotonic saline load (5% of body weight; 0. 5 ml/min). Lifetime captopril-treated SHR and untreated control SHR displayed nearly identical natriuretic and diuretic responses to the saline infusion. Thus, although lifetime captopril treatment significantly reduces mean arterial pressure in SHR, renal excretory responses appear to be unaltered. Moreover, histological examination of the kidneys of the lifetime captopril-treated SHR did not reveal significant structural damage in the kidneys at either 8 weeks of age or at 12 months of age. Together, the data suggest that lifetime captopril treatment does not adversely affect renal function and structure in SHR.     

Contribution of Renal Angiotensin Converting Enzyme(ACE) to Blood Pressure Regulation: Possible Role of Brush Border Ace

The role of renal angiotensin converting enzyme(ACE) in blood pressure regulation is not well understood. In our studies, both acute and chronic treatment of hypertensive rats SHR and SHRSP with ACE inhibitors Enalapril and SA446 had a blood pressure lowering effect that coincided with an inhibition of renal cortical and aortic ACE, but not plasma ACE. Further, ACE activities in the renal cortex and aorta were found to increase with aging of the SHRSP, therefore concomitantly with hypertension development. In the kidney, brush border membranes(BBM) contained abundant ACE. We found that the activities of ACE in the renal cortex closely correlated to the activities in isolated BBM, in Wistar Kyoto rats and in the SHRSP. Thus, renal cortical ACE activity and blood pressure correlated in cases of ACE inhibition and hypertension development. Since the ACE activity in the renal cortex appeared to reflect the enzyme activity in BBM, the brush border ACE may have to be taken into account, in view of the relationship between renal ACE, and blood pressure.     

Randomised,Double-Blind Crossover Comparison of Once-Daily Captopril and Lisinopril in Patients with Mild to Moderate Hypertension - a Community-Based Study: By Hunter Hypertension Research Group,Discipline of Clinical Pharmacology,Newcastle Mater Misericordiae Hospital,Waratah 2298 NSW Australia

Of twenty-five patients with mild to moderate hypertension, recruited and managed in the community, seventeen responded fully to, and completed a randomised cross-over study of, captopril (ceiling dose 100 mg) compared with lisinopril (ceiling dose 40 mg) both given as a single daily dose. Mean supine and standing blood pressures measured at the end of the dose interval were significantly reduced compared to placebo by both compounds at three and six weeks. However, a consistent, significant increase in blood pressure occurred between three and six weeks in both arms of the study despite good and unchanged compliance with a fixed dose of each medication. Both captopril and lisinopril were well tolerated. Drug-related cough was the principal adverse effect.     

Captopril Treatment and its Withdrawal Prevents Impairment of Endothelium-Dependent Responses in the Spontaneously Hypertensive Rat

Angiotensin converting enzyme inhibitors (ACE-I) have been shown to prevent impairment of endothelial cell function in Spontaneous Hypertensive rats (SHR). The purpose of this study was to examine the effects of early, long-term captopril (ACE-I) treatment and its withdrawal on vascular reactivity in SHR. Three groups of male SHR were studied: 1) untreated SHR; 2) SHR treated with captopril in-uteroand maintained on oral treatment post-weaning (SHRCAP); and 3) SHR treated with captopril in-uterofollowed by withdrawal of drug therapy at two months of age (OFFCAP). All rats were studied at six months of age. Isolated aortic ring segments were suspended in tissue chambers for measurement of isometric force. Ring segments were exposed to cumulative concentrations of serotonin or phenylephrine (3×10^-9-3×10^-5M). SHR demonstrated an enhanced sensitivity to serotonin induced contraction. EC₅₀value were: SHR 3.6± 1.4 × 10^-7M, SHRCAP 9.5±0.5 × 10^-7and OFFCAP 8.1±0.9 × 10^-7. Endothelium-dependent relaxation to acetylchline (ACh) was markedly impaired in the SHR. Maximum relaxation (R_max) to ACH was 61.1 ± 1.6% of serotonin induced onctaction versus 91.4± 1.2% and 90.7± 1.8% relaxation in SHRCAP and OFFCAP, respectfully (p<0.05). These data suggest that early, long-term treatment with captopril can prevent alterations in endothelial function observed in SHR even after ACE-inhibitor therapy has been stopped     

Effect of Angiotensin Converting Enzyme Inhibitor (Captopril) on Cerebral Blood Flow in Hypertensive Patients without a History of Stroke

The effect of the angiotensin converting enzyme inhibitor, captopril, on cerebral blood flow (CBF) was studied in 11 hypertensives without a history of stroke. Mean hemispheric CBF (mCBF) was measured in each patient by Xe-133 inhalation method before and after 7 days of captopril administration. Blood pressure (BP) both in the control state and at the time of CBF measurement decreased significantly after drug administration. mCBF, however, did not show any significant change. When percent changes in mCBF before and after the administration were plotted against those of mean arterial BP, significant inverse correlations were obtained in both hemispheres; the larger the BP decrease, the more increase in CBF was observed.

It is concluded that captopril lowers systemic BP without concomitant decrease in CBF in hypertensive subjects with no history of stroke. Furthermore, the results suggest that captopril may have a vasodilating action on cerebral blood vessels.     

Regulation of Prostacyclin Generation by Angiotensin Converting Enzyme Related Substances in Cultured Human Vascular Endothelial Cells

The regulation of prostacyclin (PGI₂) generation by angiotensin I-converting enzyme (ACE) related substances was investigated using cultured human vascular endothelial cells. Angiotensin I (AI) or bradykinin (BK) increased PGI₂ generation and ACE activity, while the ACE inhibitor, captopril decreased both of them, and angiotensin II (AII) did not show any effect. The increasing rate of PGI₂ generation induced by AI or BK was not affected by the pretreatment with captopril. These results suggest that the accumulation of AI or BK via the inhibition of ACE by captopril did not cause the enhancement of PGI₂ generation. Rather, it was proposed that the enhanced PGI₂ generation by AI or BK might be regulated by ACE activation derived from these substances, as an autoregulation mechanism.     

Patterns of Renal Function in Hypertension Due to Unilateral Renal Artery Occlusion

We performed renal function studies in dogs with chronic renovascular hypertension produced by complete occlusion of a renal artery. In addition, we evaluated in anesthetized dogs the acute effects of a novel angiotensin converting enzyme inhibitor, CGS 16,617, on renal function and plasma neurohormones (epinephrine, norepinephrine and vasopressin) 4 weeks after initiation of 2 kidney, 1 clip hypertension. CGS 16,617 effectively decreased blood pressure in renal hypertensive animals. This response was associated with suppression of angiotensin II indicating effective converting enzyme inhibition. In the non-clipped kidney, acute administration of CGS 16,617 increased effective renal plasma flow but not glomerular filtration rate and urinary sodium excretion. In the clipped kidney, CGS 16,617 caused no change in any parameter of renal function. Plasma norepinephrine, epinephrine and vasopressin were unaffected by administration of CGS 16,617. These studies showed that chronic occlusion of a renal artery does not result in renal infarction because of a compensatory increase in the amount of blood provided through capsular collateral vessels. The collateral circulation which has developed in the clipped kidney explains the lack of a converting enzyme inhibitor effect.     

Effect of Ketoprofen on Blood Pressure, Endocrine and Renal Responses to Chronic Dosing with Captopril in Patients with Essential Hypertension

The effects of non-steroidal anti-inflammatory drugs (NSAIDs) on the blood pressure and renal function of essential hypertensive patients depend on the specific type of NSAID and antihypertensive drug administered. Twelve patients with essential hypertension, aged 35 to 59 years, stabilized (blood pressure less than 140/90 mmHg) with captopril, received ketoprofen (100 mg bid for 7 days) or matching placebo in a randomized double-blind cross-over fashion. A 3-week wash-out period was included between treatment periods. Blood pressure on the first and last days of the placebo treatment period (137± 7(SD)/80±8 and 139±11/81±9 mmHg) was similar to respective values during ketoprofen therapy (136±10/79±7 and 143 ± 10/81 ± 9 mmHg). The mean differences in systolic and diastolic blood pressures, at the end of the treatment periods, between ketoprofen and placebo were 4(95% confidence intervals -5, +13) and 0(-8, +8) mmHg, respectively. Ketoprofen had no effect on 24-h urinary sodium excretion (160 ± 33 and 147 ± 39 mmol/24 h for ketoprofen and placebo, respectively). Ketoprofen was without effect on glomerular filtration rate, renal plasma flow and filtration fraction. In conclusion, our data suggest that ketoprofen is a safe choice when short-term treatment with a NSAID is indicated in an essential hypertensive patient treated with a converting enzyme inhibitor such as captopril.     

比较开搏通与氯沙坦在同位素肾显像中诊断肾动脉狭窄的作用

目的　比较开搏通肾显像和氯沙坦肾显像诊断肾动脉狭窄的作用。病例和方法　 2 0 0 0年 10月至 2 0 0 1年 12月 ,共 4 6例疑诊肾血管性高血压的住院患者 ,先行开搏通肾同位素显像 ,2 4小时后行氯沙坦同位素肾显像。所有可疑肾动脉狭窄患者在肾显像后 7天内行肾动脉造影。结果　肾动脉造影显示共 92个肾脏中 6 7个肾脏的肾动脉无明显狭窄 ,另 2 5个肾脏的肾动脉直径狭窄≥ 5 0 %。开搏通肾显像和氯沙坦肾显像诊断肾动脉狭窄的敏感性分别为6 0 0 %和 84 0 % ,特异性分别为 95 5 %和 97 0 % ,准确性分别为 85 8%和 93 4 %。后者诊断的敏感性和准确性显著高于前者 (P <0 0 5 )。结论　氯沙坦肾显像诊断肾动脉狭窄的敏感性和准确性明显高于开搏通肾显像。     

Renal Tissue Angiotensins During Converting Enzyme Inhibition in the Spontaneously Hypertensive Rat

To compare the effects of an angiotensin-converting enzyme inhibitor on circulating and tissue renin-angiotensin system (RAS), we measured different RAS parameters during the first day of treatment (Day1) as well as after two weeks of treatment (Day14). Ramipril was given orally once daily to adult male spontaneously hypertensive rats (SHR). Renin activity (RA), angiotensin converting enzyme (ACE) activity and levels of angiotensin I (ang I) and angiotensin II (ang II) in the plasma, renal cortex and renal medulla were assessed at Day1 and Day14 of the treatment.

In the plasma, both RA and ang I increased 10 to 15 fold one to four hours after acute as well as at Day14 of ramipril treatment and then returned to basal values within 24 hours. Plasma ang II levels were not significantly decreased at Day1 or Day14. The decrease in the ang II/ang I ratio suggested a sustained inhibition of plasma ACE at Day14.

In the renal cortex and medulla, a clearly different pattern was observed: in ramipril treated rats, RA in the renal cortex and medulla did not change at Day1 but at Day14 we observed a slight and sustained increase in RA. Despite very high basal levels of RA, ang I levels in the renal cortex were comparable to those in the plasma. The ang I level increased only one-fold one hour after ramipril intake at Day1 and Day14. This suggests that angiotensinogen may have a limiting role in the synthesis of ang I in the kidney. Ang II levels were slightly higher in the renal cortex and medulla than in the plasma suggesting local synthesis of the peptide. In the kidney, ang II levels decreased one and four hours after the acute or prolonged ramipril treatment and the ang II/ang I ratio was reduced at the same time. Our results show that the responses of the plasma and kidney components of the RAS to ACE inhibition are different in the plasma and the kidney suggesting that the circulating and tissue RAS are at least in part independent.     

Angiotensin Converting Enzyme Inhibition Reveals an Important Role for the Renin System in the Control of Normal and High Blood Pressure in Man

Captopril, given for 5 days to normotensive healthy subjects caused a significant fall in blood pressure. The fall in mean supine blood pressure was greater on a low sodium diet (10 mmols/ day) - 19.6% and was less on a high sodium diet (350 mmols/day) - 11% compared to the normal sodium intake (120 mmols/day) when the fall in blood pressure was 16.5%. Patients with essential hypertension who were studied on their normal diet had a similar fall in blood pressure for a given plasma renin activity. It seems likely that the predominant mechanism whereby captopril lowers blood pressure is through the inhibition of the formation of angiotensin II. If this is so, our results suggest that the renin system is an important control of both normal and high blood pressure when on a normal sodium intake.     

The Renal Response to Converting Enzyme Inhibition and the Treatment of Sodium-Sensitive Hypertension

Multiple lines of evidence suggest that intrarenal angiotensin All formation participates in the control of renal perfusion and function. Inappropriate activation of this intrarenal system may participate in the pathogenesis of hypertension in about 45 percent of patients with essential hypertension, a group that we call “non-modulators” (NM). In NM the renal vascular response to AII is blunted when the subjects are on a high-salt diet, but appropriate when they are on a low-salt diet. Converting enzyme inhibition in NM induces a larger increase in renal blood flow, than occurs in normal subjects or other patients with essential hypertension, most evident when they are on a high-salt diet. The renal vasodilatation is not due to prostaglandin or bradykinin accumulation in the kidney, since the increase in renal blood flow induced by converting enzyme inhibition is associated with an enhanced renal vascular response to AII. When NM are shifted from a low to a high sodium intake, they show more positive sodium balance, gain more weight and increase their blood pressure more — the characteristics of sodium sensitive hypertension. Converting enzyme inhibition corrects their inability to handle a sodium load as it improves renal blood flow, and induces a depressor response that does not correlate with plasma renin activity. Many of these characteristics are shown in a normotensive offspring of essential hypertensives: since sodium handling is genetically determined, this abnormality may represent the inherited renal abnormality. An abnormality in the control of the renal circulation by AII, reversed by converting enzyme inhibition, may represent a fundamental abnormality in the pathogenesis.     

非降压剂量血管紧张素转换酶抑制剂对高血压冠状动脉肥厚的影响

目的　研究非降压剂量的血管紧张素转换酶抑制剂 (ACEI)对高血压冠状动脉肥厚的影响。方法 16周大鼠设4组 (各组n =6 ) :分别为自发性高血压大鼠 (SHR)组、SHR口服降压剂量卡托普利组 (40mg·kg- 1 ·d- 1 )、SHR口服非降压剂量卡托普利组 (2mg·kg- 1 ·d - 1 )和正常血压大鼠 (WKY)组 ,饲养 10周。结果　降压剂量卡托普利治疗显著降低SHR的收缩压 ,非降压剂量卡托普利治疗不降低SHR的收缩压 ;降压和非降压剂量卡托普利都显著减少了SHR冠状动脉壁横截面积、横截面积 内径比 ,减轻SHR冠状动脉前降支中层血管平滑肌细胞的肥大 ,都显著提高SHR的最大冠状动脉流量。结论　ACEI治疗对冠状动脉肥厚的逆转作用和对冠状动脉功能的改善作用可以不依赖于血压下降的效果 ,临床上应用ACEI降压不明显的病人继续使用ACEI可能有助于逆转血管壁肥厚 ,改善血管功能。     

Effect of bariatric surgery on cardiac structure and function in obese patients: Role of the renin‐angiotensin system

Echocardiographic alterations have been described in obesity, but their modifications after bariatric surgery (BS) and mechanisms are little known, mostly in normotensive patients. We aimed to analyze cardiac changes 1 year post‐BS and to explore possible mechanisms. A cohort of patients with severe obesity (58% normotensives) were prospectively recruited and examined before surgery and after 12 months. Clinical and echocardiographic data, 24 h BP, renin‐angiotensin‐aldosterone system (RAAS) components, cytokines, and inflammatory markers were analyzed at these two time points. Overall reduction in body weight was mean (IQR) = 30.0% (25.9–33.8). There were statistically significant decreases in left ventricle mass index^2.7(LVMI)^2.7, septum thickness (ST), posterior wall thickness (PWT), relative wall thickness (RWT), and E/e’, both in the whole cohort and in patients without RAAS blockers (p ≤ .04 for all). Plasma renin activity (PRA) decreased from (median, IQR) = 0.8 (0.3;1.35) to 0.4 (0.2;0.93) ng/ml/h, plasma aldosterone from 92 (58.6;126) to 68.1 (56.2;83.4) ng/dl, and angiotensin‐converting enzyme (ACE)‐2 activity from 7.7 (5.7;11.8) to 6.8 (5.3;11.2) RFU/µl/h, p < .05. The body weight loss correlated with a decrease in both 24 h SBP and 24 h DBP (Pearson''s coefficient 0.353, p = .022 and 0.384, p = .012, respectively). Variation (Δ) of body weight correlated with ΔE/e’ (Pearson''s coeff. 0.414, p = .008) and with Δ lateral e’ (Pearson''s coeff. = −0.363, p = .018). Generalized linear models showed that ΔPRA was an independent variable for the final (12‐months post‐BS) LVMI^2.7 (p = .028). No other changes in cardiac parameters correlated with ΔBP. In addition to the respective baseline value, final values of PWT and RWT were dependent on 12‐month Δ of PRA, ACE, and ACE/ACE2 (p < .03 for all). We conclude that there are cardiac changes post‐BS in patients with severe obesity, normotensives included. Structural changes appear to be related to modifications in the renin‐angiotensin axis.     

Renal Haemodynamics and Comparative Effects of Captopril in Patients with Benign- or Malignant-Essential Hypertension,or with Chronic Renal Failure

Effects of captopril on arterial pressure (AP) and renal function were investigated in patients with non-malignant “benign” or malignant phase essential hypertension (EH group), or with chronic renal failure (CRF group). After captopril administration, AP and renal vascular resistance (RVR) decreased significantly, and renal blood flow (RBF) and plasma renin activity (PRA) increased in both groups. Glomerular filtration rate (GFR) increased in the EH group, but was unchanged in CRF. Filtration fraction decreased in the malignant hypertension and CRF groups. Significant correlations were found between baseline PRA and baseline RVR, and the captopril-induced decrease in mean AP, decrease in RVR, increase in RBF, and increase in GFR in the EH group, while these associations were not observed in CRF. These results indicate that the high AP, RVR, suppressed RBF and GFR in the EH group were closely related to activity of the renin-angiotensin system, but not so the low RBF and GFR in CRF. Small doses of captopril may improve impaired renal function in EH, and may not cause deterioration in the CRF group.     

Captopril reduces the risk of nephropathy in IDDM patients with microalbuminuria

Summary In insulin-dependent diabetes mellitus (IDDM), microalbuminuria predicts renal and cardiovascular disease. We report a combined analysis of 235 normotensive IDDM patients with microalbuminuria who participated in two 24-month double-blind, randomised, placebo-controlled trials to assess the effects of captopril 50 mg twice daily on the progression to overt clinical albuminuria. Of the 225 patients who were evaluable on an intent to treat basis, 25 of 114 placebo-treated patients (21.9%) and 8 of 111 captopril-treated patients (7.2%) progressed to persistent clinical albuminuria. The risk of progression over 24 months was significantly reduced by captopril (p=0.004) with a risk reduction of 69.2% (95% confidence interval (CI): 31.7 to 86.1%). This degree of risk reduction remained at the same level (62.9% [16.1–83.6%], p=0.017) after adjustment for differences in time-varying mean arterial blood pressure. Albumin excretion rate increased by an average of 14.2% [3.1–26.5%] per year in the placebo-treated group compared with a reduction of 9.6% [–18.6–0.4%] per year in the captopril-treated group (p=0.002). The rate of fall of creatinine clearance tended to be faster in the placebo-treated group than in the captopril-treated group (–6.4 [–10.2––2.5] vs –1.4 [–5.3–2.6] ml · min^–1 · 1.73 m^–2, p=0.07). Baseline albumin excretion rate (p<0.0001) and glycated haemoglobin (p=0.03) were independent predictors of progression to clinical albuminuria and changes in mean arterial blood pressure (p=0.02) and serum cholesterol level (p=0.003) were significantly associated with percentage changes in albumin excretion rate. Captopril reduces the risk of progression to overt nephropathy in IDDM patients with microalbuminuria, an effect partly independent of its blood pressure-lowering effects.Abbreviations ACE Angiotensin converting enzyme - IDDM insulin-dependent diabetes mellitus - GFR glomerular filtration rate - C captopril - P placebo - AER albumin excretion rate - MAP mean arterial pressure Corresponding author: Professor G.C. Viberti, Unit for Metabolic Medicine, United Medical and Dental Schools of Guy's and St. Thomas' Hospitals, Guy's Hospital, London SE1 9RT, UKMembership of the Study Group is listed in the Acknowledgement section     

Renal enlargement and insulin-like growth factor-1 accumulation in the Wistar rat model of experimental diabetes is not prevented by angiotensin converting enzyme inhibition

Summary Experimental diabetes is associated with renal enlargement and glomerular hyperfiltration. Possible mechanisms for these changes could be the direct effects of growth factors such as insulin-like growth factor-1 and angiotensin II. We investigated whether treatment with trandolapril, an angiotensin converting enzyme inhibitor, prevented renal enlargement in streptozotocin-diabetic rats. Seven groups of male Wistar rats were studied: C (control+placebo); CL (control+low-dose trandolapril, 0.01 mg · kg^–1 · day^–1); CH (control + high-dose trandolapril, 0.5 mg · kg^–1 · day^–1); DP (diabetic + placebo); DI (diabetic, insulin-treated); DL (diabetic + low-dose trandolapril); DH (diabetic + high-dose trandolapril) and DI (diabetic + insulin). From day 2 glucose concentrations and body weight were similar in the non-diabetic and diabetic animals treated with insulin. Diabetic animals treated with placebo and low-dose trandolapril weighed significantly less compared to the control group. The diabetic groups, not treated with insulin, showed marked hyperglycaemia throughout the study. Kidney weight was greater in the diabetic, non insulin-treated groups compared with the control and insulin-treated groups. After 24 h of diabetes, kidney insulin-like growth factor-1 content was significantly increased from baseline levels in groups DP, DL and DH but by 48 h these levels had returned to normal. Renal tissue angiotensin converting enzyme activity was similar in groups C and DI but significantly reduced in all trandolapril-treated animals. Despite inhibiting renal angiotensin converting enzyme activity renal enlargement with increased tissue insulin-like growth factor-1 still occurred. This suggests that neither angiotensin II nor glomerular hyperfiltration, with raised intraglomerular pressure, play a role in the initial renal enlargement seen in experimental diabetes. Renal accumulation of insulin-like growth factor-1 appears to be an important factor in early renal hypertrophy and its effects are not modulated by angiotensin converting enzyme or angiotensin II.Abbreviations ACE Angiotensin converting enzyme - IGF-1 insulin-like growth factor-1 - Na⁺/H⁺ exchange sodium hydrogen exchange - RPF renal plasma flow - GFR glomerular filtration rate     

Captopril inhibits in vitro and in vivo the proliferation of primitive haematopoietic cells induced into cell cycle by cytotoxic drug administration or irradiation but has no effect on myeloid leukaemia cell proliferation

Angiotensin I-converting enzyme (ACE) has been shown to be involved in the catabolism of the tetrapeptide acetyl-Ser-Asp-Lys-Pro (AcSDKP). As AcSDKP is a physiological inhibitor of haematopoietic stem cell proliferation, we investigated the in vitro and in vivo effects of captopril, one of the specific inhibitors of ACE, on the proliferation of primitive haematopoietic cells. Regenerating bone marrow cells obtained from mice given one injection of cytosine arabinoside (100 mg/kg) as well as SA2 myeloid leukaemia cells were incubated in vitro for 24 h with 10-6 M captopril. Captopril significantly reduced the proportion of high proliferative potential colony-forming cells (HPP-CFC-1) in S-phase, whereas it had no effect on the proportion of SA2 leukaemic colony-forming cells in S-phase. When given in vivo to mice 1 h after 2 Gy gamma-irradiation or cytosine arabinoside (AraC) injection, captopril (100 mg/kg) was shown to prevent HPP-CFC-1 entry into S-phase induced by these cytotoxic treatments. The observed effects correlated with a reduction in ACE degradative activity and an increase in the level of endogenous AcSDKP both in the supernatants of captopril-treated bone marrow cells and in plasma of treated animals. The present findings suggest that AcSDKP might mediate the observed in vitro and in vivo inhibitory effects of captopril on primitive haematopoietic cell proliferation.