Antihypertensive mechanism of oral angiotensin I converting enzyme inhibitor (captopril) in renin-independent essential hypertension

In order to investigate the possible role of bradykinin in the hypotensive mechanism of angiotensin I converting enzyme inhibitor (Captopril) in renin-independent essential hypertension (EHT), we studied the effects of the single administration of 100 mg captopril on plasma bradykinin levels by sensitive radioimmunoassay in 21 EHT, who showed agonistic responses to 1Sar, 8Ile-angiotensin II (A IIA). Fourteen of the patients were low renin and 7 were normal renin EHT. There was no correlation between the baseline plasma renin activity (PRA) and the fall in mean blood pressure (MBP) following captopril administration. When the patients were analyzed according to MBP response, the responders (R) showed a significantly greater bradykinin increment (delta BK, +64%) (p less than 0.05), whereas the nonresponders (NR) did not show such an increase. There was a positive correlation between delta BK and the MBP reduction after captopril in the R group (r = 0.623, p less than 0.05). Plasma aldosterone (PA) decreased profoundly in the R group (-36% from baseline, p less than 0.05). Pretreatment ACE activity was significantly higher in the R group than in the NR group (p less than 0.05). Pressor response to A IIA showed a significantly (p less than 0.05) greater response after captopril administration in the R group. There were no significant differences in blood concentration of captopril between the R and NR groups. The present results suggest that bradykinin may be involved in the hypotensive action of captopril in the EHT subgroup, where the renin-angiotensin system appears to play an inert role for the elevation of blood pressure.     

Use of Captopril in the Diagnosis of Renal Hypertension

Abstract: 1 . The effects of a single 25 mg oral dose of captopril on blood pressure, heart rate and circulating renin, angiotensin I, angiotensin II, bradykinin and catecholamine levels were examined in untreated patients with essential (n = 10, Group I), accelerated (n = 6, Group II) and renal hypertension (n = 8, Group III) studied on a normal sodium diet .
2 . Mean blood pressure fell only slightly in Group I patients, (113 ± 3 to 109 ± 3 mmHg at 60 minutes) but a greater fall was observed in Group II (153 ± 8 to 135 ± 11 mmHg) and a marked fall in Group III, (136 ± 3 to 114 ± 5 mmHg). There were no significant changes in heart rate in any group .
3 . Plasma angiotensin II levels were significantly reduced 30 minutes after captopril in all three groups and returned toward resting values after four hours. The falls in plasma angiotensin II levels were accompanied by reciprocal increases in blood angiotensin I and plasma renin, but blood bradykinin and plasma catecholamine concentrations remained unchanged .
4 . Resting plasma renin levels showed considerable overlap in the three groups and the mean renin values were not significantly different in the three groups. After captopril a marked rise in plasma renin concentration (>2.5 ng/ml/hr) was observed in seven patients in Group III, including all six patients with renovascular disease. In contrast, none of the patients with essential hypertension and only one patient with accelerated hypertension had such an increase. Determination of the acute renin and blood pressure responses to converting enzyme inhibition with a single oral dose of captopril appears to be useful in identifying patients with renovascular hypertension .     

Effect of captopril on various components of the kinin system and plasma renin activity in patients with idiopathic arterial hypertension

Authors studied effect of captopril on serum kininogen and prekallikrein concentrations, as well as on plasma renin activity (PRA) in patients with primary hypertension. The control group consisted of 18 healthy persons, 5 patients were in I, 12 in II and 8 in III WHO class. Monotherapy with 150 mg per day of captopril had been performed for 3 weeks. Patients were 3 times examined: 1--before therapy, 2--after 24 hours of treatment, 3--after 3 weeks of captopril therapy. It was proved, that captopril lowers arterial pressure with coexisting PRA increase and induces changes in kinins system such as: decrease of kininogen+ concentration and increase of serum prekallikrein level in comparison with their pretreatment values. Maximum PRA increase and blood pressure decrease were observed after 24 hours of captopril administration, whereas changes in kinins system were taking place during the whole observation period. Presented studies indicate that antihypertensive action of captopril is related to Renin-Angiotensin-Aldosterone System as well as to plasma kinins one.     

Effects of angiotensin I converting enzyme inhibitor (SQ 14,225) on the responses of blood pressure and steroid hormone to angiotensin II and ACTH infusion in hypertensive subjects

The effects of the converting enzyme inhibitor, SQ 14,225, on the renin-angiotensin system, adrenal function and blood pressure were investigated in 14 hypertensive patients, i.e., 10 with essential hypertension (EH) and 4 with renovascular hypertension (RVH). The mean blood pressure (MBP) and plasma aldosterone showed significant decreases in the EH with normal renin (NR) group and in the RVH group but no significant changes in the EH with low renin (LR) group. Plasma renin activity (PRA) increased significantly in the EH and NR group and in the RVH group but showed no significant change in the EH with LR group. Significant correlations were found between the fall in MBP after SQ 14,225 treatment and the pretreatment levels of PRA or plasma aldosterone. In an ACTH infusion study, the response of plasma aldosterone to ACTH revealed significant decreases after SQ 14,225 administration. In an angiotensin II (A II) infusion study, the response of plasma aldosterone was unchanged after SQ 14,225 administration. However, the pressor responses to A II infusion with SQ 14,225 were significantly higher than those without SQ 14,225. From these findings, it is concluded that the antihypertensive mechanism of SQ 14,225 may be due mainly to the decrease in levels of endogenous A II and that the reduction in plasma aldosterone after SQ 14,225 were significantly higher than those without SQ 14,225. From these findings, it is concluded that the antihypertensive mechanism of SQ 14,225 administration may be due to reduction of endogenous A II levels by converting enzyme inhibition.     

Atenolol improves blood pressure control in patients taking captopril and frusemide

In a double-blind randomised cross-over study atenolol 100 mg daily and matching placebo were given to 14 patients whose blood pressure (BP) was uncontrolled on a fixed dose of captopril and frusemide. Atenolol produced a further reduction in both supine (170/105 mmHg to 163/94 mmHg) and standing (171/114 mmHg to 160/96 mmHg) BP and a significant fall in pulse rate and plasma renin activity (PRA). This fall in BP showed a highly significant correlation with pre-treatment plasma renin levels. No adverse side effects were encountered during the study. Previous suggestions that beta-blockade had no additional hypotensive effect in patients receiving captopril were not substantiated. For patients whose BP was poorly controlled with captopril and a diuretic, a selective beta-blocker is suggested as a useful third line agent.     

Effect of inhibition of converting enzyme by captopril on arterial pressure, renin and aldosterone in essential hypertension

The response of arterial blood pressure, plasma renin activity (PRA) and plasma (PA) or urinary aldosterone (UA) concentrations to the administration of captopril, was studied in patients with established essential hypertension. Captopril was effective in lowering significantly the blood pressure (189.4/111.2 +/- 23.9/9.7 to 163.4/98.1 +/- 20.7/8.6 mmHg. mean +/- SD, p less than 0.01/0.001). Normal arterial blood pressure values (140.4/86.5 +/- 20.7/10.8 mmHg, were achieved by the addition of hydrochlorothiazide. Captopril administration was followed by a decrease in PA and in UA and an increase in PRA, suggesting the inhibition of angiotensin II formation. Captopril attenuated hypokalemia and hyperaldosteronism produced by the simultaneous administration of hydrochlorothiazide.     

The antihypertensive effect of captopril in essential hypertension: relationship to prostaglandins and the kallikrein-kinin system

Two groups, each with nine essential hypertensive patients, were maintained on 10 mmol sodium daily over 14-17 days and treated in this sequence: placebo; captopril (25 or 50 mg given thrice daily) or indomethacin (50 mg given thrice daily) alone; captopril plus indomethacin, and (4) captopril alone. The initial fall in mean blood pressure induced by captopril (118 +/- 1 to 102 +/- 1 mmHg) was unaffected by the addition of indomethacin. However, if indomethacin treatment preceded captopril, the antihypertensive effect was attenuated (116 +/- 4 to 109 +/- 4), and was associated with significant reductions in urinary prostaglandin and kinin excretion. Addition of captopril to indomethacin returned kinin excretion to placebo levels but did not affect indomethacin-induced reduction in prostaglandin excretion. Captopril alone stimulated plasma renin activity (PRA) fivefold; aldosterone excretion was lowered by 25% and further reduced by indomethacin. Thus, when captopril and indomethacin are administered together, the order of administration is critical to the antihypertensive effect of captopril.     

Vascular wall renin in spontaneously hypertensive rats. Potential relevance to hypertension maintenance and antihypertensive effect of captopril

Relationships among systolic blood pressure (SBP), plasma renin activity (PRA), arterial renin concentrations (ARC), and venous renin concentrations (VRC) were examined in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats before and after treatment with captopril. The ARC was elevated in SHR relative to WKY whereas VRC was not. Similarly, ARC was related to SBP (r = 0.69, p less than 0.01) whereas PRA was not (r = 0.04). Captopril (100 mg/kg daily by mouth for 8 days) decreased blood pressure significantly in both SHR and WKY. PRA as well as ARC and VRC were all increased by captopril. Bilateral nephrectomy virtually eliminated PRA but ARC was not significantly reduced over a 24-hour period. Bilateral nephrectomy also markedly attenuated the acute antihypertensive effects of captopril in SHR; however, a modest effect was still apparent. It is suggested that ARC in SHR, being higher than in WKY, may play a role in the genesis or maintenance of hypertension in this model. Furthermore, the effects of captopril in both intact and nephrectomized SHR may be related to the ability of captopril to inhibit the vascular formation of angiotensin II. Finally, vascular renin is probably not renal in origin and responds to typical feedback inhibition as unmasked by captopril administration.     

Effect of pressor agents on blood pressure, plasma renin activity and plasma aldosterone concentration in essential hypertension.

The responses of blood pressure, plasma renin activity (PRA) and plasma aldosterone concentration (PAC) to infusion of either angiotensin II (10 ng/Kg/min) or norepinephrine (100 ng/Kg/min) were observed in 25 patients with essential hypertension. The difference in modes of response between low renin essential hypertension and normal or high renin essential hypertension was analyzed. For comparison, 5 patients with Conn's syndrome, 4 with renovascular hypertension, and 5 normotensive subjects were also studied. Following infusion of antiotensin II the changes in diastolic blood pressure (DBP) were +24+/-3.0 mmHg in low renin essential hypertension and +25+/-3.1 mmHg in normal or high renin essential hypertension in PRA -0.28+/-0.06 ng/ml/h in low renin essential hypertension and -0.69+/-0.02 mg/ml/h in order and in PAC +3.7+/-1.4 and +7.6+/-1.8 ng/100 ml respectively. There was a significant difference in magnitude of response in PRA between the 2 groups of essential hypertension (p less than 0.05). Norepinephrine induced rise in DBP with decreases both in PRA and PAC. The mean changes in DPB were +6+/-1.4 mmHg in low renin essential hypertension and +16+/-2.2 mmHg in another and the pressor response in the later was significantly greater (p less than 0.01). The changes in PRA were -0.14+/-0.07 ng/ml/h in low renin essential hypertension and -0.67+/-0.26 ng/ml/h in normal or high renin essential hypertension, and in PAC -4.9+/-1.3 and -3.3+/-1.9 ng/100 ml respectively. The greater fall in PRA in normal or high renin essential hypertension was observed but the difference between the 2 groups of essential hypertension was not significant. The changes in PAC did not parallel the changes in PRA. Angiotensin II indcued essentially similar effects on blood pressure in both groups but the greater feedback inhibition of PRA was produced by this peptide in normal or high renin essential hypertension than in low renin essential hypertension. Norepinephrine induced significantly greater pressor effect in normal or high renin essential hypertension. The adopted dose of norepinephrine suppressed both PRA and PAC and a tendency to the greater fall in PRA was observed in normal or high renin essential hypertension. There was no difference in responses of PAC to both agents between the 2 groups of essential hypertension.     

Reversible renin-dependent renovascular hypertension successfully treated with percutaneous transluminal renal angioplasty and stenting

A 37-year old woman was suspected of having renovascular hypertension because of recent onset severe hypertension (blood pressure 220/135 mmHg; compared to 132/65 mmHg two years earlier) and an abdominal bruit. A captopril renal scan indicated the presence of right renal artery stenosis. Additionally, a captopril plasma renin activity (PRA) provocation test showed a positive result for renovascular hypertension (baseline PRA = 291 microU/mL; 1 hour post-captopril PRA = 1444 microU/mL). Selective renal angiography demonstrated a severe critical stenotic lesion at the distal portion of the right renal artery. Blood pressure (BP) decreased to 136/80 mmHg one day after successful percutaneous transluminal renal angioplasty and stenting. Repeat renal angiography six months after the procedure revealed no evidence of in-stent restenosis. Blood pressure (BP = 137/76 mmHg) and plasma renin profile (baseline PRA = 23.8 microU/mL; 1 hour post-captopril PRA=22.3 microu/mL) also were normal six months following initial revascularization. Moreover, blood pressure (137/84 mmHg) and renin profile remained normal 2.5 years after the procedure (baseline PRA = 24.3 microU/mL; 1 hour post-captopril = 25.6 microU/mL). The results of this study have thus demonstrated a case of renin-dependent renovascular hypertension in which both the blood pressure and plasma renin activity profile normalized following successful percutaneous transluminal angioplasty and stenting.     

Peripheral and renal vein renin activity in patients with renovascular hypertension due to nonspecific aortoarteritis.

The diagnostic utility of peripheral and renal vein renin estimations in relation to angiographic findings was evaluated in 13 patients with renovascular hypertension and non-specific aortoarteritis (NSAA, Gr I), in comparison with 10 patients with renal artery stenosis due to other causes (Gr II). Plasma renin activity (PRA) was measured by radioimmunoassay. Blood samples were collected after angiography from the femoral vein and renal vein on the affected side followed by sampling from the less affected or unaffected side. Renal vein renin ratio (RVRR) was calculated from renal vein renin values. The effect of captopril (25 mg oral) on blood pressure, PRA, and RVRR was examined in 8 patients from each group. Normotensive volunteers (8) with moderately low salt intake were also included in the study for comparison of twenty-four-hour urinary sodium output, peripheral PRA, and response to captopril. The mean peripheral PRA was high in both groups as compared with normotensive controls; however, the values were lower in patients with NSAA. The rise in PRA in response to captopril was insignificant in Gr I (p greater than 0.05) and RVRR greater than 1.5 was observed in 5 of 13 patients in contrast to 9 of 10 in Gr II (p less than 0.05). A paradoxical ratio, ie, (high renal vein renin levels on the less stenotic side) was noticed in 3 patients of Gr I, whereas none of the patients of GR II showed such a ratio. An improvement in RVRR after captopril was observed in 50% of patients of Gr I as compared with a marked response in all patients of Gr II.(ABSTRACT TRUNCATED AT 250 WORDS)     

Studies on the Mechanism of the Synergistic Antihypertensive Activity of Captopril and Hydrochlorothiazide Following Acute Administration in Spontaneously Hypertensive Rats

In spontaneously hypertensive rats (SHR), captopril at 30 and hydrochlorothiazide (HCTZ) at 100 mg/kg/day p.o. for 2 days lowered mean arterial blood pressure (MABP) 16 and 10 mm Hg, respectively. Treatment with the combination of captopril plus HCTZ for one day lowered MABP to the same extent as captopril alone, but produced a synergistic 44 mm Hg MABP lowering after the second day combination treatment. Bilateral ureteral ligation did not prevent the synergistic antihypertensive effect demonstrating that removal of electrolytes was not the cause of this effect. Cardiovascular responses to angiotensin-I and -II, norepinephrine or bradykinin did not differ in rats given the combination or captopril alone. After the combination treatment for one day, captopril but not HCTZ alone on the second day lowered MABP in rats to the same degree as in those receiving the combination treatment for 2 days, suggesting that the diuretic action per se is unimportant. Captopril and HCTZ increased plasma renin activity (PRA) but only the combination of captopril and HCTZ produced a greater and longer lasting increase of PRA. It is concluded that the mechanism for the synergism is the renin dependency, created by the combination of HCTZ and captopril, resulting in a greater role of the renin system in blood pressure control and increased responsiveness to angiotensin converting enzyme inhibition by captopril.     

Converting Enzyme Inhibition in Mild and Moderate Essential Hypertension. II

ABSTRACT. In 24 patients with mild/moderate essential hypertension, we studied the effects of captopril with/without hydrochlorothiazide (Htz) on blood pressure, the renin-angiotensin system, blood bradykinin concentration (BBK), plasma volume, exchangeable sodium and glomerular filtration. Daily captopril doses of 75 and 150 mg were equally effective in reducing the blood pressure. Addition of Htz caused further blood pressure reductions. Nineteen patients attained a diastolic blood pressure ≤90 mmHg. Angiotensin converting enzyme inhibition with captopril led to a fall in plasma concentrations of angiotensin II (PAII) and renin substrate, and an increase in plasma concentrations of renin and angiotensin I. Patients starting with Htz had a higher PAII and subsequently a larger fall in blood pressure on captopril than untreated patients. BBK remained unchanged, indicating that the hypotensive action of captopril does not involve an accumulation of circulating kinin. Body fluid volumes and renal function were not affected by the various treatment regimens.     

Angiotensin I-Converting Enzyme Gene Polymorphism and Acute Response to Captopril in Essential Hypertension

Insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene has been shown to be a determinant for serum ACE level and a marker for several cardiovascular diseases. We investigated whether the ACE gene can predict the therapeutic efficacy of ACE inhibitors in essential hypertensive patients. The response of blood pressure and plasma renin activity (PRA) 1 h after 50 mg captopril administration were evaluated in 82 inpatients with untreated essential hypertension (42 men, 40 women; mean age ± SD: 52 ± 13 years; range: 27 to 79 years) in relation to ACE genotypes. There were no differences in age, gender, blood pressure, and PRA in the basal conditions, among essential hypertensive patients with the II, ID, and DD genotypes (n = 36, 34, and 12, respectively). The acute responses of PRA and blood pressure to an ACE inhibitor were similar in the three groups. The blood pressure response was negatively correlated with baseline PRA (r = 0.497). These data suggest that PRA but not the I/D polymorphism of the ACE gene is a useful predictor of the short-term antihypertensive effects of ACE inhibitors.     

Influence of renin levels on the treatment of essential hypertension with thiazide diuretics

Initial plasma renin activity (PRA) was measured in 213 patients with untreated hypertension before beginning thiazide (chlorothiazide and hydrochlorothiazide) therapy alone to test whether patients with low-renin hypertension exhibited a greater response to diuretic therapy. Diastolic blood pressure response to treatment in the low, mid-range, and high PRA groups did not differ significantly (delta diastolic blood pressure, -13.6 +/- 1.6, -11.6 +/- 1.5, and -10.8 +/- 2.6 mm Hg, respectively). Moreover, eight subjects with the highest PRA values exhibited the same magnitude of decrease in diastolic blood pressure as did the low PRA group (15.0 +/- 4.2 vs 13.6 +/- 1.6, respectively). This study thus provides no evidence for increased sensitivity to diuretic therapy among patients with low-renin essential hypertension.     

Differences in response to the peptidyldipeptide hydrolase inhibitors SQ 20,881 and SQ 14,225 in normal-renin essential hypertension

We compared vascular and hormonal responses to teprotide (SQ 20,881) and captopril (SQ 14,225) in patients with normal renin essential hypertension given a 10 mEq sodium diet. In 10 patients receiving SQ 20,881, significant changes occurred in diastolic blood pressure (DBP, -13 +/- 2.5 mm Hg), angiotensin II (-7.1 +/- 2.1 pg/ml), and plasma renin activity (PRA, +6.6 +/- 1.9 ng/ml/hr) (p < 0.01 in all cases). Twenty-one patients receiving SQ 14,225 had significant changes in mean DBP (-18 +/- 1.5 mm Hg), angiotensin II (-6.6 +/- 1.5 pg/ml), and PRA (+7.8 +/- 2.4 ng/ml/hr) (all p values < 0.01). In spite of a significantly greater hypotensive response (p < 0.02), patients receiving SQ 14,225 showed increments in PRA and decrements in angiotensin II that did not differ significantly from those seen after SQ 20,881. Moreover, there was a significant change in plasma kinins in patients receiving SQ 20,881 (+2.0 +/- 0.9 ng/ml, p < 0.01) but no change in kinins in patients receiving SQ 14,225 (0.0 +/- 0.1, ns). We conclude that there are important differences in the mechanism mediating the hypotensive response to SQ 20,881 and SQ 14,225 in normal renin essential hypertension.     

Low dose of hydrochlorothiazide, in combination with angiotensin receptor blocker, reduces blood pressure effectively without adverse effect on glucose and lipid profiles

Previous studies have shown highly effective lowering of blood pressure with thiazide diuretics in combination with angiotensin receptor blockers. However, thiazide diuretics may cause the development of diabetes and abnormal lipid metabolism. Little is known as to whether dysmetabolic potential of thiazide diuretics could be neutralized when adding angiotensin receptor blockers. This study consisted of 26 patients with essential hypertension. Patients were randomized to 24 weeks of treatment with either candesartan, 12 mg monotherapy (n = 13, group A), or hydrochlorothiazide (HCTZ), 6.25 mg in combination with candesartan, 8 mg (n = 13, group B). Before and after treatment, we assessed glucose and lipid profiles including adiponectin, resistin, and active glucagon-like peptide-1 (GLP-1) levels. At baseline, there were no differences in age, body mass index, systolic blood pressure (SBP), and diastolic blood pressure (DBP), as well as plasma levels of hemoglobin A1c, insulin, low-density lipoprotein cholesterol, triglycerides, adiponectin, resistin, and active GLP-1 between the two groups. There were significant reductions in SBP (from 152 ± 10 mmHg at baseline to 134 ± 12 mmHg after treatment) and DBP (from 84 ± 5 mmHg at baseline to 71 ± 8 mmHg after treatment) in group A. There were also significant reductions in SBP (from 148 ± 10 at baseline to 128 ± 7 mmHg after treatment) and DBP (from 90 ± 9 at baseline to 74 ± 12 mmHg after treatment) in group B. There were no differences in reduction of SBP or DBP after 24 weeks of treatment between the two groups. There were no changes of the glucose and lipid profiles, including adiponectin, resistin, insulin, and active GLP-1 levels after 24 weeks of treatment in both groups. A low dose of HCTZ in combination with candesartan reduces blood pressure effectively without adverse effects on the glucose and lipid profiles. Therefore, the combination of thiazide diuretics and angiotensin receptor blockers could assist patients in achieving long-term control of blood pressure with good tolerability.     

The Clinical Application of Converting Enzyme Inhibitors

Chronic blockade of the renin angiotensin system became possible when orally active inhibitors of angiotensin converting enzyme, the enzyme which catalyzes the transformation of angiotensin I into angiotensin II, were synthetized. Two compounds, captopril and enalapril, have been investigated in clinical studies. The decrease of the pressor response to exogenous angiotensin I and of the circulating levels of angiotensin II following administration of these inhibitors has been demonstrated to be directly related to the degree of suppression of plasma angiotensin converting enzyme activity. These inhibitors have been shown to normalize blood pressure alone in some hypertensive patients whereas in many others, satisfactory blood pressure control can be achieved only after the addition of a diuretic. Captopril and enalapril also markedly improve cardiac function of patients with chronic congestive heart failure. Chronic blockade of the renin angiotensin system has therefore provided an interesting new approach to the treatment of clinical hypertension and heart failure.     

No Substrate Specificity of Converting Enzyme for N-Terminal Substituted Angiotensin I in Man

In 5 normal men sarcosinel-angiotensin II (Sarl-ANG II) (Exp. 1) and sarcosinel-angiotensin I (Sarl-ANG I) (Exp. 2) infused iv at a rate of 5 pmol/kg-min from 0900 h to 0930 h caused the same degree of rise in blood pressure (BP). But 100 mg of captopril given orally at 0800 h (Exp. 3) completely abolished the BP rise by Sarl-ANG I. In Exps. 1 and 2 plasma renin activity (PRA) decreased and plasma aldosterone (PA) increased after the infusions. In Exp. 3 PRA increased markedly and PA decreased 60 min after captopril, and at 30 min of Sarl-ANG I infusion PRA decreased to the pre-captopril level despite no BP change but PA was kept at the pre-infusion level. Hence, substrate specificity of converting enzyme previously demonstrated for N-terminal deleted ANG I was not shown for N-terminal substituted ANG I in man because the conversion of Sar¹-ANG I to Sar¹-ANG II was 100%. Sar¹-ANG I may possibly inhibit renin release in normal men.     

Effect of DOCA-salt on angiotensin dependency and surgical reversal of hypertension in two-kidney, one clip renal hypertensive rats

The development of hypertension in two-kidney, one clip renal hypertensive rats (2K, 1C RHR) was not altered by treatment with DOCA and saline solution as drinking fluid for two months of observation. However, the administration of DOCA and salt suppressed plasma renin activity (PRA), the renal renin content (RRC) of the clipped kidney and the response to a single oral dose of captopril (10 mg/kg). The weight of the contralateral kidney was increased by the administration of DOCA-salt, while that of the ischaemic kidney was not changed. The withdrawal of DOCA-salt treatment restored the PRA and the effects of captopril to a similar degree to the non-treated group. The acute hypotensive effects of captopril were reduced on the 10th week compared with the 7th week after renal arterial constriction in 2K, 1C RHR. The fall in blood pressure induced by captopril significantly correlated with the initial PRA both in the 7th and 10th week after clipping. There was a significant correlation between PRA and RRC of the clipped kidney. Rats previously treated with DOC-salt had either removal of the contralateral kidney with removal of the clip from the ischaemic kidney, or removal of the ischaemic kidney. Blood pressure fell to normal levels in the unclipped group and in the nephrectomy group, but the fall in the latter group was transient and within two weeks had risen to significantly higher levels than in the unclipped group. It is concluded that structural vascular change following DOC-salt hypertension is insufficient to cause persisting hypertension except when it occurs in the renal circulation.