Vasoactive Peptides and Hypertension: Role of Angiotensin Converting Enzyme

Abstract: Angiotensin converting enzyme plays a key role in the hormonal regulation of blood pressure. It is responsible for the production of the vasconstrictor 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     

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.     

Stimulation of Plasma Renin Activity by Captopril in Renovascular Hypertensive Conscious Dogs

The increase in plasma renin activity induced by captopril is used in the clinical evaluation of renovascular hypertensive patients. This increase in plasma renin activity could result from either the concomitant fall in systemic pressure or other effects of captopril, such as the removal of an angiotensin II inhibitory effect on renin release, the increased production of bradykinin or prostaglandins, etc. To examine the effect captopril has on plasma renin activity, independent of changes in systemic pressure, captopril (5, 10 and 50 μg/kg iv) was administered to conscious dogs before and following the development of 1 clip-2 kidney Goldblatt hypertension. Plasma renin activity, under normal conditions remained unchanged, while during hypertension It increased 2.0, 2.8 and 3.5 fold respectively in response to the three doses of captopril. These results suggest that the development of renovascular hypertension sensitized the kidney to release renin when challenged by captopril and that the effect is independent of changes in systemic pressure.     

Single administration of captopril and combined use with beta-blocker and/or thiazide diuretic in the treatment of essential hypertension.

Thirty-four patients with essential hypertension at WHO stage I or II were divided into three groups. Group I consisted of 22 cases who displayed normal renin activity (NR) or low renin activity (LR) and who received a single administration of captopril. Group II consisted of 6 cases given beta-blockers after administration of captopril. Group III consisted of 6 cases in whom beta-blocker was replaced with thiazide diuretics after administration of captopril alone. Blood pressure decreased significantly by captopril treatment alone in group I of the NR and LR subgroups (except for the diastolic blood pressure [DBP] of the NR subgroup) and fell below the target blood pressure (SBP of 165 mmHg and DBP of 95 mmHg) in 86% of the NR subgroup and 73% of the LR subgroup. Combined treatment with captopril and beta-blocker in Group II did not decrease blood pressure any lower than with captopril alone treatment and achieved the target blood pressure in only 50% of the patients. In group III, combined treatment with captopril and thiazide achieved the target blood pressure in 100% of the patients. Plasma renin activity (PRA) was increased by captopril but reduced by captopril in combination with beta-blocker. However, when beta-blocker was replaced with thiazide, PRA increased. The serum sodium concentration was significantly reduced in the LR subgroup after a single administration of captopril, but there was no other variation.     

Effects of a single administration of captopril on hemodynamics and serum angiotensin converting enzyme activity, plasma renin activity and plasma aldosterone concentration in hypertensive patients

Hemodynamic responses and behaviors of the renin-angiotensin-aldosterone system to a single administration of captopril (50 mg) were studied in 16 hypertensive patients (essential hypertension, n = 10; renovascular hypertension, n = 3; primary aldosteronism, n = 2; Cushing's syndrome, n = 1). In 10 essential hypertensive patients, the immediate blood pressure reduction caused by decreased total peripheral resistance after the administration of captopril was observed without changes of cardiac output and heart rate. Serum angiotensin converting enzyme activity and plasma aldosterone concentration significantly decreased, whereas plasma renin activity significantly elevated 2 hours after the administration of captopril. The close relationship between the pretreatment value of plasma renin activity and the maximum decrease in mean blood pressure in 16 hypertensive patients suggests that the depressor response to a single administration of captopril could evaluate the degree of angiotensin II dependency in the maintenance of high blood pressure in various types of hypertension.     

Converting Enzyme Inhibition in Mild and Moderate Essential Hypertension: I. Acute Effects on Blood Pressure,the Renin-Angiotensin System and Blood Bradykinin after a Single Dose of Captopril

ABSTRACT. The acute effects of 25 mg captopril on blood pressure, heart rate, components of the renin-angiotensin system and blood concentration of bradykinin were followed in a single-blind placebo study of untreated (group A, n = 15) and thiazide-treated (group B, n = 13) patients with mild or moderate essential hypertension. A drug-related fall in blood pressure was seen in both groups. The blood pressure reduction was more marked in group B than in group A. Heart rate remained unchanged. Plasma concentrations of angiotensin II decreased significantly with concurrent increases in plasma concentrations of renin and angiotensin I, indicating the in vivo inhibition of converting enzyme. Blood concentrations of bradykinin showed no systemic changes. The magnitude of blood pressure reduction was correlated both with the pretreatment levels and the concurrent decreases in plasma angiotensin II. Inhibition of angiotensin II formation can explain a large part of the acute hypotensive pharmacological action of captopril. Other vasoactive systems may be involved. The kallikrein-kinin system does not appear to participate as indicated by the unchanged concentrations of kinin in blood.     

Role of Renin-Angiotensin and Kallikrein-Kinin Systems on the Mechanism of the Hypotensive Effects of Converting Enzyme Inhibitor,Alacepril

In four patients with essential hypertension and one patient with renovascular hypertension, decreases in blood pressure and plasma angiotensin II levels, and increases in plasma renin activity and plasma kinin levels were observed during eight days of alacepril treatment. Significant correlations between the changes in mean arterial pressure and those in plasma angiotensin II or kinin levels were observed positively or negatively, respectively, in the essential hypertensives. These findings suggest that the hypotensive effect of alacepril might be caused mainly by a decrease in plasma angiotensin II levels and, at least in part, by an increase in plasma kinin levels.     

Evidence for the role of kinins in the acute antihypertensive effect of captopril in low-renin hypertension

In low-renin hypertensive patients, the acute effect of the angiotensin I-converting enzyme inhibitor, captopril, was evaluated in relation to the response of plasma bradykinin (PBK) levels as a parameter of its inhibitory effect on kininase II. Captopril significantly lowered the blood pressure and increased PBK levels. While there was no significant relationship between the reduction of blood pressure and pretreatment plasma renin activity, a significant correlation was observed between the antihypertensive effect of captopril and changes in PBK (r = -0.834, p less than 0.01, n = 10). Furthermore, in a patient with primary aldosteronism and, also, in a patient with glucocorticoid responsive hyperaldosteronism, captopril increased plasma PBK with reduction of the blood pressure. It is likely, therefore, that in low-renin hypertension, the vasodepressor effect of acute converting enzyme inhibition is due mainly to kinin accumulation rather than inhibition of angiotensin II formation.     

Cardiovascular regulation during angiotensin converting enzyme inhibition with captopril in diabetes-associated hypertension

Diabetes-associated hypertension is accompanied by high levels of body sodium and cardiovascular hyper-reactivity to noradrenaline. Captopril, a promising drug for the treatment of hypertension in diabetics, may influence sodium metabolism and adrenergic pathways. This possibility was investigated in 11 patients with non-azotaemic diabetes mellitus and hypertension, studied after a 3-week placebo phase and after an 8-week phase of captopril treatment (50-100 mg/day). Blood pressure, exchangeable body sodium, blood volume, plasma renin activity, angiotensin II (Ang II), aldosterone, catecholamine levels and the pressor reactivity to infused Ang II or noradrenaline were measured. Compared with placebo, captopril caused a significant decrease in arterial pressure and stimulation of plasma renin activity. Exchangeable sodium, blood volume, plasma Ang II, aldosterone, noradrenaline and adrenaline levels, the pressor and aldosterone responsiveness to infused Ang II and the pressor response to infused noradrenaline (alone or combined with atropine) were not modified. These findings suggest that in hypertensive diabetics angiotensin converting enzyme inhibition causes a marked decrease in blood pressure. The mechanism of action is unrelated to changes in body sodium or noradrenergic-dependent pressor reactivity. In the stable phase of therapy, Ang II-dependent pathways are left unaltered when captopril is administered twice a day.     

Oral calcium treatment lowers blood pressure in renovascular hypertensive rats by suppressing the renin-angiotensin system

The effects of calcium supplementation on blood pressure and its mechanisms were investigated in two-kidney, one clip renovascular hypertensive rats. Two series of experiments were performed: one was begun just after renal artery constriction, the other after the onset of hypertension. Calcium supplementation significantly attenuated the development of hypertension (systolic blood pressure: 183 +/- 8 vs 130 +/- 2 mm Hg) and was found to abate existing renovascular hypertension (systolic blood pressure: from 183 +/- 8 to 151 +/- 4 mm Hg). Calcium treatment did not cause significant alterations in fluid intake, urine volume, or urinary sodium excretion in either study. However, increased plasma renin activity and plasma aldosterone concentration were suppressed to the basal levels at the end of 3 weeks of calcium treatment (14 +/- 3 vs 8 +/- 2 ng angiotensin I/ml/hr; 530 +/- 50 vs 380 +/- 40 pg/ml). Blood pressure of calcium-treated renovascular hypertensive rats responded poorly to blockade of the renin-angiotensin system with captopril injection and angiotensin II analogue (saralasin) infusion. Further, in rats with chronic established renovascular hypertension, calcium treatment attenuated the enhanced pressor response to norepinephrine, but not to angiotensin II. These results suggest that the blood pressure-lowering actions of calcium supplementation are related primarily to suppression of renin secretion and secondarily to alteration of pressor response to norepinephrine in two-kidney, one clip renovascular hypertensive rats.     

Effects of converting enzyme inhibition on split renal function in renovascular hypertension

The effects of captopril on effective renal plasma flow and glomerular filtration rate were studied using a noninvasive radioisotopic method on individual kidneys in eight patients with renovascular hypertension and 12 patients with essential hypertension with various renin levels. Four patients with renovascular hypertension had unilateral while three had bilateral renal artery stenosis. The effective renal plasma flow and glomerular filtration rate were determined by using 131I-iodohippurate sodium and 99mTc-diethylenetriamine pentaacetic acid, respectively. Glomerular filtration rate and effective renal plasma flow were significantly reduced in the stenotic kidneys of patients with renovascular hypertension compared with values in nonstenotic kidneys (p less than 0.01). Treatment with captopril, 37.5 to 75 mg/day for 1 to 48 weeks, further reduced the glomerular filtration rate only in stenotic kidneys, and effective renal plasma flow increased in both kidney types. In two of the three renal hypertensive patients with bilateral renal artery stenosis, captopril produced a reversible azotemia that was unrelated to the fall in blood pressure, as evidenced by the lack of azotemia seen after a moderate blood pressure reduction induced by other antihypertensive medications. These results indicate that endogenous angiotensin II is essential in maintaining the glomerular filtration rate in stenotic kidneys and suggest that a reduction in glomerular filtration rate during captopril administration could indicate the presence of renal artery stenosis.     

Effects of captopril on the renin angiotensin system, oxidative stress, and endothelin in normal and hypertensive rats

There is substantial evidence suggesting that angiotensin II plays an important role in elevating blood pressure of spontaneously hypertensive rats, despite normal plasma renin activity, and that converting enzyme inhibitors (captopril) can effectively normalize blood pressure in the spontaneously hypertensive rats. One mechanism by which angiotensin II induces hypertension is via oxidative stress and endothelin, as seen in subpressor angiotensin II-induced hypertension. In fact, it has been shown that antioxidants lower mean arterial pressure in spontaneously hypertensive rats. However, the relationship between angiotensin II, oxidative stress, and endothelin in the spontaneously hypertensive rats is still relatively undefined. This study examines the relationship between mean arterial pressure, plasma renin activity, angiotensin II, oxidative stress, and endothelin in spontaneously hypertensive rats compared with normotensive Wistar Kyoto rats, and the effects of captopril on this association. Untreated spontaneously hypertensive rats had increased plasma angiotensin II levels despite normal plasma renin activity, oxidative stress, and endothelin. Captopril treatment in spontaneously hypertensive rats lowered mean arterial pressure, angiotensin II, oxidative stress, and endothelin, and increased plasma renin activity. In contrast, captopril increased plasma renin activity (suggesting effective captopril treatment) but did not significantly alter mean arterial pressure, angiotensin II, oxidative stress, or endothelin of Wistar Kyoto rats. These results suggest that in spontaneously hypertensive rats, angiotensin II is a primary instigator of hypertension, and that captopril selectively lowers angiotensin II, oxidant stress, and endothelin, which in turn may contribute to the blood pressure-lowering efficacy of captopril in spontaneously hypertensive rats.     

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.     

The captopril test for identification of renovascular hypertension: value and immediate adverse effects

Abstract. To develop a screening test for identification of renovascular hypertension, the blood pressure and plasma renin concentration responses to an oral test dose of captopril (6.25 mg) were studied in 47 hypertensive patients of mean age 61 years (range 34-85 years). Blood pressure was measured at 15-min intervals for 90 min after administration of captopril. Blood samples for plasma renin determination were drawn immediately before and 90 min after drug administration. Eleven patients had renal artery stenosis. The fall in diastolic blood pressure in these patients was greater, on average, than in patients with other forms of hypertension (30 mmHg vs. 14 mmHg, P < 0.01), as was the increase in plasma renin concentration (188 mU l^?1 vs. 2 mU l^?1, P < 0.01). This study demonstrates that the short-term captopril test is useful for distinguishing patients with renovascular disease from those with other forms of hypertension. During the test, 7 patients (15%) exhibited reversible cerebral symptoms. In two of these subjects digital subtraction angiography was performed, which revealed stenosis of the carotid artery. Consequently, it is suggested that captopril should not be used in patients with arteriosclerotic stenoses of the carotids.     

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.     

Captopril in the management of hypertension with renal artery stenosis: Its long-term effect as a predictor of surgical outcome

Fifteen patients with hypertension and unilateral renal artery disease were treated with captopril alone; 10 came to operation and were later assessed postoperatively with no drug treatment. Captopril caused both immediate and sustained decreases in plasma angiotensin II and aldosterone, with increases in plasma active renin and blood angiotensin I concentrations. Decrements in systolic and diastolic pressure 2 hours after the first dose of captopril were closely correlated with the initial decreases in plasma angiotensin II. Blood pressure was decreased by long-term captopril therapy irrespective of whether plasma angiotensin II was abnormally high before treatment. The long-term response of both systolic and diastolic pressure correlated well with the response to surgery. By contrast, the blood pressure decrease 2 hours after the initial dose of captopril variously underestimated and overestimated the decrease during prolonged use of the drug and did not relate to surgical outcome. In patients who, before treatment, had secondary aldosteronism, hyponatremia, hypokalemia and sodium and potassium deficiency, captopril corrected these abnormalities. In the remaining patients, long-term captopril therapy did not alter exchangeable sodium, plasma sodium or total body potassium, although plasma potassium levels increased.     

Effect of angiotensin blockade and converting enzyme inhibition on renovascular hypertension: comparison between unilateral and bilateral renal artery stenosis

The response to angiotensin II analog infusion during sodium deletion and the effects of a one-month captopril treatment were compared between 15 renovascular hypertensive patients with unilateral and 6 with bilateral renal artery stenosis. Plasma renin activity, its response to sodium depletion, and the renal vein renin ratio during sodium depletion were greater in unilateral than in bilateral stenosis. A fall in diastolic blood pressure induced by analog infusion during sodium depletion was correlated with the preinfusion plasma renin activity and with the renal vein renin ratio. Treatment with captopril showed a comparable hypotensive effect in unilateral and bilateral stenosis. The reduction in blood pressure was not correlated with the pretreatment renin levels or changes in blood pressure observed during analog infusion. Plasma renin activity rose and plasma aldosterone level fell in all patients. These results indicate that the mechanism maintaining high blood pressure is more renin dependent in unilateral than in bilateral stenosis and that the long-term effect of captopril does not depend solely on the suppression of the renin-angiotensin-aldosterone system.     

A prospective evaluation of a simplified captopril test for the detection of renovascular hypertension

Renovascular hypertension is potentially curable but of low prevalence. A previous retrospective study has demonstrated the use of a potentiated increase in plasma renin activity after captopril administration as a diagnostic test for renovascular hypertension; this requires two blood samples for plasma renin activity determination and three inclusive criteria for a positive test result. We applied this test prospectively to screen 100 hypertensive patients for renovascular hypertension. We evaluated 29 patients with renovascular hypertension; the remainder were diagnosed as having essential hypertension. In our patient population, a postcaptopril plasma renin activity of 5.7 ng of angiotensin per milliliter per hour (ngAl.mL-1.h-1) or greater had a 100% sensitivity and an 80% specificity for renovascular hypertension. An absolute increase in plasma renin activity with captopril of 4.7 ngAl.mL-1.h-1 or greater had a lower sensitivity of 90% and a specificity of 87%, whereas a fractional increase in plasma renin activity after captopril of 150% or higher had the lowest sensitivity of 69% and a specificity of 86%. A subgroup analysis of 38 patients who were receiving diuretic therapy demonstrated that the test sensitivity was unchanged but the specificity was reduced. In conclusion, a single postcaptopril plasma renin activity value of 5.7 ngAl.mL-1.h-1 or greater is a simplified screening test for renovascular hypertension, with excellent sensitivity and acceptable specificity. This test is well tolerated, inexpensive, and easy to perform.     

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.     

The captopril test for identifying renovascular disease in hypertensive patients

To develop a screening test for identifying renovascular hypertension, the blood pressure and plasma renin activity responses to an oral test dose of captopril were studied in 246 quietly seated hypertensive patients. The following criteria were developed that exploit the hyperresponsiveness of renin secretion in renovascular hypertensive patients: a 60-minute post-captopril plasma renin activity of 12 ng/ml per hour or more and an absolute plasma renin activity increase of 10 ng/ml per hour or more, along with a 150 percent increase in plasma renin activity (or a 400 percent increase if the baseline plasma renin activity was below 3 ng/ml per hour). Retrospectively, the test identified, among 200 hypertensive patients without evidence of renal dysfunction, all 56 patients with proved renovascular disease. In this group, false-positive results occurred only in two of 112 patients with essential hypertension and in six with secondary hypertension. Nine untreated patients had blood pressure levels of less than 160/100 mm Hg. The test was neither as sensitive nor specific in the 46 patients with renal insufficiency. This study demonstrates that the renin response to oral captopril is a useful screening test for identifying patients with unilateral or bilateral renovascular disease. Since the test also characterizes the renin dependency of the hypertension, it may have other diagnostic and therapeutic uses.