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.     

Brain Renin Angiotensin System Contributes to the Salt-Induced Enhancement of Hypertension in Shr

The study was performed to determine whether the brain renin angiotensin system may contribute to the acceleration in hypertension following long-term salt loading in spontaneously hypertensive rats(SHR). Five weeks old SHR and normotensive Wistar-Kyoto(WKY) were given 1% NaCl solution or plain tap water as drinking for 7 weeks. The salt treatment exaggerated the development of hypertension in SHR, but did not change the blood pressure (BP) in WKY. The hypotensive actions of intracerebroventricular(ICV) captopril was greater in SHR treated with salt than in those without treatment, whereas ICV All increased BP to a similar degree between salt and control SHR. In WKY, the effects of ICV captopril and All were not altered by the salt loading. The increases in BP induced by ICV hypertonic saline were not different between the rats with and without saline drinking in either SHR or WKY. The intravenous (IV) hexamethonium led to a greater fall in BP in SHR treated with saline than in those without salt, while it tended to produce a smaller decrease in BP in WKY with salt overload than in those without loading. Both duration and magnitude of the depressor effects of IV captopril were reduced by the chronic saline treatment in SHR. The plasma renin concentration (PRC) in both SHR and WKY was significantly suppressed by the salt load. The present results suggest that long-term salt overload may result in the enhanced activity of brain renin angiotensin system, which could be responsible for the exaggerated development of hypertension in SHR. Our observations also provide further evidence that the central renin angiotensin system is independent of the peripheral system.     

Central and peripheral mechanisms of the enhanced hypertension following long-term salt loading in spontaneously hypertensive rats

We evaluated whether or not increased sodium (Na) concentrations of cerebrospinal fluid (CSF) and stimulated activities of brain renin-angiotensin system (RAS) contribute to an enhanced hypertension by salt overload in spontaneously hypertensive rats (SHR). Long-term salt loading (1% NaCl solution as drinking fluid) accelerated the development of hypertension in SHR, but did not alter the blood pressure (BP) in normotensive Wistar-Kyoto rats (WKY). CSF Na concentration was elevated in uninephrectomized (Nx) group as compared to that in control SHR, while in WKY CSF Na was not influenced by the treatment. A fall in BP by intravenous AVP antagonist or hexamethonium was greater in salt-loaded SHR than in controls. This hypotensive response to the combined blockade of AVP and SNS correlated with CSF Na in SHR but not in WKY. Plasma concentration of AVP and epinephrine tended to increase in relation to the degree of salt loading in SHR but not in WKY. Pressor responses to intracerebroventricular (ICV) angiotensin II (AII) and NaCl were greater in SHR than in WKY, although these responses were not influenced by chronic salt load in either SHR or WKY. The enhanced hypertensive action of ICV NaCl in SHR was abolished by pretreatment with ICV AII antagonist. Chronic saline drinking enhanced the depressor effect of ICV captopril in SHR but not in WKY. These observations suggest that salt overload in SHR may cause an elevated CSF Na concentration and an enhanced activity of brain RAS, which may increase activity of SNS and release of AVP, resulting in an enhanced development of hypertension.     

Alterations in Renal Vascular Reactivity Induced by Chronic Central Administration of Captopril in the Spontaneously Hypertensive Rat

We have previously demonstrated that chronic intracerebroventricular (ICV) administration of captopril attenuates the development of hypertension in young SHR in association with a depression in whole animal reactivity to vasoactive agents and an increased baroreflex sensitivity. In the present study we analyzed vascular reactivity in perfused kidneys from SHR treated with captopril or vehicle to determine whether the depression in reactivity, was due to changes. in baroreflex activity or an effect on the vasculature. Captopril (1.25μg/hr) was infused (osmotic mini pumps) for 4 weeks. Vasctivity to norepinephrine, angiotensin and vasopressin was assessed in isolated kidneys perfused with an artificial medium at constant flow. SHR treated with ICV captopril showed a significantly lower arterial pressure and basal renal vascular resistance than SHR treated with ICV vehicle or IV captopril. In addition, these rats showed decreased vascular reactivity to all vasoactive agents tested as signified by a shift in the dose-response curves to the right with an increase in threshold (ED₁₆) and ED(tm). Kidneys from WKY treated with ICV captopri also showed a decrease in vascular reactivity in comparison to WKY treated with ICV vehicle. Our data suggest that captopril, through a central action, attenuates the development of hypertension by decreasing vascular reactivity to vasoconstrictors.     

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.     

Dietary sodium restriction and the renin-angiotensin system in young spontaneously hypertensive rats

Severe dietary sodium restriction initiated early in life is required to prevent development of hypertension in spontaneously hypertensive rats (SHR). Moderate sodium restriction does not affect hypertension development. This relative insensitivity to sodium restriction may be related to compensatory increases in other pressor mechanisms, specifically the renin-angiotensin system. We evaluated this possibility by measuring plasma renin activity, the blood pressure response to the angiotensin converting enzyme inhibitor captopril as well as blood pressure responsiveness to exogenous angiotensin II in SHR and Wistar-Kyoto rats (WKY) raised from birth until 6 or 16 weeks on control (101 mumol Na+/g food), moderate (26 mumol/g) or two severe (17 or 9 mumol/g) sodium-restricted diets. Moderate sodium restriction did not affect development of hypertension, but also did not cause significant increases in PRA or the blood pressure response to captopril in SHR or WKY. In contrast, severe sodium restriction blunted or prevented the development of hypertension in SHR and was associated with (1) marked increases in plasma renin activity (2) increased maintenance of blood pressure by the renin-angiotensin system (as assessed by captopril), and (3) a marked decrease in the blood pressure response to angiotensin II. We conclude that the relative insensitivity of hypertension development in SHR to dietary sodium restriction does not relate to a compensatory increase in the activity of the renin-angiotensin system. The moderate sodium restriction employed (26 mumol/g) may rather represent the lower end of the normal range.     

Effect of captopril on plasma prolactin in patients with essential hypertension

The effects of the angiotensin-converting enzyme inhibitor captopril on blood pressure, heart rate, plasma prolactin, and renin activity were examined in a single-blind, placebo-controlled trial on 30 patients with essential hypertension (15 given drug, 15 placebo). Captopril, 25 mg administered orally, reduced the blood pressure and increased the plasma renin activity. Captopril decreased mean plasma prolactin from 17.5 +/- 1.4 ng/mL to 9.1 +/- 1.0 ng/mL (p less than 0.001). Significant correlation was found between captopril-induced change from control values of plasma prolactin (delta plasma prolactin) vs delta plasma renin activity (r = -0.688, p less than 0.001). These results suggest that acute administration of captopril was accompanied by a reduction in plasma prolactin and that this reduction may be of clinical significance during therapy of hypertension.     

Central and Peripheral Contributions of the Renin-Angiotensin System in Two Models Experimental Hypertension in Rats

To examine the relationships between the central and pepirheral renin angiotensin system in normotensive Wistar Kyoto (WKY) rats, two-kidney, one-clip Goldblatt renovascular hypertension (RVH), spontaneously hypertensive rats (SHR), SQ 14225 (captopril) was administered intraventricularly (IVT and intravenously (IV) in the alternative manner and there combination. Also, the effects of IVT captopril on the peripheral sympathetic nervous system were evaluated using an intravenous injection of prazosin.

IVT captopril induced a significant reduction of blood pressure in both types hypertensive rats but not in normotensive rats. Greater depressor effects of IV captopril not IV prazosin following IVT captopril were observed in RVH. compared to those in SHR.

These results indicate that the pressor action of the brain renin angiotensin system is closely related with the sympathetic nervous system in hypertensive conditions and that these functions are independent from the peripheral renin angiotensin system. Furthermore. their roles were different in different types of experimental hypertension in rats.     

Chronic Cardiovascular Effects of Central Vasopressin in Conscious Rats

To clarify the cardiovascular effects of central vasopressin (AVP), a chronic intracerebroventricular (ICV) infusion of AVP was performed in conscious Wistar normotensive rats. Animals were divided into 3 groups: 1) AVP 1 ng/hr (Low), 2) AVP 100 ng/hr (High), and 3) saline (control) ICV infusion. After a 6 day control period, AVP or saline was continuously infused into the lateral cerebroventricle at a rate of 1 μ/hr using osmotic minipump for 7 days. As a result, a dose-related elevation of AVP concentration in CSF was achieved. Systolic blood pressure in both Low and High AVP infusion was slightly (7-12 mmHg) but significantly higher than that in control. ICV infusion of AVP did not alter urine volume, electrolytes excretion or osmolality, and AVP vascular antagonist injected intravenously failed to affect mean arterial pressure. Furthermore, plasma catecholamines and renin activity did not differ significantly among the groups. Thus, chronic ICV infusion of AVP induced the elevation of blood pressure, which is due to centrally mediated effect of AVP.     

Effect of captopril on arterial pressure, systemic hemodynamics and renin activity in the blood plasma of rats with spontaneous hypertension

An angiotensin-I-converting enzyme, captopril, was administered since birth onward to normotensive (NR) and spontaneously hypertensive rats (SHR). It produced a marked hypotensive effect in SHR only. Cardiac output and circulating blood volume were similar in intact and experimental animals, NR and SHR alike. Captopril considerably increased plasma renin activity in NR and SHR.     

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.     

Studies on the Mechanism of the Enhancement of the Antihypertensive Activity of Captopril by A Diuretic in Spontaneously Hypertensive Rats

Captopril (30 mg/kg/day orally for two days) in spontaneously hypertensive rats (SHR) inhibited serum angiotensin converting enzyme (ACE) activity 92.3%; increased plasma renin activity (PRA) 18-fold and reduced mean arterial blood pressure (MABP) 19 mm Hg. Hydrochlorothiazide (HCTZ) (100 mg/kg-day 1; 10 mg/kg-day 2, orally) increased PRA 3-fold but did not affect serum ACE or MABP. HCTZ plus captopril inhibited serum ACE 95.2%; increased PRA 38-fold and reduced MABP 47.5 mm Hg. Captopril or HCTZ plus captopril did not alter the responses of isolated aortic strips to norepinephrine (NE), serotonin, angiotensin II (AII) or isoproterenol. Pressor responses of conscious SHR to AII and NE were unaltered by captopril or HCTZ plus captopril although the bradykinin-induced depressor responses were significantly but equally potentiated. These results suggest that the potentiating effect of HCTZ is due to some mechanism that shifts the animal's blood pressure maintenance system to a renin-dependent state and is not due to changes in vascular reactivity.     

Acute and chronic treatment of severe and malignant hypertension with the oral angiotensin-converting enzyme inhibitor captopril

The patients with severe and 10 with accelerated or malignant hypertension were treated with the angiotensin-converting enzyme inhibitor captopril. Captopril acutely reduced blood pressure in all patients except two who had suppressed plasma renin activity. Four patients with encephalopathy showed immediate improvement after the first dose. Two patients could be withdrawn from nitroprusside infusion upon administration of captopril. Nineteen of 20 patients have remained on captopril for 12-32 months. Blood pressure is controlled in 18 and improved in two. Eleven required addition of diuretic and one addition of clonidine. The maximal antihypertensive effect of captopril with or without diuretics was evident after 3 months of continuous therapy and was associated with elevated plasma renin levels, normal aldosterone excretion and preservation of renal function. Captopril was well-tolerated, but produced occasional rash, loss of taste and proteinuria. We conclude that captopril, alone or in combination with other drugs, is effective in both the acute and long-term management of severe and malignant hypertension.     

Role of vasopressin in cardiovascular and neurohormonal responses to intracerebroventricular hypertonic NaCl

To determine the significance of vasopressin in cardiovascular and neurohormonal responses caused by centrally administered hypertonic NaCl, we examined the effects of a vasopressin antagonist on blood pressure, heart rate, plasma levels of catecholamines, cortisol and renin activity in anesthetized dogs. Intracerebroventricular (ICV) injections of 0.2 ml of 1.5 M NaCl increased mean arterial blood pressure (+29.7 +/- 3.0 mmHg, mean +/- SE), heart rate (+27.9 +/- 7.0 beats/min), plasma concentrations of vasopressin (+48.9 +/- 8.2 pg/ml), norepinephrine (+40.0 +/- 6.2 pg/ml), epinephrine (+231.4 +/- 21.4 pg/ml) and cortisol (+5.3 +/- 1.1 micrograms/dl) and decreased plasma renin activity (-2.0 +/- 0.4 ng/ml/hr). An intravenous vasopressin antagonist, d(CH2)5Tyr(Me)AVP, at a dose of 10 micrograms/kg, attenuated the pressor response and augmented the heart rate response to ICV 1.5 M NaCl. The vasopressin antagonist also augmented the change in plasma norepinephrine and significantly attenuated the responses of cortisol and renin. Baseline levels of these variables were not altered by the vasopressin antagonist except for an increase in renin activity. Two injections of hypertonic NaCl without any pretreatment produced similar cardiovascular and hormonal responses. These results suggest that vasopressin contributes not only to an increase in blood pressure, but also to changes in the sympathetic nervous system, the hypothalamo-adrenocortical axis and the peripheral renin-angiotensin system in response to a central sodium stimulus.     

Different effects of captopril on blood pressure in the acute and chronic two-kidney Goldblatt hypertensive dogs

Captopril was administered to acute (8 to 14 days after unilateral renal artery constriction) and chronic (71 to 127 days after the constriction) two-kidney Goldblatt hypertensive dogs, and to normotensive ones for 21 days (oral administration of 10, 20 and 40 mg/kg/day, consecutively each 7-day period). The decrease of arterial blood pressure was remarkable in hypertensive animals with high plasma renin activity, but not in the normotensive animals. In the acute stage of hypertension, the antihypertensive effect of captopril was dose-dependent and persistent even after its cessation. In the chronic stage of hypertension, blood pressure also decreased, but the response was not dose-dependent and did not continue after cessation. Plasma renin activity rose in both hypertensive and normotensive animals during the treatment with captopril. There were no significant changes in heart rate, daily urinary volume, sodium balance, and renal clearances of sodium (CNa), potassium (CK), chloride (CCl) and creatinine (CCr). Circulating blood volume was also not altered. These results indicate that the main mechanism of antihypertensive effect of captopril in two-kidney Goldblatt hypertensive dogs is an inhibition of the angiotensin converting enzyme. In addition, the different effects in the acute and chronic hypertensive dogs suggest that some differences exist in the mechanism(s) of maintaining blood pressure between the two stages of two-kidney Goldblatt hypertension in dogs.     

Angiotensin II is a necessary component for the development of hypertension in the two kidney, one clip rat

The current study was undertaken to define the role of the renin-angiotensin system in the development of hypertension in the two kidney, one clip Goldblatt rat. Captopril was administered orally (100 mg/kg/day) to two groups of rats (n = 8 each) 24 hours before and each day after unilateral renal artery clipping (0.2 mm internal diameter): the drug was given for either 16 weeks (group I) or 24 weeks (group II). Sham-operated (n = 5) and Goldblatt (n = 8) rats not receiving captopril were prepared for comparisons of plasma renin activity and systolic blood pressure. Indomethacin (20 mg/kg/day subcutaneously) was administered for 48 hours concomitantly with captopril to the rats in group I. In group II, systolic blood pressure was monitored for 7 weeks after cessation of captopril. Continual captopril administration to Goldblatt rats completely prevented the rise in systolic blood pressure, a rise that was observed in Goldblatt rats not receiving captopril. Whereas systolic blood pressure of captopril-treated rats approximated 100 mm Hg throughout the study, that of Goldblatt rats not receiving the drug increased to nearly 180 mm Hg within 6 weeks after clipping. Systolic blood pressure of sham-operated rats remained normal. Indomethacin did not change systolic blood pressure in the drug-treated rats in group I. On cessation of captopril therapy in group II, systolic blood pressure increased gradually in a manner that paralleled the development of the disease in the Goldblatt rats that did not receive captopril. Plasma renin activity was determined in Goldblatt and sham-operated rats at either 16 weeks (group I) or 24 weeks (group II) after clipping; the rats from either group with mild hypertension (systolic blood pressure less than 180 mm Hg) had normal plasma renin activity whereas those with severe hypertension (systolic blood pressure greater than 180 mm Hg) had greatly elevated plasma renin activity. In summary, captopril can completely prevent the increase in systolic blood pressure for up to 24 weeks in Goldblatt rats, and this hypotensive effect is not mediated by the prostaglandins. It is concluded that the renin-angiotensin system is a necessary component of the hypertensive process in this experimental model.     

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.     

Renin dependency of blood pressure in isolated systolic hypertension

The role of the renin system in the maintenance of the elevated systolic blood pressure in isolated systolic hypertension was investigated in 31 patients who received long-term treatment with propranolol (120 mg daily) and in another group of 22 patients with isolated systolic hypertension who received a test dose of captopril (25 or 50 mg). The greatest systolic blood pressure decrease (35 +/- 5 mm Hg) by propranolol occurred in the high-renin group (n = 9), and the smallest decrease (3 +/- 2 mm Hg) in the low-renin group (n = 9), whereas in the normal-renin group (n = 13), systolic blood pressure was decreased by propranolol by 22 +/- 5 mm Hg. For all the propranolol-treated patients, the decrement in the systolic blood pressure by propranolol was related to the control plasma renin activity (r = 0.63, p less than 0.01) and to the concurrent change in plasma renin activity (r = 0.70, p less than 0.001). Captopril decreased the systolic blood pressure by 55 +/- 10 mm Hg in the high-renin group (n = 11) and by 17 +/- 5 mm Hg in the normal-renin group (n = 6), whereas the smallest decrease (12 +/- 5 mm Hg) in systolic blood pressure occurred in the low-renin group (n = 5). In all the captopril-tested patients (n = 22), the decrease in systolic blood pressure by captopril was related to the control plasma renin activity (r = 0.75, p less than 0.001). These results indicate that the plasma renin activity value indicates the participation of the renin-angiotensin system in the maintenance of the elevated systolic blood pressure in patients with isolated systolic hypertension.     

Involvement of brain mineralocorticoid receptor in salt-enhanced hypertension in spontaneously hypertensive rats

We recently showed that brain mineralocorticoid receptors (MRs) are involved in blood pressure and kidney function control in normotensive Wistar rats. We now assessed the involvement of brain MRs in spontaneously hypertensive rats (SHR), in which the presence of adrenocorticoids has been shown to be required for the development of hypertension. The effect of a single intracerebroventricular (ICV) injection of an MR antagonist (RU28318) on systolic blood pressure (SBP) and renal function was examined in conscious adult SHR and Wistar-Kyoto rats (WKY) maintained on a standard-sodium diet (0.4% Na(+)). In WKY, a long-lasting decrease in SBP was caused by the ICV injection of 10 ng RU28318 as previously reported in Wistar rats, associated with increased urinary excretion of water and electrolytes. In SHR maintained on the standard diet, the ICV injection of RU28318 (10 or 100 ng) had no effect on cardiovascular and renal functions. However, the ICV injection of 10 ng RU28318 in SHR after 3 weeks of high sodium intake (8% Na(+)) caused a long-lasting decrease in SBP. The effect was present at 8 hours (DeltaSBP 34+/-2 mm Hg), persisted at 24 hours (DeltaSBP 29+/-1 mm Hg), and disappeared at 48 hours after the injection. The hypotension was not associated with changes in heart rate, urinary excretion of water and electrolytes, and plasma renin activity, whereas renal denervation did not affect the decrease in SBP. A more pronounced decrease in SBP (49+/-3 mm Hg at 8 hours) was observed with 100 ng RU28318. This dose of the antagonist was without effect after subcutaneous administration. Thus, brain MRs appear to participate in the maintenance of hypertension in conscious adult SHR sensitized by sodium loading.     

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.