Effect of captopril on kidney function in insulin-dependent diabetic patients with nephropathy.

The influence of angiotensin II on kidney function in diabetic nephropathy was assessed by studying the effect of 12 weeks'' monotherapy with captopril (25-50 mg twice a day) in 16 hypertensive insulin dependent diabetic patients with persistent albuminuria. In an initial one week randomised single blind trial of captopril versus placebo, captopril (for nine patients) reduced arterial blood pressure from 148/94 (SD11/6) to 135/88 (8/7) mm Hg (p less than 0.05) and albuminuria from 1549 (range 352-2238) to 1170 (297-2198) micrograms/min (p less than 0.05), while glomerular filtration rate remained stable. No significant changes occurred in seven patients treated with placebo. During the 12 weeks of captopril treatment arterial blood pressure in all patients fell from 147/94 (11/6) to 135/86 (13/7) mm Hg (p less than 0.01), albuminuria fell from 1589 (range 168-2588) to 1075 (35-2647) micrograms/min (p less than 0.01), and glomerular filtration rate fell from 99 (SD19) to 93 (25) ml/min/1.73 m2 (p less than 0.01). The renin-angiotensin system showed suppressed plasma concentrations of angiotensin II and increased concentrations of angiotensin I and renin. The study showed that glomerular filtration rate is not dependent on angiotensin II, that captopril reduces albuminuria, probably by lowering glomerular hypertension, and that captopril represents a valuable new drug for treating hypertension in diabetics dependent on insulin with nephropathy.     

Moderate sodium restriction with angiotensin converting enzyme inhibitor in essential hypertension: a double blind study.

Fifteen unselected patients who had essential hypertension and whose average supine blood pressure when they were not receiving any treatment and their usual sodium intake was 162/107 mm Hg were treated with captopril 50 mg twice daily. After one month''s treatment their supine blood pressure had decreased to 149/94 mm Hg. They were then instructed to reduce their sodium intake to about 80 mmol(mEq)/day. After two weeks of moderate sodium restriction they were entered into a double blind randomised crossover study comparing the effect of 10 Slow Sodium tablets (100 mmol sodium chloride) with matching placebo tablets while continuing to take captopril and restrict sodium in their diet. After one month of taking placebo their mean supine blood pressure was 137/88 mm Hg with a urinary sodium excretion of 83 mmol/24 h, while after one month of taking Slow Sodium tablets their mean supine blood pressure was 150/97 mm Hg (p less than 0.001) with a sodium excretion of 183 mmol/24 h. The mean supine blood pressure during moderate sodium restriction therefore decreased by 9% and correlated significantly with the reduction in urinary sodium excretion. These results suggest that the combination of treatment with a moderate but practical reduction in sodium intake and an angiotensin converting enzyme inhibitor is effective in decreasing the blood pressure in patients with essential hypertension. This combined approach overcomes some of the objections that have been made to salt restriction alone and to converting enzyme inhibitors alone.     

Protection of kidney function and decrease in albuminuria by captopril in insulin dependent diabetics with nephropathy.

STUDY OBJECTIVE--To assess whether long term inhibition of angiotensin converting enzyme with captopril and frusemide or bendrofluazide protects kidney function in diabetic nephropathy. DESIGN--Non-randomised controlled before-after trial of matched hypertensive insulin dependent diabetics with nephropathy treated with captopril and frusemide or bendrofluazide. SETTING--Outpatient diabetic clinic in tertiary referral centre. PATIENTS--Treatment group of 18 hypertensive insulin dependent diabetics with nephropathy (mean age 33), who had not been treated previously. Control group of 13 patients (mean age 32) fulfilling the same entry criteria from a prospective study. INTERVENTIONS--Treatment group was given daily captopril 37.5-100.0 mg and frusemide (mean) 98 mg (10 patients) or bendrofluazide (mean) 4 mg (seven). Treatment was continued for about two and a half years. Controls were not treated. END POINT--Measurement of arterial blood pressure, albuminuria, and glomerular filtration. MEASUREMENTS AND MAIN RESULTS--Baseline values were identical in treated and untreated groups respectively: mean blood pressure 146/93 (SE 3/1) mm Hg v 137/95 (2/1) mm Hg; geometric mean albuminuria 982 (antilog SE 1.2) micrograms/min v 936 (1.2) micrograms/min; and mean glomerular filtration rate 98 (SE 5) ml/min/1.73 m2 v 96 (6) ml/min/1.73 m2. Mean arterial blood pressure fell by 8.7 (1.3) mm Hg with captopril and rose by 6.6 (1.5) mm Hg in controls, (p less than 0.001); Albumin excretion decreased to 390 (1.1) micrograms/min with captopril and rose to 1367 (1.3) micrograms/min in controls (p less than 0.001). The rate of decrease in glomerular filtration rate was lower with captopril (5.8 (0.7) ml/year v 10.0 (1.3) ml/year) (p less than 0.01). Rate of fall in glomerular filtration rate and mean arterial blood pressure were significantly correlated (n = 31, r = 0.37, p less than 0.05). CONCLUSIONS--Captopril is a valuable new drug for treating hypertension in insulin dependent diabetics with nephropathy.     

Effects of an angiotensin-converting enzyme inhibitor (captopril) on blood pressure in anephric subjects.

Randomised, double-blind cross-over trials were performed in seven anephric patients to determine the effect of the orally active angiotensin-converting enzyme inhibitor captopril on blood pressure in fluid-depleted and fluid-replete patients. Patients were given captopril, 100 mg orally, or placebo one hour after haemodialysis, when they were fluid depleted. Their mean (+/- SEM) supine blood pressure fell from 127 +/- 12/71 +/- 6 mm Hg before captopril to 106 +/- 13/54 +/- 4 mm Hg 24 hours after the drug, while on placebo it rose from 123 +/- 11/73 +/- 5 mm Hg to 134 +/- 10/82 +/- 8 mm Hg. All patients developed orthostatic hypotension after captopril. In the fluid-replete state, two days after haemodialysis, captopril had no effect on blood pressure. The plasma concentration of active renin was extremely low and did not rise after fluid withdrawal or captopril. Thus the hypotensive effect of captopril did not appear to depend on circulating renin concentrations. The concept of "renin-dependent" hypertension, which is responsive to captopril, as opposed to "volume-dependent" hypertension, which is not responsive to captopril, may therefore be invalid.     

Role of nifedipine in treatment of hypertension.

The efficacy of nifedipine in the treatment of hypertension was assessed in 15 patients whose hypertension continued while being treated with atenolol 100 mg and bendrofluazide 5 mg daily. Nifedipine was added in doses of 10, 20, and 30 mg three times daily in a placebo controlled, double blind trial. One patient was withdrawn from the trial because of severe postural hypotension with the highest dose. Erect and supine blood pressure in the remaining 14 patients were significantly reduced by all doses of nifedipine. The drug was well tolerated but plasma potassium fell by 0.3 mmol(mEq)/1 during treatment (p less than 0.05). Nifedipine is thus effective in the treatment of hypertension but should probably be used in combination with a potassium sparing diuretic.     

Beneficial effects of angiotensin converting enzyme inhibition on renal function in patients with diabetic nephropathy.

The effects of angiotensin converting enzyme inhibition with captopril were investigated in patients with diabetic nephropathy and hypertension. After nine days'' treatment with captopril glomerular filtration rate was unchanged in 13 patients, whereas renal plasma flow had increased from 265 to 302 ml/min/1.73 m2 body surface area (p less than 0.05) and the filtration fraction had decreased from 14.3 to 12.8% (p less than 0.025). During two years'' treatment with captopril in 14 patients the mean arterial blood pressure had fallen by 5 mm Hg (p less than 0.005) and the deterioration in glomerular filtration rate had decreased from 10.3 to 2.4 ml/min/year (p less than 0.005). There was no correlation between the fall in blood pressure and the reduction in the deterioration of glomerular filtration rate. These findings suggest that the effects of angiotensin converting enzyme inhibition on renal haemodynamics protect renal function. Inhibitors of angiotensin converting enzyme should be considered for lowering blood pressure in patients with diabetic nephropathy.     

Essential hypertension: effect of an oral inhibitor of angiotensin-converting enzyme.

Captopril, a specific oral inhibitor of angiotensin-converting enzyme, was given to 18 unselected patients with moderate essential hypertension. Mean blood pressure fell by 14.5% at the maximum dose given, and this fall was significantly correlated with the initial plasma renin activity. The main fall in blood pressure occurred two hours after the first dose of captopril. These results suggest that captopril effectively lowers blood pressure in patients with essential hypertension and that the renin-angiotensin aldosterone system may maintain blood pressure in essential hypertension. This does not necessarily imply that the renin-angiotensin system is the cause of the high blood pressure.     

Captopril in essential hypertension; contrasting effects of adding hydrochlorothiazide or propranolol.

Twenty-four patients with moderate to severe hypertension were treated for four weeks with captopril, an oral inhibitor of angiotensin-converting enzyme. The fall in blood pressure with captopril alone correlated with pretreatment plasma renin activity. The effect of adding either hydrochlorothiazide or propranolol to the captopril treatment was then studied. The addition of hydrochlorothiazide to captopril produced a dose-dependent fall in blood pressure. At the higher dose of the diuretic this fall in blood pressure correlated with weight loss, suggesting that when the diuretic-induced compensatory rise in angiotensin II is prevented by captopril the fall in blood pressure becomes dependent on loss of sodium and water. In contrast, the addition of propranolol to captopril produced no further fall in blood pressure, suggesting that inhibition of angiotensin-converting enzyme prevents the blood pressure lowering effect of propranolol. This may have implications for the mechanism whereby beta-blockers alone lower blood pressure. These contrasting effects of hydrochlorothiazide and propranolol in the presence of captopril indicate that in patients whose hypertension is not controlled by captopril alone the addition of increasing doses of diuretic is likely to control the blood pressure. The addition of a beta-blocker, however, is less likely to be effective.     

Evidence for a dual action of converting enzyme inhibitor on blood pressure in normal man

We studied the effect of a converting enzyme inhibitor (CEI), Captopril SQ 14,225 50 mg p.o. in eight supine normal subjects under a high sodium (150 mEq/d) and low sodium (25 mEq/d) diet. On high sodium, plasma renin (PRA) and aldosterone were basal and Saralasin did not lower mean blood pressure. However, CEI induced an 11.4 +/- 3.2 mm fall in blood pressure (p less than 0.02) and either indomethacin 50 mg or ibuprofen 800 mg (PI), when given simultaneously on another day abolished the blood pressure response (2.5 +/- 0.9 mm Hg, p greater than 0.5). In contrast, on a low salt diet where renin was increased, CEI induced a drop in blood pressure which was not significantly altered by PI (12.8 +/- 1.1 vs. 10.0 +/- 3.1 mm Hg, p greater than 0.5). CEI increased plasma renin on both diets (1.7 +/- 0.5 to 3.5 +/- 0.8 and 2.8 +/- 0.6 to 12.5 +/- 3.1 ng/ml/hr respectively both p less than 0.05). Aldosterone did not change (high Na+) or fell (low Na+). Inhibition of Prostaglandin synthesis did not significantly block the renin rise from CEI suggesting that the direct angiotensin II negative feedback is relatively independent of acute prostaglandin release. Our studies suggest that CEI has a dual hypotensive action. In a low renin state, the hypotensive action appears to be mediated through vascular prostaglandins.     

Relation between arterial pressure,dietary sodium intake,and renin system in essential hypertension.

Forty-one patients with mild essential hypertension, 36 patients with severe hypertension, and 28 normotensive subjects were studied on a high sodium intake of 350 mmol/day for five days and low sodium intake of 10 mmol/day for five days. The fall in mean arterial pressure on changing from the high-sodium to the low-sodium diet was 0.7 +/- 1.7 mm Hg in normotensive subjects, 8 +/- 1.4 mm Hg in patients with mild hypertension, and 14.5 +/- 1.4 mm Hg in patients with severe hypertension. The fall in blood pressure was not correlated with age. Highly significant correlations were obtained for all subjects between the ratio of the fall in mean arterial pressure to the fall in urinary sodium excretion on changing from a high- to a low-sodium diet and (a) the level of supine blood pressure on normal diet, (b) the rise in plasma renin activity, and (c) the rise in plasma aldosterone. In patients with essential hypertension the blood pressure is sensitive to alterations in sodium intake. This may be partly due to some change either produced by or associated directly with the hypertension. A decreased responsiveness of the renin-angiotensin-aldosterone system shown in the patients with essential hypertension could partly account for the results.     

Treating hypertension in black compared with white non-insulin dependent diabetics: a double blind trial of verapamil and metoprolol.

STUDY OBJECTIVE--To compare responses of blood pressure to the calcium antagonist verapamil and the beta blocker metoprolol in black compared with white diabetics with hypertension and to monitor urinary albumin excretion in relation to fall in blood pressure. DESIGN--Double blind, placebo controlled, random order crossover trial with four week placebo run in period and two six week active phases separated by a two week placebo washout period. SETTING--Outpatient department of a general hospital in a multiethnic health department. Patients--Diabetic patients with hypertension. Four dropped out before randomisation; 25 black and 14 white patients completed the trial. INTERVENTIONS--Patients given slow release verapamil 120 mg or 240 mg twice daily with placebo or metoprolol 50 mg or 100 mg twice daily with placebo. Treatment for diabetes (diet alone or with oral hypoglycaemic drugs) remained unchanged. END POINT--Comparison of changes in blood pressure in the two groups taking both drugs. MEASUREMENTS AND MAIN RESULTS--Metoprolol had little effect on blood pressure in black patients (mean fall 4.0 mm Hg systolic (95% confidence interval -2.5 to 10.4 mm Hg), 4.3 mm Hg diastolic (-0.8 to 9.5)) but more effect in white patients (mean falls 13.4 mm Hg (0.1 to 26.7) and 10.6 mm Hg (4.5 to 16.7) respectively). Verapamil was more effective in both groups, with mean falls of 8.8 mm Hg (2.4 to 15.0) and 8.1 mm Hg (5.0 to 11.2) in black patients and 19.1 mm Hg (5.4 to 32.9) and 11.4 mm Hg (0.9 to 22.0) in white patients. Heart fate fell significantly in black patients taking metoprolol, which suggested compliance with treatment. Metabolic variables were unaltered by either treatment. Plasma renin activity was low in both groups after metoprolol treatment, but change in blood pressure could not be predicted from baseline plasma renin activity. Urinary albumin:creatinine ratio was independently related to baseline blood pressure but not significantly changed by treatment. CONCLUSIONS--beta Blockers alone are not effective in treating hypertension in black diabetics. Verapamil is effective but less so than in white patients. As yet no ideal monotherapy exists for hypertension in black patients.     

Efficacy of captopril in postponing nephropathy in normotensive insulin dependent diabetic patients with microalbuminuria.

OBJECTIVE--To assess the effectiveness of angiotensin converting enzyme inhibition in preventing the development of diabetic nephropathy (albuminuria greater than 300 mg/24h). DESIGN--Open randomised controlled study of four years'' duration. SETTING--Outpatient diabetic clinic in tertiary referral centre. PATIENTS--44 normotensive (mean blood pressure 127/78 (SD 12/10) mm Hg) insulin dependent diabetic patients with persistent microalbuminuria (30-300 mg/24h). INTERVENTIONS--The treatment group (n = 21) was initially given captopril (25 mg/24 h). The dose was increased to 100 mg/24 h during the first 16 months and thiazide was added after 30 months. The remaining 23 patients were left untreated. MAIN OUTCOME MEASURES--Albuminuria, kidney function, development of diabetic nephropathy (albuminuria greater than 300 mg/24 h), and arterial blood pressure. RESULTS--Clinical and laboratory variables were comparable at baseline. Urinary excretion of albumin was gradually reduced from 82 (66-106) to 57 (39-85) mg/24 h (geometric mean (95% confidence interval)) in the captopril treated group, whereas an increase from 105(77-153) to 166 (83-323) mg/24 h occurred in the control group (p less than 0.05). Seven of the untreated patients progressed to diabetic nephropathy, whereas none of the captopril treated patients developed clinical overt diabetic nephropathy (p less than 0.05). Systemic blood pressure, glomerular filtration rate, haemoglobin A1c concentration, and urinary excretion of sodium and urea remained practically unchanged in the two groups. CONCLUSIONS--The findings suggest that angiotensin converting enzyme inhibition postpones the development of clinical overt diabetic nephropathy in normotensive insulin dependent diabetic patients with persistent microalbuminuria.     

Effect on intra-arterial blood pressure of slow release metoprolol combined with placebo or chlorthalidone.

Thirty patients with essential hypertension participated in a double blind crossover trial in which they were randomly allocated to treatment with either once daily slow release metoprolol (200 mg) with placebo or once daily slow release metoprolol (200 mg) with chlorthalidone (25 mg). Ambulatory intra-arterial blood pressure was recorded continuously for 24-48 hours before treatment and two months after each change in regimen. The response of blood pressure and pulse rate to a standard exercise protocol that included supine rest and tilt, isometric, and dynamic bicycle exercise was measured during the same recording periods. Both treatments appreciably reduced blood pressure and pulse rate; mean daytime intra-arterial blood pressure was reduced from 174/95 mm Hg to 158/85 mm Hg by metoprolol plus placebo and to 143/78 mm Hg by metoprolol plus chlorthalidone. This reduction with the combined treatment was significantly greater than with metoprolol and placebo (p systolic = 0.001, p diastolic = 0.004). Mean night time pressures were reduced from 148/78 mm Hg to 139/75 mm Hg by metoprolol plus placebo and to 116/61 mm Hg by metoprolol plus chlorthalidone. Again the reduction in blood pressure was significantly greater with combined treatment (p less than 0.001) than with metoprolol plus placebo. Once daily slow release metoprolol is effective in controlling blood pressure, but this effect is greatly enhanced by the addition of a diuretic.     

Attenuation of hypotensive effect of propranolol and thiazide diuretics by indomethacin.

The effects of 100 mg indomethacin daily for three weeks on blood pressure and urinary excretion of prostaglandin F2 alpha were studied in a double-blind, placebo-controlled comparison of two groups of patients with essential hypertension, eight receiving propranolol and seven thiazide diuretics. Compared with placebo, adding indomethacin to the patients'' established antihypertensive treatment increased blood pressure by 14/5 Hg supine and 16/9 mm Hg erect in the patients receiving propranolol, and by 13/9 mm Hg supine and 16/9 mm Hg erect in the patients receiving thiazide diuretics (all p less than or equal to 0.05). The excretion of the major urinary metabolite of prostaglandin F2 alpha was reduced by 67% in the propranolol-treated patients and by 57% in those receiving a thiazide diuretic. Body weight increased by 0 . 8 kg (propranolol) and 1 . 1 kg (thiazide diuretic) when indomethacin was given, but there were no significant changes in creatinine clearance, urinary sodium excretion, or packed cell volume in either treatment group. These results suggest that products formed by the arachidonic acid cyclo-oxygenase contribute to the regulation of blood pressure during treatment with both propranolol and thiazide diuretics. Inhibition of the cyclo-oxygenase with indomethacin partially antagonises the hypotensive effect of these drugs.     

Nocturnal blood pressure in normotensive subjects and those with white coat,primary, and secondary hypertension.

OBJECTIVE--To compare the mean nocturnal blood pressure of patients with various forms of renal and endocrine hypertension with that in patients with primary and white coat hypertension, and normal blood pressure. DESIGN--Ambulatory monitoring of blood pressure over 24 hours in a prospective study. SETTING--Two German centres for outpatients with hypertension and kidney diseases. SUBJECTS--176 normotensive subjects, 490 patients with primary hypertension including mild and severe forms, 42 with white coat hypertension, 208 patients with renal and renovascular hypertension, 43 with hypertension and endocrine disorders, and three with coarctation of the aorta. MAIN OUTCOME MEASURES--Fall in nocturnal blood pressure. RESULTS--Blood pressure in normotensive subjects fell by a mean of 14 mm Hg (11%) systolic and 13 mm Hg (17%) diastolic overnight (2200 to 0600). The falls in patients with primary and white coat hypertension were not significantly different. In all patients with renal and renovascular hypertension, however, the fall was significantly reduced (range of fall from 3/3 mm Hg to 7/9 mm Hg). In patients with hypertension and endocrine disorders the pattern of night time blood pressure was not uniform: patients with hyperthyroidism, primary hyperaldosteronism, and Cushing''s syndrome had significantly smaller reductions in blood pressure (6/8, 4/7, 3/6 mm Hg, respectively). In patients with phaeochromocytoma the mean night time blood pressure increased by 4/2 mm Hg. In patients with hypertension, primary hyperparathyroidism, and unoperated coarctation of the aorta the falls in blood pressure were normal. CONCLUSIONS--In normotensive subjects and those with primary hypertension there is usually a reduction in blood pressure at night. In all renal forms of secondary hypertension and in most endocrine forms the reduction in blood pressure is only a third to a half of normal. Patients with primary hyperparathyroidism and unoperated coarctation of the aorta show a normal reduction.     

Minoxidil for severe hypertension after failure of other hypotensive drugs.

Forty-four patients with severe hypertension who were resistant to treatment with more conventional hypotensive drugs or could not tolerate the side effects were treated with minoxidil, a potent peripheral vasodilator. A beta-blocking drug and a diuretic were used routinely to control, respectively, the tachycardia and fluid retention caused by minoxidil. During treatment the outpatient supine blood pressure fell from a mean of 221/134 mm Hg to 162/98 mm Hg. Eleven patients required additional or alternative hypotensive agents before blood pressure was adequately controlled. Side effects were minor, although the invariable hirsuties caused by minoxidil was unacceptable to three women. The possibility of cardiotoxic effects, raised by early studies in dogs, has not been excluded, and therefore this drug should be used only in patients with severe hypertension. In such patients minoxidil appears to be most effective.     

Effects of various doses of captopril on plasma aldosterone concentrations in patients with essential hypertension

Various doses (5 mg, 12.5 mg and 25 mg) of angiotensin I converting enzyme inhibitor (SQ 14,255, captopril) were administered to 8 patients with essential hypertension on a three-crossover study design, and the time course of mean blood pressure (MBP), plasma renin activity (PRA), plasma angiotensin converting enzyme activity (ACE-A), plasma cortisol (PC) and plasma aldosterone (PA) were determined following administration of the drug. MBP fell in a dose dependent manner, and PRA showed a minor but significant increases in cases receiving 5 and 12.5 mg of the drug. A large and significant increase in PRA was observed following 25 mg of captopril. ACE-A was also reduced in a dose dependent manner. There was no difference between changes in PC at any of the three dose levels. The serum potassium concentration was determined before and 3 hr after 25 mg of captopril treatment and no significant change was observed. In spite of the dose dependent and theoretical changes in the above parameters, lowered responses of PA to each dose of the drug were shown in reverse order against an increasing dose. That is to say, the grade of fall in PA following 25 of captopril was smaller than that following the other doses of the drug, and 5 mg induced a greater decrease in PA than 12.5 mg. Based on these findings, the relatively high dose of captopril in the present study was apparently more effective in increasing some factors which suppressed reduction of PA by a fall in angiotensin II than a low dose of the drug.     

Sodium restriction and blood pressure in hypertensive type II diabetics: randomised blind controlled and crossover studies of moderate sodium restriction and sodium supplementation.

OBJECTIVE--To determine the effect of moderate dietary sodium restriction on the hypertension of non-insulin-dependent (type II) diabetes. DESIGN--Randomised parallel controlled study of moderate sodium restriction for three months compared with usual diabetic diet, followed by randomised double blind crossover trial of sustained release preparation of sodium for one month versus placebo for one month in patients continuing with sodium restriction. SETTING--Patients attending diabetic outpatient clinic of city hospital. PATIENTS--Thirty four patients with established type II diabetes complicated by mild hypertension (systolic blood pressure greater than 160 mm Hg or diastolic pressure greater than 95 mm Hg on three consecutive occasions). Patients already taking antihypertensive agents (but not diuretics) not barred from study provided that criteria for mild hypertension still met. Conditions precluding patients from study were diabetic or hypertensive nephropathy, cardiac failure, and pregnancy. INTERVENTIONS--After run in phase with recordings at seven weeks, three weeks, and time zero patients were allocated at random to receive moderate dietary sodium restriction for three months (n = 17) or to continue with usual diabetic diet. Subsequently nine patients in sodium restriction group continued with regimen for a further two months, during which they completed a randomised double blind crossover trial of sustained release preparation of sodium (Slow Sodium 80 mmol daily) for one month versus matching placebo for one month. END POINT--Reduction in blood pressure in type II diabetics with mild hypertension. MEASUREMENTS AND MAIN RESULTS--Supine and erect blood pressure, body weight, and 24 hour urinary sodium and potassium excretion measured monthly during parallel group and double blind crossover studies. After parallel group study sodium restriction group showed significant reduction in systolic blood pressure (supine 19.2 mm Hg, erect 21.4 mm Hg; p less than 0.001) and mean daily urinary sodium excretion (mean reduction 60 mmol/24 h). There were no appreciable changes in weight, diabetic control, or diastolic pressure. No significant changes occurred in controls. In double blind crossover study mean supine systolic blood pressure rose significantly (p less than 0.005) during sodium supplementation (to 171 mm Hg) compared with value after three months of sodium restriction alone (159.9 mm Hg) and after one month of placebo (161.8 mm Hg). CONCLUSIONS--Moderate dietary restriction of sodium has a definite hypotensive effect, which may be useful in mild hypertension of type II diabetes.     

Prolonged blood pressure reduction by orally active renin inhibitor RO 42-5892 in essential hypertension.

OBJECTIVE--To investigate the effects of a novel specific renin inhibitor, RO 42-5892, with high affinity for human renin (Ki = 0.5 x 10(-9) mol/l), on plasma renin activity and angiotensin II concentration and on 24 hour ambulatory blood pressure in essential hypertension. DESIGN--Exploratory study in which active treatment was preceded by placebo. SETTING--Inpatient unit of teaching hospital. PATIENTS--Nine men with uncomplicated essential hypertension who had a normal sodium intake. INTERVENTIONS--Two single intravenous doses of RO 42-5892 (100 and 1,000 micrograms/kg in 10 minutes) given to six patients and one single oral dose (600 mg) given to the three others as well as to three of the patients who also received the two intravenous doses. RESULTS--With both intravenous and oral doses renin activity fell in 10 minutes to undetectably low values, while angiotensin II concentration fell overall by 80-90% with intravenous dosing and by 30-40% after the oral dose. Angiotensin II concentration was back to baseline four hours after the low and six hours after the high intravenous dose and remained low for at least eight hours after the oral dose. Blood pressure fell rapidly both after low and high intravenous doses and after the oral dose and remained low for hours. With the high intravenous dose the daytime (0900-2230), night time (2300-0600), and next morning (0630-0830) systolic blood pressures were significantly (p less than 0.05) lowered by 12.5 (95% confidence interval 5.6 to 19.7), 12.2 (5.4 to 19.3), and 10.7 (3.2 to 18.5) mm Hg respectively, and daytime diastolic pressure was lowered by 9.3 (2.2 to 16.8) mmHg. With the oral dose daytime, night time, and next morning systolic blood pressures were lowered by 10.3 (5.5 to 15.4), 10.5 (4.2 to 17.2), and 9.7 (4.0 to 15.6) mm Hg, and daytime and night time diastolic pressures were lowered by 5.8 (0.9 to 11.0) and 6.0 (0.3-12) mm Hg respectively. CONCLUSIONS--The effect of the inhibitor on blood pressure was maintained over a longer period than its effect on angiotensin II. RO 42-5892 is orally active and has a prolonged antihypertensive effect in patients who did not have sodium depletion. This prolonged effect seems to be independent, at least in part, of the suppression of circulating angiotensin II.     

Community care compared with hospital outpatient care for hypertensive patients.

Three hundred and seventy-six patients with treated diastolic blood pressures of less than 105 mm Hg and no history of accelerated hypertension or renal failure were selected from among those attending the Hammersmith Hospital hypertension clinic. Their average lying treated blood pressure was 146 mm Hg systolic and 90 mm Hg diastolic and average age 56 years; 18% were black, 6% Asian, and 76% white. The patients were mostly having multiple treatment, 90% receiving a diuretic, 35% methyldopa, 33% propranolol, 18% atenolol, 9% hydrallazine, and 7% bethanidine. They were randomly allocated to either two years of further hospital outpatient care or referred back to their general practitioners. During the two years 19 (10%) of the 187 patients followed up in hospital defaulted and three had their treatment discontinued. Twelve (6%) of the 189 followed up by their general practitioners defaulted from follow-up and nine had their treatment discontinued. At the end of the trial the average lying blood pressure was 148 mm Hg systolic and 88 mm Hg diastolic in the hospital group and 149 mm Hg systolic and 90 mm Hg diastolic in the general practice group. The change in blood pressure was calculated for each individual and showed an average fall of 1.6 mm Hg in standing diastolic pressure in the hospital group and a rise of 1.4 mm Hg in the general practice group (p less than 0.05). The 90% confidence limits for a difference in standing diastolic pressure between the groups were 1 and 5 mm Hg with the pressure lower in the hospital group. General practice care was not quite as effective in controlling blood pressure as continued specialist supervision over two years in this selected group of treated outpatients with mild or moderate hypertension, but these results show that the discharge back to general practitioners of patients who are well controlled after hospital treatment is a sensible policy.