Jørn Giese

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 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.

Effect of captopril on blood pressure and kidney function in normotensive insulin dependent diabetics with nephropathy.

OBJECTIVE--To assess whether inhibition of angiotensin converting enzyme protects kidney function in diabetic nephropathy. DESIGN--Open, randomised follow up study of normotensive insulin dependent diabetics with nephropathy either treated or not with captopril for one year. SETTING--Outpatient diabetic clinic in a tertiary referral centre. PATIENTS--32 Normotensive patients with insulin dependent diabetes complicated by nephropathy who were randomised either to the treatment group (n = 15) or to the control group (n = 17). INTERVENTIONS--The treatment group was given captopril (25-100 mg/day) for 12 months, the average dose during the second six months of the study being 40 mg daily. Controls were not treated. MAIN OUTCOME MEASURES--Albuminuria, arterial blood pressure, and the glomerular filtration rate. RESULTS--Mean arterial blood pressure fell by 3 (SE 2) mm Hg in the captopril treated group and rose by 6 (1) mm Hg in the controls. In addition, albuminuria declined by 11% in the captopril treated group and rose by 55% in the controls, fractional albumin clearance fell by 17% in the captopril treated group and increased by 66% in the controls, and the glomerular filtration rate declined by 3.1 (2.8)ml/min/1.73 m2 with captopril and by 6.4 (3.1) ml/min/1.73 m2 in the controls. CONCLUSION--Inhibition of angiotensin converting enzyme arrests the progressive rise in albuminuria in normotensive insulin dependent diabetics with nephropathy.

Plasma Renin Concentration Measured by Use of Radioimmunoassay for Angiotensin I

A method for determination of plasma renin concentration is described in which efficient inactivation of angiotensinases, use of human renin as internal standard, and radioimmunological quantitation of angiotensin I are combined. The mean recovery of angiotensin I through incubation and extraction was 84%, SD 1.3 %. In normal subjects, the plasma renin concentration was, on an average, 24 μGU/ml, range 6–59. The coefficient of variation for plasma renin determinations was 12–15%. This includes variations due to storage or dilution of plasma. The method is well-suited for routine clinical use.

Peripheral and Renal Venous Plasma Renin Concentration in Hypertensive Patients with Unilateral Renal or Renovascular Disease

Renal venous catheterization was carried out in a consecutive series of 32 hypertensive patients with unilateral renal or renovascular disease. Plasma renin concentration (PRC) was measured in systemic and renal venous blood with a method allowing the expression of results in terms of Goldblatt Units. Blood samples were collected before and after intravenous injection of furosemide (0.33–0.66 mg/kg body weight).Systemic PRC was elevated in ten out of 19 patients with lesions of the main renal artery. Only one out of 11 patients with unilateral parenchymal renal disease had elevated systemic PRC. A unilateral significant veno-arterial renin concentration difference over the affected kidney was found in eight out of 15 patients with renal artery stenosis and in three, out of 11 patients with unilateral parenchymal renal disease. In patients with renal artery stenosis, a close association was found between increased systemic PRC and renal venous PRC-ratios <1.8. Furosemide led to an increased release of reni...

Does the decrease in heart rate prevent a detrimental decrease of the end-systolic volume during central hypovolemia in man?

Central hypovolemia occurring with epidural anesthesia was investigated by measurement of hemodynamic and endocrine variables in 10 patients. Responses fell into two categories. Four patients experienced a hypotensive bradycardic episode after seventeen ± four minutes. In this group epidural anesthesia initially induced a tendency toward an increase in heart rate from 65 ± 4 to 73 ± 5 beats/min concomitantly with decreases in end-diastolic (172 ± 22 to 138 ± 16 mL), end-systolic (67 ± 12 to 51 ± 9 mL), and stroke (105 ± 10 to 85 ± 7 mL) volumes (radionuclide cardiography). A subsequent decrease in mean arterial pressure from 76 ± 3 to 67 ± 4 mmHg was associated with a decrease in venous return as reflected by the decrease in cardiac output from 6.1 ± 0.4 to 4.7 ± 0.7 L/min. In this situation when the venous return was critically reduced, the heart rate was 49 ± 4 beats/min and no further reduction in end-diastolic and end-systolic volumes was observed. The observed endocrine changes were compatible with a response to central hypovolemia. In the other 6 patients the reaction to epidural anesthesia did not induce statistically signif icant changes in hemodynamic and endocrine variables. It is concluded (1) that the decrease in heart rate associated with central hypovolemia during epidural anesthesia seems to be elicited when the left ven tricular end-systolic volume is decreased by about 25% and (2) that a further decrease in end-systolic volume during progressive central hypovolemia is avoided possibly as a direct consequence of the slowing of the heart.

Plasma noradrenaline concentration in hypertensive and normotensive forty-year-old individuals: Relationship to plasma renin concentration

Forty-year-old individuals with labile and with mild sustained essential hypertension, identified during a survey of a population born in 1936, were investigated. None had ever received antihypertensive treatment. In thirty-three individuals (26 M, 7F) with diastolic blood pressure (DBP) greater than or equal to 95 mmHg at the very first examination and in thirty-one (14 M, 17 F) randomly selected normotensive controls plasma noradrenaline concentration (PNAC) was measured at rest supine. In twenty-two patients (16 M, 6 F), with sustained diastolic hypertension (diastolic blood pressure greater than or equal to 95 mmHg on at least three different occasions) and in twenty-four (14 M, 10 F) normotensive controls PNAC and plasma renin concentration (PRC) were measured supine at rest and again 2 h after furosemide and ambulation. Basal and acutely stimulated values for PNAC and PRC were identical in hypertensive and normotensive individuals. A close correlation between PNAC and PRC after acute stimulation (r = 0.77, P < 0.001) as well as between the absolute changes from resting to acutely stimulated values (r = 0.72, P < 0.001) were found in the hypertensive individuals. It is concluded that sympathetic nerve activity, as defined from measurements of plasma noradrenaline concentration, is similar in young patients with mild hypertension and in normotensive controls. We propose that the discrepancies found in the literature might be related to a lack of comparability between hypertensive and normotensive individuals studied, as far as the source of study populations is concerned.

Captopril Treatment in Bartter's Syndrome

A 13-year-old girl presented with lassitude, polyuria and hypokalemia. Plasma renin concentration and urinary prostaglandin excretion were elevated, whereas plasma aldosterone concentration, urinary aldosterone excretion and blood pressure were normal. A diagnosis of Bartters syndrome was made. The result of treatment with oral potassium was unsatisfactory. Treatment with acetylsalicylic acid had some effect, but an allergic reaction rendered withdrawal necessary. Treatment with the angiotensin converting enzyme inhibitor captopril and oral potassium led to clinical and biochemical improvement.

Haemodynamic and humoral effects of lower body negative pressure in normal, sodium-replete man during angiotensin-converting enzyme inhibition with captopril.

The significance of the renin-angiotensin system (RAS) for circulatory homeostasis during gravitational stress (10 min of lower body negative pressure, LBNP, at -40 mmHg) was investigated in eight men on liberal sodium intake. The function of RAS was inhibited by a single oral dose of 100 mg captopril, an angiotensin-converting enzyme inhibitor. Plasma concentrations of renin and angiotensin I were normal before and increased after captopril and during LBNP. Plasma concentration of angiotensin II was normal before captopril, increased during LBNP, and fell to low values after captopril. Systolic blood pressure decreased more during LBNP after captopril than in the control situation. In three cases, the LBNP experiment after captopril had to be interrupted due to marked hypotension. Heart rate and plasma concentration of adrenaline increased above pre-captopril levels. In six subjects, plasma concentration of noradrenaline increased more during LBNP after captopril, less in two subjects, whereas the arginine vasopressin concentration increased more after captopril in all five subjects where measurements were available. The results demonstrate that RAS participates in blood pressure homeostasis also in sodium-replete, normal man. The enhanced increases in heart rate and plasma catecholamines after captopril do not suggest that sympathetic reflex activity during gravitational stress is blunted after captopril, in contrast to the evidence from animal experiments.

Postpartum Renal Failure and Malignant Hypertension Treated with Captopril

A case of postpartum renal failure and malignant hypertension in a 24-year-old woman is reported. The condition occurred three weeks after caesarian section following a normotensive pregnancy. Treatment with a converting enzyme inhibitor, captopril, for one year normalized the blood pressure, with concurrent reduction of plasma angiotension II concentration and markedly improved glomerular filtration rate. It is suggested that activation of the renin-angiotensin system may cause the hypertension and impairment of renal function in postpartum renal failure, and that use of drugs blocking the renin system may be of particular clinical value in this situation.