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.     

Effect of antihypertensive treatment on kidney function in diabetic nephropathy.

The effect of long term, aggressive antihypertensive treatment on kidney function in diabetic nephropathy was studied prospectively in 11 insulin dependent diabetics (mean age 30). During the mean pretreatment period of 32 (range 23-66) months the glomerular filtration rate decreased significantly and albuminuria and the arterial blood pressure increased significantly. During the 72 (range 32-91) month period of antihypertensive treatment the average arterial blood pressure fell from 143/96 mm Hg to 129/84 mm Hg and albuminuria decreased from 1038 micrograms/min to 504 micrograms/min. The rate of decline in the glomerular filtration rate decreased from 0.89 (range 0.44-1.46) ml/min/month before treatment to 0.22 (range 0.01-0.40) ml/min/month during treatment. The rate of decline in the glomerular filtration rate was significantly smaller during the second three years compared with the first three years in patients who received long term antihypertensive treatment (greater than or equal to 6 years). One patient died from acute myocardial infarction (glomerular filtration rate 46 ml/min/1.74 m2). Effective antihypertensive treatment postpones renal insufficiency in diabetic nephropathy.     

Effect of deletion polymorphism of angiotensin converting enzyme gene on progression of diabetic nephropathy during inhibition of angiotensin converting enzyme: observational follow up study.

OBJECTIVE: To evaluate the concept that an insertion/deletion polymorphism of the angiotensin converting enzyme gene predicts the therapeutic efficacy of inhibition of angiotensin converting enzyme on progression of diabetic nephropathy. DESIGN: Observational follow up study of patients with insulin dependent diabetes and nephropathy who had been treated with captopril for a median of 7 years (range 3-9 years). SETTING: Outpatient diabetic clinic in a tertiary referral centre. PATIENTS: 35 patients with insulin dependent diabetes and nephropathy were investigated during captopril treatment (median 75 mg/day (range 12.5 to 150 mg/day)) that was in many cases combined with a loop diuretic, 11 patients were homozygous for the deletion allele and 24 were heterozygous or homozygous for the insertion allele of the angiotensin converting enzyme gene. MAIN OUTCOME MEASURES: Albuminuria, arterial blood pressure, and glomerular filtration rate according to insertion/deletion polymorphism. RESULTS: The two groups had comparable glomerular filtration rate, albuminuria, blood pressure, and haemoglobin A1c concentration at baseline. Captopril induced nearly the same reduction in mean blood pressure in the two groups-to 103 (SD 5) mm Hg in the group with the deletion and 102 (8) mm Hg in the group with the insertion-and in geometric mean albumin excretion-573 (antilog SE 1.3) micrograms/min and 470 (1.2) micrograms/min, respectively. The rate of decline in glomerular filtration rate (linear regression of all glomerular filtration rate measurements during antihypertensive treatment) was significantly steeper in the group homozygous for the double deletion allele than in the other group (mean 5.7 (3.7) ml/min/year and 2.6 (2.8) ml/min/year, respectively; P = 0.01). Multiple linear regression analysis showed that haemoglobin A1c concentration, albuminuria, and the double deletion genotype independently influenced the sustained rate of decline in glomerular filtration rate (R1 (adjusted) = 0.51). CONCLUSION: The deletion polymorphism in the angiotensin converting enzyme gene reduces the long term beneficial effect of angiotensin converting enzyme inhibition on the progression of diabetic nephropathy in patients with insulin dependent diabetes.     

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.     

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.     

Long-term antihypertensive treatment inhibiting progression of diabetic nephropathy

Six men aged 26-35 years with proteinuria due to insulindependent juvenile-onset diabetes were treated for moderate hypertension (mean blood pressure 162/103 mm Hg) and studied for a mean of 73 months for the effect on the progression of nephropathy. All patients were of normal weight. During a mean control period of 28 months before treatment the mean glomerular filtration rate (three or four measurements) was 86·1 ml/min and mean 24-hour urinary albumin excretion (also three or four measurements) 3·9 g (range 0·5-8·8 g).During antihypertensive treatment the mean systolic blood pressure fell to 144 mm Hg and mean diastolic pressure to 95 mm Hg. In the control period five patients had shown a mean monthly decline in glomerular filtration rate of 1·23 ml/min; with antihypertensive treatment, however, this decline fell to 0·49 ml/min (2p=0·042). In the remaining patient the glomerular filtration rate was 137 ml/min before treatment and 135 ml/min at the end of the treatment period. In all patients the mean yearly increase in albumin clearance (expressed as a percentage of the glomerular filtration rate) fell from 107% before treatment to 5% during treatment (2p=0·0099).This small study indicates that antihypertensive treatment slows the decline in renal function in diabetic nephropathy. Clinical trials beginning treatment in the incipient phase of diabetic nephropathy will define the optimal modality of treatment in this large patient population.     

Plasma lipid and coagulation factor concentrations in insulin dependent diabetics with microalbuminuria.

OBJECTIVE--To determine whether insulin dependent diabetics with microalbuminuria have significant abnormalities in concentrations of lipoproteins, apolipoproteins AI and B, fibrinogen, and clotting factor VII which could result in increased cardiovascular risk. DESIGN--Case-control study. SETTING--Outpatient department of a metabolic ward. PATIENTS--Group of 20 insulin dependent diabetics with urinary albumin excretion rates greater than 30 micrograms/min (microalbuminuria) and 20 individually matched insulin dependent diabetics with normal urinary albumin excretion rates (below 30 micrograms/min) matched for age, sex, and duration of diabetes. INTERVENTIONS--Fasting venous blood samples were taken for determination of concentrations of glucose, glycated haemoglobin, lipoproteins, apolipoproteins AI and B, fibrinogen, and factor VII. Height, weight, arterial pressure, and usual insulin dose were recorded, and each patient was given a dietary questionnaire to be completed at home. END POINT--Comparison of blood pressure and concentrations of lipoproteins, apolipoproteins AI and B, and fibrinogen in the diabetics with microalbuminuria and the controls. MEASUREMENTS AND MAIN RESULTS--Patients with microalbuminuria had significantly higher concentrations of low density lipoprotein cholesterol (mean 3.33 (SE 0.20) v 2.84 (0.12) mmol/l) and very low density lipoprotein cholesterol (0.30 (0.05) v 0.17 (0.03) mmol/l) than controls but significantly lower concentrations of high density lipoprotein 2 subfraction cholesterol (0.32 (0.04) v 0.54 (0.04) mmol/l). Concentrations of total triglyceride (1.11 (0.14) v 0.68 (0.08) mmol/l), very low density lipoprotein triglyceride (0.56 (0.10) v 0.30 (0.05) mmol/l), apolipoprotein B (0.88 (0.06) v 0.67 (0.03) g/l) and fibrinogen (2.2 (0.1) v 1.9 (0.1) g/l), and diastolic arterial pressure (80 (2) v 74 (2) mm Hg), were also higher in patients with microalbuminuria. CONCLUSIONS--Cardiovascular risk factors--namely, disturbances in lipoprotein and apolipoprotein concentrations, increased fibrinogen concentration, and increased arterial pressure--are already present in insulin dependent diabetics with microalbuminuria. The increased risk of coronary heart disease in patients with clinical proteinuria may result from prolonged exposure to these risk factors, which are present before any impairment of renal function.     

Raised arterial pressure in parents of proteinuric insulin dependent diabetics.

Arterial pressure is raised early in the subset of insulin dependent diabetics at risk of later development of progressive renal failure, suggesting that liability to arterial hypertension may play a part in the aetiology of diabetic kidney disease. Evidence for a genetic basis was therefore sought by measuring the blood pressures of the 26 surviving parents of 17 insulin dependent diabetic patients with proteinuria and comparing them with those of the parents of 17 matched insulin dependent diabetic patients without proteinuria selected from the same cohort. Systolic and diastolic pressures were significantly higher in parents of the proteinuric (mean (SD) 161 (27)/94 (14) mm Hg) than in parents of the non-proteinuric patients (146 (21)/86 (11) mm Hg). The difference between the sample mean blood pressures was 15 mm Hg (95% confidence interval 3.3 to 26.7 mm Hg) for systolic pressure and 8 mm Hg (95% confidence interval 0.8 to 15.2 mm Hg) for diastolic pressure. These differences were independent of age, sex, and adiposity. There was a significant correlation between the mean arterial pressures in the proteinuric patients and the higher mean blood pressure in their parents. High blood pressure in non-diabetic parents may be a marker of susceptibility to clinical nephropathy in their insulin dependent diabetic offspring.     

ACE activity during the hypotension produced by standardized aqueous extract of Cecropia glaziovii Sneth: A comparative study to captopril effects in rats

To evaluate the effect of the standardized aqueous extract (AE) of Cecropia glaziovii Sneth on the plasma angiotensin I converting enzyme (ACE-EC 3.4.15.1) activity, rats were treated with a single dose of AE (1 g/kg, p.o.) or repeatedly (0.5 g/kg/bid, p.o.) for 60 days. Captopril (50 mg/kg, p.o.) was used as positive control on the same animals. The effects on the blood pressure were recorded directly from the femoral artery (single dose), or indirectly by the tail cuff method (repeated doses) in conscious rats. The plasma ACE activity was determined spectrofluorimetrically using Hypuril-Hystidine-Leucine as substrate. The arterial blood pressure, heart rate and plasma ACE activity were not significantly modified within 24 h after a single dose administration of AE. Comparatively, blood pressure in captopril treated rats was reduced by 7-16% and heart rate was increased by 10-20% from 30 min to 24 h after drug administration. ACE activity after captopril presented a dual response: an immediate inhibition peaking at 30 min and a slow reversal to 32% up-regulation after 24 h. To correlate the drug effects upon repeated administration of either compound, normotensive rats were separated in three groups: animals with high ACE (48.8+/-2.6 nmol/min/ml), intermediate ACE (39.4+/-1.4 nmol/min/ml) and low ACE (23.5+/-0.6 nmol/min/ml) activity, significantly different among them. Repeated treatment with AE reduced the mean systolic blood pressure (121.7+/-0.5 mm Hg) by 20 mm Hg after 14 days. The hypotension was reversed upon washout 60 days afterwards. Likely, repeated captopril administration decreased blood pressure by 20 mm Hg throughout treatment in all groups. After 30 days treatment with AE (0.5 g/kg/bid, p.o.) the plasma ACE activity was unchanged in any experimental group. After captopril (50 mg/kg/bid, p.o.) administration the plasma ACE activity was inhibited by 50% within 1 h treatment but it was up-regulated by 120% after 12 h in all groups. It is concluded that the hypotension produced by prolonged treatment with AE of C. glaziovii is unrelated to ACE inhibition.     

Cardiac and hemodynamic responses to synthetic atrial natriuretic factor in rats

To determine the hemodynamic effects of a hypotensive dose of atrial natriuretic factor (ANF), a synthetic peptide containing 26 amino acids of endogenous rat ANF (Arg-Arg-Ser-Ser-Cys-Phe-Gly-Gly-Arg-Ile-Asp-Arg-Ile-Gly-Ala-Gln-Ser-Gly -Leu-Gly-Cys-Asn-Ser-Phe-Arg-Tyr-COOH) was studied in two groups of barbiturate anesthetized rats. In the first experiment, a 20-minute infusion of a hypotensive dose, 95 pmole/min i.v., of the synthetic ANF decreased mean arterial pressure (MAP) by 40 +/- 3 mm Hg from a baseline of 128 +/- 5 mm Hg, and cardiac output (CO) (microsphere method) by 7.8 +/- 1.8 ml/min/100 gm from a baseline of 23.5 +/- 1.3 ml/min/100 gm. Synthetic ANF did not significantly affect the total peripheral resistance (TPR) measured at the end of the 20-minute infusion. Sodium nitroprusside (SNP), infused at an equihypotensive dose of 20 micrograms/kg/min i.v., produced the same hemodynamic profile in seven other animals; in contrast, 0.3 mg/kg i.v. of hydralazine (n = 7) lowered MAP by 56 +/- 6 mm Hg and reduced TPR index by 3.0 +/- 0.6 mm Hg/ml/min/100 gm, but did not change CO. Other than an increase in coronary blood during SNF infusion, there were no significant changes in the distribution of cardiac output. Infusion of the saline vehicle had no significant effects on any of these parameters. The results of the second experiment in anesthetized rats confirmed that hypotensive doses of 40 and 100 pmole/kg/min i.v. lowered CO (dye dilution method) from a baseline of 33 +/- 6 to a minimum of 24 +/- 2 ml/min/100 gm (p less than 0.05) without affecting TPR. In addition, synthetic ANF did not significantly affect heart rate (HR) but it slightly reduced cardiac contractility (dp/dt50). These results suggest that the hypotensive dose of synthetic ANF reduced cardiac output, partially by diminishing stroke volume, and perhaps contractility.     

Short term effect of captopril on microalbuminuria induced by exercise in normotensive diabetics.

OBJECTIVE--To investigate whether captopril has any effect on microalbuminuria induced by exercise in normotensive diabetic patients with early stage nephropathy. DESIGN--Randomised, double blind, crossover trial. SETTING--Outpatient department. PATIENTS--22 diabetics with stage II nephropathy (urinary albumin excretion rate less than 20 micrograms/min; 15 with type I diabetes and seven with type II), 32 patients with stage III nephropathy (urinary albumin excretion rate 20-200 micrograms/min; 14 with type I diabetes and 18 with type II), and 10 normal subjects. INTERVENTIONS--Four exercise tests on a cycle ergometer: the first two under basal conditions and the third and fourth after subjects had received captopril (two 25 mg doses in 24 hours) or placebo (two tablets in 24 hours). END POINT--Exercised until 90% of maximum heart rate achieved. MEASUREMENTS AND MAIN RESULTS--Mean urinary excretion one hour after the first two exercise tests was 21 micrograms/min in normal subjects, 101 micrograms/min in diabetic patients with stage II nephropathy, and 333 micrograms/min in those with stage III nephropathy. Similar results were obtained after placebo. After captopril the urinary excretion rate one hour after exercise was significantly decreased in diabetics with stage II (36 micrograms/min) and stage III (107 micrograms/min) disease compared with placebo but not in normal subjects. Systolic and diastolic pressures were similar in the three groups after placebo and captopril had been given. CONCLUSIONS--Captopril significantly reduces microalbuminuria induced by exercise in normotensive diabetics without affecting systemic blood pressure. Captopril may reduce renal intracapillary pressure.     

Contrasting effects of enalapril and metoprolol on proteinuria in diabetic nephropathy.

OBJECTIVE--To assess whether angiotensin converting enzyme inhibition reduces proteinuria in diabetic nephropathy more than blood pressure reduction with other antihypertensive treatment. DESIGN--Prospective, open randomised study lasting eight weeks in patients with diabetic nephropathy. SETTING--Outpatient nephrology clinics. PATIENTS--40 Patients with type I diabetes and diabetic nephropathy with reduced renal function. INTERVENTION--Antihypertensive treatment with enalapril or metoprolol, usually combined with frusemide. MAIN OUTCOME MEASURES--Arterial blood pressure and urinary excretion of albumin and protein. RESULTS--Arterial blood pressure after eight weeks was 135/82 (SD 13/7) mm Hg in the group given enalapril and 136/86 (16/12) mm Hg in the group given metoprolol. Proteinuria and albuminuria were similar in both groups before randomisation. After eight weeks'' treatment, the geometric mean albumin excretion was 0.7 (95% confidence interval 0.5 to 1.2) g/24 h in the patients given enalapril and 1.6 (1.1 to 2.5) g/24 h in the patients given metoprolol (p less than 0.02). The proteinuria was 1.1 (0.7 to 1.7) and 2.4 (1.6 to 3.6) g/24 h respectively (p less than 0.02). CONCLUSIONS--Antihypertensive treatment with enalapril reduced proteinuria in patients with diabetic nephropathy more than an equally effective antihypertensive treatment with metoprolol. This points to a specific antiproteinuric effect of the angiotensin converting enzyme inhibitor independent of the effect on systemic blood pressure.     

Long term renal outcome of childhood haemolytic uraemic syndrome.

OBJECTIVE--To evaluate the long term outcome of renal function in infants and children after diarrhoea associated haemolytic uraemic syndrome. SETTING--The Hospital for Sick Children, Great Ormond Street, and the Royal Free Hospital, London. SUBJECTS--103 children with the syndrome who presented between 1966 and 1985; 88 attended for follow up investigations (40 male, 48 female) with a mean age 11.6 (range 5.2-22.6) years and a mean duration of follow up of 8.5 (range 5.1-21.3) years. MAIN OUTCOME MEASURES--Blood pressure, ratio of early morning urine albumin to creatinine concentration, glomerular filtration rate, and plasma renin activity. RESULTS--The mean (SD) systolic blood pressure standard deviation score was 0.38 (0.67) and diastolic blood pressure SD score was 0.10 (0.76). The geometric mean ratio of overnight urine albumin to creatinine concentration was 1.27 (range 0.03-48.2), significantly higher than the value observed in 77 normal children (0.32 (0.05-1.95), p less than 0.0001). Glomerular filtration rate estimated from the plasma clearance of chromium-51 EDTA was 95.1 (22.7) ml/min/1.73 m2 surface area, and 16 children had a rate of less than or equal to 80 ml/min/1.73 m2. Significant negative correlations were found between glomerular filtration rate and urinary albumin to creatinine ratio (r = -0.41, p less than 0.0001) and glomerular filtration rate and systolic blood pressure SD score (r = -0.48, p less than 0.0001). A significant positive correlation was found between urinary albumin to creatinine ratio and systolic blood pressure SD score (r = 0.25, p = 0.02). CONCLUSIONS--After an acute episode of diarrhoea associated haemolytic uraemic syndrome 31% (27/88) of children had an increased albumin excretion, 18% (16/88) had a reduced glomerular filtration rate and 10% (9/88) had both, in association with a higher systolic blood pressure, indicating considerable residual nephropathy in this group.     

Converting enzyme inhibition and kidney function in normotensive diabetic patients with persistent microalbuminuria.

The effects of a long term reduction in blood pressure on the kidney function of normotensive diabetic patients who had persistent microalbuminuria (30-300 mg albumin/24 hours) were studied in two groups of 10 such patients before and during six months of treatment with either 20 mg enalapril or placebo daily. Treatments were assigned randomly in a double blind fashion. Before treatment both groups had similar clinical characteristics, weight, diet, total glycosylated haemoglobin, median albumin excretion rate (enalapril group 124 mg/24 h, placebo group 81 mg/24 h), and mean arterial pressure (enalapril group 100 (SD 8) mm Hg, placebo group 99 (6) mm Hg). During treatment weight, urinary urea excretion, and total glycosylated haemoglobin remained unchanged. The mean arterial pressure decreased in the enalapril group but not in the placebo group (enalapril group 90 (10) mm Hg, placebo group 98 (8) mm Hg). The median albumin excretion rate also fell in the enalapril group but not in the placebo group (enalapril group 37 mg/24 h, placebo group 183 mg/24 h.) The glomerular filtration rate rose in the enalapril group from 130 (23) ml/min/1.73 m2 to 141 (24) ml/min/1.73 m2, and total renal resistances and fractional albumin clearance decreased while fractional albumin clearance increased in the placebo group. These results show that in patients who have diabetes but not hypertension a reduction in blood pressure by inhibition of converting enzyme for six months can reduce persistent microalbuminuria, perhaps by decreasing the intraglomerular pressure.     

Cardiovascular effects of training for a marathon run in unfit middle aged men.

The effects of a 30 week exercise programme on serum lipid values, blood pressure, and cardiac function were assessed in a group of sedentary men aged 35-50 training for their first marathon. Mean serum cholesterol concentration (n = 33) fell by 12% from 6.54 (SE 0.18) to 5.76 (0.15) mmol/l (mean fall 0.78 mmol/l; 95% confidence interval 0.52 to 1.04 mmol/l), serum triglyceride concentration (n = 33) by 22% from 1.56 (0.17) to 1.21 (0.09) mmol/l (mean fall 0.34 mmol/l; 95% confidence interval 0.12 to 0.56 mmol/l), and mean blood pressure (n = 27) by 10% from 102 (2) to 92 (2) mm Hg (mean fall 10 mm Hg; 95% confidence interval 7 to 13 mm Hg). These changes were not explained by changes in body composition. Peak exercise left ventricular end diastolic volume (n = 16) increased with training; as a result of this and an increased exercise left ventricular ejection fraction peak exercise cardiac output increased from 19.9 (1.2) to 23.1 (3.0) l/min (mean rise 3.2 l/min; 95% confidence interval 1.5 to 5.0 l/min). Maximum oxygen consumption increased from 33.9 (1.6) to 39.0 (1.3) ml/kg/min (mean rise 5.0 ml/kg/min; 95% confidence interval 1.8 to 8.2 ml/kg/min). This study showed favourable effects on coronary risk factors and cardiac function and supports the place of regular exercise in coronary prevention programmes.     

Effects of low dose versus conventional dose thiazide diuretic on insulin action in essential hypertension.

OBJECTIVE--To see whether low dose thiazide diuretics given to patients with essential hypertension might avoid the adverse metabolic consequences seen with conventional doses. DESIGN--Double blind randomised crossover study of two 12 week treatment periods with either low dose (1.25 mg) or conventional dose (5.0 mg) bendrofluazide given after a six week placebo run in period. SETTING--Outpatient clinics serving the greater Belfast area. SUBJECTS--16 white non-diabetic patients (9 male) under 65 with essential hypertension recruited from general practices within the greater Belfast area. MAIN OUTCOME MEASURES--Systolic and diastolic blood pressure and peripheral and hepatic insulin action. RESULTS--One man failed to complete the study. There were no differences between doses in their effects on systolic and diastolic blood pressure. Bendrofluazide 1.25 mg had substantially less effect on serum potassium concentration than the 5.0 mg dose. There were no intertreatment differences in fasting glucose, insulin, cholesterol, and triglyceride concentrations. Bendrofluazide 5.0 mg significantly increased postabsorptive endogenous glucose production compared with baseline (mean 10.9 (SD 1.2) v 10.0 (0.8) mumol/kg/min), whereas bendrofluazide 1.25 mg did not. Postabsorptive endogenous glucose production was significantly higher with bendrofluazide 5.0 mg compared with 1.25 mg (10.9 (1.2) v 9.9 (0.8) mumol/kg/min) but was suppressed to a similar extent after insulin (bendrofluazide 5.0 mg 2.8 (1.5) mumol/kg/min v bendrofluazide 1.25 mg 2.2 (1.5) mumol/kg/min). Exogenous glucose infusion rates required to maintain euglycaemia were not significantly different between doses and were similar to baseline. CONCLUSIONS--Bendrofluazide 1.25 mg is as effective as conventional doses but has less adverse metabolic effect. In contrast with conventional doses, low dose bendrofluazide has no effect on hepatic insulin action. There is no difference between low and conventional doses of bendrofluazide in their effect on peripheral insulin sensitivity.     

Effect of protein restriction in insulin dependent diabetics at risk of nephropathy.

Persistent proteinuria is strongly associated with increased mortality in insulin dependent diabetes, and risk of this condition can be predicted many years in advance by subclinical increases in albumin excretion rate (microalbuminuria). Eight normotensive insulin dependent diabetics with microalbuminuria who had overnight albumin excretion rates of between 15 and 200 micrograms/min underwent a three week randomised crossover study of their normal protein diet (median 92 (range 55-117) g/day) and a low protein diet (47 (38-57) g/day). Both diets were isoenergetic, and the low protein diet was supplemented with calcium and phosphate. Median overnight albumin excretion rate fell from 23.0 (15.0-170.1) micrograms/min during the normal diet to 15.4 (4.1-97.8) micrograms/min during the low protein diet. No consistent change was found in urinary excretion of beta 2 microglobulin during the two diets. The reduction in albumin excretion rate was accompanied by a significant fall in median glomerular filtration rate and fractional renal clearance of albumin. Kidney volume remained unchanged. There were no significant changes in glycaemic control or arterial blood pressure. In these few patients restriction of dietary protein had a beneficial effect on microalbuminuria, independent of changes in glucose concentrations and arterial blood pressure.     

Reference cardiopulmonary values in normal dogs

The purpose of this project was to collate canine cardiopulmonary measurements from published and unpublished studies in our laboratory in 97 instrumented, unsedated, normovolemic dogs. Body weight; arterial and mixed-venous pH and blood gases; mean arterial, pulmonary arterial, pulmonary artery occlusion, and central venous blood pressures; cardiac output; heart rate; hemoglobin; and core temperature were measured. Body surface area; bicarbonate concentration; base deficit; cardiac index; stroke volume index, systemic and pulmonary vascular resistance indices; left and right cardiac work indices; alveolar partial pressure of oxygen (pO2) ; alveolar-arterial pO2 gradient (A-apO2); arterial, mixed-venous, and pulmonary capillary oxygen content; oxygen delivery; oxygen consumption; oxygen extraction; venous admixture; arterial and mixed-venous blood CO2 contents; and CO2 production were calculated. In the 97 normal, resting dogs, mean arterial and mixed-venous pH were 7.38 and 7.36, respectively; partial pressure of carbon dioxide (pCO2), 40.2 and 44.1 mm Hg, respectively; base-deficit, -2.1 and -1.9 mEq/liter, respectively; pO2, 99.5 and 49.3 mm Hg, respectively; oxygen content, 17.8 and 14.2 ml/dl, respectively; A-a pO2 was 6.3 mm Hg; and venous admixture was 3.6%. The mean arterial blood pressure (ABPm), mean pulmonary arterial blood pressure (PAPm), pulmonary artery occlusion pressure (PAOP) were 103, 14, and 5.5 mm Hg, respectively; heart rate was 87 beats/min; cardiac index (CI) was 4.42 liters/min/m2; systemic and pulmonary vascular resistances were 1931 and 194 dynes.sec.cm-5, respectively; oxygen delivery, consumption and extraction were 790 and 164 ml/min/m2 and 20.5%, respectively. This study represents a collation of cardiopulmonary values obtained from a large number of dogs (97) from a single laboratory using the same measurement techniques.     

Renal functional effects of prostaglandin synthesis inhibition in patients with insulin-dependent diabetes mellitus of long duration without nephropathy.

The short-term effects of prostaglandin synthesis inhibition (PGSI; single dose 500 mg of naproxen) on renal function were studied in six women (age: 21.9 +/- 2.4 yrs) with insulin dependent diabetes mellitus (IDDM) of 14.3 +/- 2.8 yrs' duration, and in nine age- and sex-matched controls. The diabetics had no overt signs of nephropathy (Albustix neg, normal serum creatinine, and blood pressure). The clearance of inulin (CIn) and PAH; the filtration fraction (FF); and the excretion of Na, albumin and PGE2 were studied under water diuresis on two separate mornings, first without and then with PGSI. With PGSI all individuals has lower PGE2 excretion. The CIn and FF were significantly (p less than 0.05) higher in the diabetics than in the controls both without (129.4 +/- 23.9 ml/min/1.73 m 2 and 23.4 +/- 2.8% vs. 107.6 +/- 10.3 and 19.7 +/- 1.6) and with (133.7 +/- 29.4 and 22.6 +/- 2.1, vs. 106.8 +/- 10.3 and 20.1 +/- 1.5) PGSI. The diuresis and Na excretion were significantly lower with PGSI, than without, in both groups. The albumin excretion was significantly higher in the diabetics under both conditions (29.9 +/- 16.6 and 34.2 +/- 19.9 micrograms/min/100 ml GFR, vs. 14.5 +/- 10.6 and 12.9 +/- 8.3 in controls). We conclude that the hyperfiltration in this stage of IDDM does not appear to be PG dependent, and that PGSI does not give any immediate effects on the albumin excretion.