J. Giese

Measurement of angiotensin II in human plasma: technical modifications and practical experience.

This paper presents our experience in measurement of plasma angiotensin II concentration according to the method described by Düsterdieck, G. and McElwee, G. (1971) Eur. J. Clin. Invest. 2, 32-38. Certain technical modifications of the procedure have been worked out. For each individual plasma sample, the recovery across extraction and elution steps is determined by addition of radio-iodinated angiotensin II. A time-saving recycling elution procedure is described. Evidence for the clinical applicability of the modified method is presented.

On the pathogenesis of arterial blood pressure elevation early in the course of diabetic nephropathy

We measured plasma- and extracellular fluid volume (125I-albumin, 51Cr-EDTA), plasma concentrations of renin, angiotensin I and II, aldosterone and atrial natriuretic peptide by radio-immunoassays in insulin-dependent diabetic (IDDM) patients with (n=28) and without (n=11) nephropathy and in 14 normal control subjects matched for sex and age. Glomerular filtration rate (GFR) (ml/min/1.73 m2, single intravenous bolus 51Cr-EDTA technique) was within normal range in all nephropathic patients; 107 (range 78-134). Mean arterial blood pressure (mmHg) was elevated 102 +/- 13 (+/- S.D.) compared to the diabetic and normal control group, 92 +/- 8 and 87 +/- 5, respectively (p less than 0.01). Plasma volume was identical in all three groups while extracellular volume (1/1.73 m2) was expanded in nephropathic patients, 14.5 +/- 1.5 vs 13.1 +/- 0.9 and 12.4 +/- 1.3 in the diabetic and non-diabetic control groups, respectively (p less than 0.05). A significant correlation between extracellular fluid volume and mean arterial blood pressure was found (n=53, r=0.49, p less than 0.001). Active renin was significantly increased in patients with diabetic nephropathy compared with the normal control subjects, while all the remaining hormones were about the same in the three groups. Our study suggests that fluid retention plays a dominant role in the initiation and maintenance of arterial blood pressure elevation early in the course of diabetic nephropathy.

Normal renal tubular response to changes of sodium intake in hypertensive man.

In a comparative study the influence of changes in dietary sodium intake on blood pressure, renal function, extracellular fluid volume, the renin-angiotensin-aldosterone system and plasma concentrations of arginine vasopressin, atrial natriuretic factor and cyclic guanosine monophosphate (GMP) was investigated in 12 patients with essential hypertension and in 10 normotensive controls. The subjects were studied after 4 days on a low (50 mmol/day), medium (180 mmol/day) or high (380 mmol/day) sodium intake. Renal sodium handling was assessed by simultaneous measurements of 51Cr-ethylenediaminetetraacetic acid (EDTA), lithium and sodium clearances. Identical values for the extracellular fluid volume, glomerular filtration rate and proximal and distal tubular resorption rates of sodium and water were found in the hypertensive patients and the controls at all three levels of sodium intake. In both groups, raising the sodium intake from low to high significantly increased 51Cr-EDTA and lithium clearance (an indirect measure of end-proximal fluid delivery), with intermediate values for the medium-sodium diet. The estimated values of fractional proximal and distal sodium resorption decreased when sodium intake was raised; the absolute proximal sodium resorption rate did not change, whereas the absolute distal sodium resorption rate as well as the extracellular fluid volume and sodium clearance increased. Blood pressure and the heart rate were unaffected by sodium intake. In both hypertensives and controls, plasma concentrations of active renin, angiotensin II and aldosterone decreased with increasing sodium intake, arginine vasopressin did not change, and atrial natriuretic factor and cyclic GMP increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of insulin on renal haemodynamics and sodium handling in normal subjects

Diabetic patients treated with insulin injected subcutaneously are characterized by peripheral hyperinsulinaemia and an increased mass of total body exchangeable sodium. We hypothesized that this may cause, at least in part, the glomerular hyperfiltration seen in the diabetic state. Six normal subjects were studied on 2 days in random order. Day A: Basal state for 40 min, hyperinsulinaemic euglycaemic clamp for 1 h (insulin infusion rate 2 mU kg-1 min-1 and 50% glucose infusion) and hyperinsulinaemic euglycaemic clamp combined with volume expansion (2 1 isotonic sodium chloride) for 2 h. Day B: as day A, but without insulin and glucose infusion. During combined volume expansion and hyperinsulinaemia an increase in glomerular filtration rate (GFR) (128 +/- 6 vs 117 +/- 8 ml min-1 1.73 m-2, p less than 0.01) and lithium clearance (CLi) (50 +/- 4 vs 33 +/- 5 ml min-1 1.73 m-2, p less than 0.01) was observed compared with basal conditions. GFR and CLi were unchanged during day B. Insulin infusion reduced renal sodium excretion. Absolute proximal tubular reabsorption was unchanged on both days. Insulin infusion without volume expansion caused a decrease of 24% in the fractional distal sodium excretion. Superimposed volume expansion and the concomitant increase in GFR and CLi was accompanied by a subsequent enhanced fractional distal sodium excretion of 27%. The changes in plasma concentrations of aldosterone, renin, angiotensin II, atrial natriuretic peptide and catecholamines did not explain the differences in GFR. An increase in GFR of 10%, comparable with that observed in diabetic patients, was induced by combined hyperinsulinaemia and volume expansion in euglycaemic normal subjects. The enhanced GFR is probably a compensatory response to the sodium retention induced by the action of insulin on the distal tubules.

Glomerular Filtration Rate Measurement and 131I-Hippuran Renography Before Unilateral Nephrectomy

Plasma creatinine, IVP, GFR, and renography were analysed in 53 candidates for unilateral nephrectomy. Renography was used to determine how the function was distributed between the two kidneys. Twelve of 29 patients with normal plasma creatinine had decreased GFR. One-third of 74 individual kidneys showing normal function at IVP had GFR values below 30 ml/min. There was poor agreement between the radiological and renographic estimation of function distribution. In 6 of 14 patients who were not nephrectomized mainly because the other kidney had a reduced function, the kidney scheduled for removal had the major function. GFR and renography were particularly informative in cases with elevated plasma creatinine and normal IVP.

Diurnal monitoring of blood pressure and the renin-angiotensin system in hypertensive patients on long-term angiotensin converting enzyme inhibition

The temporal blood pressure course and the diurnal profile of the renin-angiotensin system were examined in 13 patients with essential hypertension receiving hydrochlorothiazide and enalapril once daily. Blood samples were taken and blood pressure was measured before the habitual morning dose of hydrochlorothiazide and enalapril (at 8.00 a.m.) and at seven time points over the next 24 h. During the period of maximal effect of enalapril (from 11.00 a.m. to 2.00 p.m.), the increase in plasma renin concentration ranged from no change to an 800% increase. A negative correlation was observed between an increase in plasma renin and a decrease in immunoreactive plasma angiotensin II concentration (Spearman rank-order correlation coefficient = 0.83). Notably, the greatest changes in plasma renin and angiotensin II concentrations after enalapril were seen in those patients whose blood pressure fell most during the day. We conclude that hypertensive patients on long-term therapy with enalapril once daily vary widely in their between-dose biochemical response to the drug, and that there is a significant association between the responsiveness of the plasma renin-angiotensin system and the effect on 24 h blood pressure.

Unchanged lithium clearance during acute amiloride treatment in sodium-depleted man

To evaluate the validity of the lithium clearance method as a marker of overall proximal tubular fluid delivery in moderately sodium-depleted humans, the effects of a single dose of 10 mg amiloride on lithium clearance and glomerular filtration-rate were studied in normal volunteers maintained on a sodium diet of 50 mmol/day. Amiloride caused no changes of the glomerular filtration-rate or of lithium clearance. The effects of amiloride on tubular sodium, potassium and water handling were in accordance with a distal tubular action of amiloride. The results suggest that significant distal lithium reabsorption does not occur in measurable amounts during moderate sodium depletion in humans. The lithium clearance method may, therefore, be used to assess proximal fluid delivery in man when dietary sodium intake is as low as in the present study.

Changed cyclic guanosine monophosphate atrial natriuretic factor relationship in hypertensive man.

Plasma concentrations of atrial natriuretic factor (ANF) and cyclic guanosine monophosphate (cGMP) were measured in 10 patients with essential hypertension and 10 normotensive controls on the fifth day of a low (50 mmol/day), a medium (180 mmol/day) and a high (380 mmol/day) dietary sodium intake. Plasma ANF and cGMP concentrations were less on the low than on the high sodium intake. Values for ANF on the medium sodium intake were intermediate. In normotensive subjects cGMP concentrations did not differ significantly on the low and the medium sodium intake. As compared with the controls plasma concentrations of cGMP were significantly increased in hypertensive patients on all three levels of sodium intake, while ANF concentrations were identical in the two groups. Since cGMP is a second messenger to ANF the data suggest an increased cellular response to ANF in patients with essential hypertension.

The renin-angiotensin-aldosterone system in normal 85-year-old people.

Active and total plasma renin concentration, as well as plasma angiotensin II, aldosterone and renin substrate concentrations were measured in venous blood samples from 17 normal 85-year-old people at rest. No discernible sex-related differences were seen. Active plasma renin and plasma aldosterone concentrations were significantly lower in the old people compared to a group of normal 40-year-old people. Plasma angiotensin II concentration showed no decrease with increasing age. Active plasma renin concentration constituted approximately 20% of total plasma renin concentration, with a significant correlation between the two renin moieties. The values for plasma renin substrate concentration are similar to those reported for younger age groups. The lack of standardization of methods severely hampers inter-laboratory comparisons of both active plasma renin and total plasma renin concentrations.

The renin–angiotensin system and kidney function during initial insulin treatment in diabetic man

Glomerular filtration rate, renal plasma flow, active renin, renin substrate and angiotensin II concentrations were monitored in nine consecutive patients (3 women, 6 men, mean age 31 years) with newly diagnosed, insulin-dependent diabetes. Measurements were performed before and during the initial eight days of intensive insulin treatment. All patients had ketonuria but none had acidosis. Glomerular filtration rate and renal plasma flow were significantly increased at the time of diagnosis as compared with values from normal subjects. A highly significant decline in glomerular filtration rate from 160 +/- 9 (SEM) to 133 +/- 5 ml/min x 1.73 m2 was seen during the initial eight days of treatment (p less than 0.01). Likewise renal plasma flow declined from 601 +/- 33 to 558 +/- 35 ml/min x 1.73 m2 (p less than 0.05). Plasma concentration of renin was within normal range at day 0, and remained unchanged during the eight day study. Also renin substrate concentration was normal and unchanged during the observation period, whereas angiotensin II concentration was low and unchanged. Our study does not support the suggestion that the renin-angiotensin system contributes to the hyperfiltration characteristically found in newly diagnosed insulin-dependent diabetic patients.