G. A. Sagnella

ANGIOTENSIN CONVERTING ENZYME INSERTION/DELETION POLYMORPHISM: ASSOCIATION WITH ETHNIC ORIGIN

Objective To determine the distribution of the insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene in several ethnic groups: Caucasian Europeans, Black Nigerians, Samoan Polynesians and Yanomami Indians. Results The ratio of the frequencies of the II, ID and DD genotypes were 1:2:1 in the Europeans, but there was a tendency towards a higher frequency of the D allele in the Nigerians. In contrast, the Samoans and the Yanomami Indians displayed a much higher frequency of the I allele than of the D allele. Conclusion The relationship between ACE genotype and disease in these latter groups is still not known, but the present results clearly suggest that ethnic origin should be carefully considered in the increasing number of studies on the association between I/D ACE genotype and disease aetiology.

The effect of sodium and angiotensin-converting enzyme inhibition on the classic circulating renin-angiotensin system in autosomal-dominant polycystic kidney disease patients.

Background It has been suggested that inappropriate stimulation of the renin–angiotensin system (RAS) is responsible for the increase in blood pressure that occurs in autosomal-dominant polycystic kidney disease (ADPKD) before the development of renal failure. However, the interpretation of previous studies in ADPKD patients is confounded by inadequate matching with control populations for blood pressure and renal function, or failure to control the sodium intake of participants. Methods A double-blind, placebo-controlled study of two different sodium intakes (350 and 50 mmol/day for 5 days) in a group of 11 hypertensive ADPKD patients and eight matched control subjects with essential hypertension. In addition, blood pressure and hormonal responses were measured after the administration of the angiotensin-converting enzyme inhibitor enalapril for 3 days. Results Blood pressure and hormonal responses of the RAS after a reduction in sodium intake and after the administration of enalapril were identical in ADPKD patients and controls. Conclusions Activation of the classic circulating RAS is no greater in hypertensive ADPKD patients than in individuals with essential hypertension.

Lack of Effect of Captopril on the Sodium Retention of the Nephrotic Syndrome

The mechanism of sodium retention in the nephrotic syndrome remains controversial, though the classic pathophysiological explanation is stimulation of the renin-angiotensin-aldosterone system. Recent evidence has shown that many patients with the nephrotic syndrome have a normal or low plasma renin activity suggesting that there might be an intrarenal cause for their sodium retention. We gave captopril, an oral angiotensin-converting enzyme inhibitor, during 10 separate episodes of sodium retention in nephrotic syndrome. There was evidence of stimulation of the renin system in 7 of these episodes. Despite a marked fall in plasma aldosterone, all patients continued to retain sodium and water and gain weight. This demonstrates that the sodium retention of nephrotic syndrome is not due to stimulation of the renin-angiotensin-aldosterone system, but must be due to some other mechanism, which is probably intrarenal.

Urinary calcium excretion, sodium intake and blood pressure in a multi-ethnic population : results of the Wandsworth Heart and Stroke Study

Background: Hypertension is associated with increased urinary calcium excretion (UCa). A high sodium intake increases both UCa and blood pressure (BP). However, it is not clear whether these effects are modified by gender or ethnic origin.Objectives: To examine the relationships between BP, urinary sodium (UNa), gender and ethnic origin with both daily and fasting UCa in a population-based study.Design and Methods: Out of 1577 individuals taking part in a cross-sectional survey, 743 were considered for the present analysis (407 women, 336 men) as they were all untreated, had provided a complete 24-h urine collection, and had all measurements of anthropometry, BP, UNa and UCa. They were 277 whites, 227 of black African origin and 239 South Asians. Comparisons were also carried out in the 690 participants who also provided 3-h fasting urine collections.Results: After adjustment for confounders including age, and gender, 24-h UCa was significantly and independently associated with ethnic origin, BP and UNa. Mean 24-h UCa was 4.62 (s.e. 0.11)u2009mmol/d in whites, 3.33 (0.12) in South Asians and 3.16 (0.13) in blacks (Pu2009<u20090.001). a 100u2009mmol higher UNa predicted a 1.04u2009mmol higher daily UCa (Pu2009<u20090.001), and a 20 mmu2009Hg higher systolic BP predicted a 0.28u2009mmol higher UCa. The slopes were not significantly different by ethnic group. The ethnic differences in UCa were present when fasting UCa was used instead (1.64 [0.05;[thinsp;μmol/min in whites, 1.08 [0.06] in South Asians and 1.13 [0.06] in blacks; Pu2009<u20090.001).Conclusions: These results indicate that BP, salt intake and ethnic origin are independent predictors of UCa in an unselected population. These relationships are unlikely to be the result of differences in Ca intake or intestinal Ca absorption as they are seen also after an overnight fast, suggesting that they may reflect differences in renal tubular handling. The estimated effects of either BP or sodium intake on UCa, sustained over many years, may be associated with significant effects on bone calcium content.

T594M and G442V polymorphisms of the sodium channel β subunit and hypertension in a black population

Polymorphisms of the epithelial sodium channel may raise blood pressure by increasing renal sodium reabsorption. This study examines frequency distributions and associations with hypertension of the T594M and of the G442V polymorphisms of the β subunit of the epithelial sodium channel in a population-based sample. We studied a stratified random sample of 459 subjects (279 women), aged 40–59 years, of black African origin from general practices’ lists within a defined area of South London. All were first generation immigrants. The polymorphic variants were detected using single strand conformational polymorphism technique (SSCP). The prevalence of hypertension (BP ⩾160 and/or 95 mmu2009Hg or on drug therapy) was 43%; of these, 76% were on drug therapy. The main analysis was carried out by three ordered blood pressure categories (I to III) according to increasing blood pressure and presence or absence of drug therapy. The frequency of the 594M variant (heterozygotes and homozygotes) was 4.6%; the frequency of the 442V variant was higher (27.0%). The frequency of the 594M variant increased with increasing blood pressure category (P = 0.05) and was more common in hypertensives than normotensives. By contrast the frequency of the 442V variant did not vary across increasing blood pressure categories (P = 0.62). No gender difference was observed. Adjustment for age, sex and body mass index did not alter these findings. These results suggest that the 594M variant may contribute to high blood pressure in black people of African origin whereas the G442V polymorphism is unlikely to influence blood pressure in this population.

Concentrations of N-terminal ProANP in human plasma: evidence for ProANP (1-98) as the circulating form.

Plasma levels of immunoreactive N-terminal ProANP have been measured in plasma from 19 healthy individuals, 15 patients with essential hypertension, 8 cardiac transplant recipients and 8 patients with chronic renal failure using two separate radioimmunoassays (RIAs), one directed against ProANP (1-30) and the other against ProANP (79-98). The mean concentrations of ProANP (1-30) and ProANP (79-98) were elevated in these groups of patients. There were positive correlations between levels of ProANP (1-30) and ProANP (79-98), with a correlation coefficient of 0.97 (P less than 0.001, n = 50). In healthy individuals a 2-1 (isotonic) saline infusion significantly increased both ANP (99-126) (P less than 0.05, n = 8) and N-terminal ProANP (P less than 0.005, n = 8) within 15 min of the end of the infusion. Plasma N-terminal ProANP levels were still significantly elevated after 75 min (P less than 0.05, n = 8) and 225 min (P less than 0.05, n = 8), by contrast ANP (99-126) had returned to basal values. Gel filtration of plasma extracted on Sep-Pak C-18 from normal individuals and patients gave a single immunoreactive peak for N-terminal ProANP as measured by both N-terminal ProANP assays, indicating an absence of small N-terminal fragments and the presence of a single high molecular weight form. These studies demonstrate that the major circulating N-terminal ANP in man is probably ProANP (1-98) and that it is cosecreted with ANP (99-126).

Lack of Association of ACE/Angiotensinogen Genotype with Renal Function in Autosomal Dominant Polycystic Kidney Disease

ACE polymorphisms have recently been shown to associate with worse renal and or cardiovascular outcome, with the D allele widely reported as a risk factor for cardiovascular disease. In autosomal dominant polycystic kidney disease (ADPKD), there are conflicting reports of an association between ACE polymorphisms and disease phenotype. There are no previous reports of any association between angiotensinogen polymorphisms and clinical phenotype in ADPKD. We examined the ACE I/D and angiotensinogen M235T polymorphisms in 176 patients with ADPKD. Patients are categorized into three groups according to the reason for initial investigation. Clinical history and examination findings were recorded at the time of first referral. A cohort of 17 patients had progressive renal impairment observed after 3 or more years of follow-up. Reciprocal creatinine against time was plotted in this group. From the patient population of 176, a total of 33 patients reached end-stage renal failure (ESRF) or a serum creatinine greater than 500 microm/liter. ACE genotype and M235T polymorphism frequencies were compared across groups. Serum creatinine and presence of hypertension and onset of ESRF were taken as outcome variables; age and source of referral were taken as confounding variables. There was no association of any genotype or allele with either creatinine, inverse creatinine, hypertension, or age at end-stage renal failure. These findings do not support the proposition that ACE genotype or angiotensinogen polymorphisms are associated with a worse prognosis in patients with ADPKD.

Long-Term Reduction in Sodium Balance: Possible Additional Mechanism Whereby Nifedipine Lowers Blood Pressure

OBJECTIVEnTo assess the changes in sodium excretion and sodium balance after withdrawal of long term nifedipine.nnnDESIGNnSingle blind, placebo controlled study in patients receiving fixed sodium and potassium intakes.nnnSETTINGnBlood pressure unit of a teaching hospital in south London.nnnPATIENTSnEight patients with mild to moderate uncomplicated essential hypertension who had been taking nifedipine 20 mg twice daily for at least six weeks.nnnINTERVENTIONSnWithdrawal of nifedipine and replacement with matching placebo for one week.nnnMAIN OUTCOME MEASURESnUrinary sodium excretion and cumulative sodium balance, body weight, plasma atrial natriuretic peptide concentrations, plasma renin activity and aldosterone concentrations, and blood pressure.nnnRESULTSnDuring nifedipine withdrawal there was a significant reduction in urinary sodium excretion (day 1: -62.7 mmol/24 h; 95% confidence interval -90.3 to -35.0) and each patient retained a mean of 146 (SEM 26) mmol sodium over the week of replacement with placebo. Body weight and plasma atrial natriuretic peptide concentrations increased during the placebo period and seemed to be associated with the amount of sodium retained. Systolic blood pressure rose from 157 (9) to 165 (9) mmHg (95% confidence interval of difference -7.1 to 22.1) when nifedipine was replaced with matching placebo, and the rise seemed to be related to the amount of sodium that was retained.nnnCONCLUSIONSnNifedipine causes a long term reduction in sodium balance in patients with essential hypertension. This long term effect may contribute to the mechanism whereby nifedipine lowers blood pressure.

Atrial natriuretic peptide in human plasma — comparison of radioreceptor versus radioimmunoassay

A sensitive and specific procedure for the measurement of atrial natriuretic peptide (ANP) in human plasma by radioreceptor assay, using bovine adrenal membranes treated with Triton-X-100, is described. Plasma levels (mean +/- SEM) of ANP in healthy subjects on a normal sodium intake were 8.4 +/- 1.4 pg/ml and could be modified by changes in sodium intake with increases in sodium intake being associated with higher levels. Mean plasma ANP was approximately 2-fold higher in patients with essential hypertension and 4-fold higher in patients with cardiac or renal disease. The values obtained were comparable in magnitude to those obtained by radioimmunoassay and there was a strong correlation (r = 0.94; p less than 0.001) between the values obtained by radioimmuno- and radioreceptor-assay. These results suggest that circulating ANP corresponds to the biologically active peptide and point to an important role of the atrial peptides in the control of sodium balance.

Hormonal and renal responses to neutral endopeptidase inhibition in normal humans on a low and on a high sodium intake.

Abstract. Hormonal and renal effects of candoxatril, a neutral endopeptidase 24.11 inhibitor, were investigated in eight subjects equilibrated on a low sodium diet (10 mmol sodium per day) and a high sodium (350 mmol per day) diet. After candoxatril treatment, plasma ANP increased to a maximum at 2–4 h and declined to baseline within 24 h. The increases were relatively greater on the high sodium diet, which was also associated with increases in urinary sodium, with highest values at 4h. On the low sodium diet, the magnitude of the changes was significantly lower (24 h cumulative sodium excretion was 11.4± 5.5 mmol on the low sodium diet and 73.1± 25.6 mmol on the high sodium diet; P < 0.01). There were no significant effects on urinary potassium excretion, creatinine clearance or haematocrit. After candoxatril treatment there were reductions in PRA, especially on the low sodium diet. On either diet there were no effects on systemic blood pressure. These results demonstrate that dietary sodium intake is an important determinant of the renal and hormonal responses to neutral endopeptidase inhibition.