The renal epithelial sodium channel: genetic heterogeneity and implications for the treatment of high blood pressure.

The renal epithelial sodium channel (ENaC) is of fundamental importance in the control of sodium reabsorption through the distal nephron. ENaC is an important component in the overall control of sodium balance, blood volume and thereby of blood pressure. This is clearly demonstrated by rare genetic disorders of sodium channel activity (Liddle's Syndrome and Pseudohypoaldosteronism type 1 associated with contrasting effects on blood pressure). Subtle dysregulation of ENaC however may also be important in essential hypertension - a common condition and a major cause of cardiovascular morbidity and mortality. The epithelial sodium channel is formed from three partly homologous subunits. In this review we deals firstly with current views of structural and functional features of the renal epithelial sodium channel with particular emphasis on mechanisms and processes involved in the control of sodium channel activity at the biochemical and cellular levels. We then focus on genetic aspects with reference to the significance of genetic variation in the sodium channel genes in relation to blood pressure. In particular, we review recent investigations on the potential clinical significance of mutations within the genes encoding ENaC subunits in individuals with high blood pressure. Lastly, we also examine the potential value of pharmacological targeting of the renal epithelial sodium channel with the sodium channel inhibitor amiloride for the treatment of hypertension.

Effect of salt intake on renal excretion of water in humans.

Two studies were performed to determine the quantitative relationship between salt intake and urinary volume (U(v)) in humans. In study 1, 104 untreated hypertensives were studied on the fifth day of a high- and a low-salt diet. The 24-hour U(v) was 2.2 L (urinary sodium [U(Na)] 277 mmol) on the high-salt diet and decreased to 1.3 L (P<0.001) (U(Na) 20.8 mmol) on the low-salt diet. The reduction in 24-hour U(v) was significantly related to the decrease in 24-hour U(Na) (P<0.001) and predicts that a 100-mmol/d reduction in salt intake would decrease 24-hour U(v) by 367 mL. In study 2, 634 untreated hypertensives were studied on their usual diet. There was a significant relationship between 24-hour U(v) and U(Na) (P<0.001). This predicts that a 100-mmol/d reduction in salt intake would decrease 24-hour U(v) by 454 mL. The International Study of Salt and Blood Pressure (INTERSALT) of 1731 hypertensives and 8343 normotensives on their usual diet showed that 24-hour U(v) was significantly related to U(Na) (P<0.001) and predicted that a 100-mmol/d reduction in salt intake would decrease 24-hour U(v) by 379 and 399 mL in hypertensives and normotensives, respectively. These findings document the important effect that salt intake has on U(v). The recommended reduction in salt intake in the general population is from 10 to 5 g/d. This would reduce fluid intake in the population by approximately 350 mL/d per person. This would have a large impact on the sales of soft drinks, mineral water, and beer.

In-vivo intracellular pH at rest and during exercise in patients with essential hypertension.

BACKGROUND: Several studies in isolated cells have reported that intracellular pH (pHi) in individuals with essential hypertension may be relatively alkaline compared to normotensive individuals. Such an abnormality of pHi in hypertension would be consistent with enhanced sodium-hydrogen exchanger activity and may provide potential mechanisms by which hypertension and its complications could develop. OBJECTIVES: To determine in-vivo intracellular pH of skeletal muscle at rest and during recovery from exercise-induced acidosis in hypertensive and normotensive subjects. METHODS: Using 31-phosphorus magnetic resonance spectroscopy, pHi of the dominant flexor digitorum superficialis was measured in 20 Caucasian subjects (14 male) with essential hypertension and 20 normotensive controls matched for gender, age, race and body mass index. Measurements were made at rest and during the exercise and recovery periods of a stepped incremental maximal exercise protocol. The rate of pHi recovery from exercise-induced acidosis was calculated by linear regression over the first 210 s of recovery from the pHi time plots of respective subjects. RESULTS: Mean resting pHi in the hypertensive (7.05 +/- 0.04) and normotensive groups (7.06 +/- 0.04) were not significantly different. There was a significant effect of gender on pHi: mean pHi was 7.07 +/- 0.03 in males and 7.02 +/- 0.03 in females, respectively (P < 0.0005). The mean intracellular pH achieved by exercise was 6.74 +/- 0.31 in hypertensive individuals and not significantly different in normotensive individuals (6.68 +/- 0.19; P = 0.4). The mean rate of pHi recovery in the hypertensives was 0.08 +/- 0.03 pH units/min and not significantly different in normotensives (0.08 +/- 0.02; P = 0.4). CONCLUSIONS: These results contrast with previously documented abnormalities in the control of pHi in hypertension and demonstrate the absence of major in-vivo disturbances of pHi in skeletal muscle, both at rest and during recovery from exercise-induced acidosis, in essential hypertension. Therefore, it is possible that previously documented abnormalities of pHi and activity of the exchanger may be either specific to cell type or not present under in-vivo conditions.

Platelet sodium-hydrogen exchanger activity and left ventricular mass.

INTRODUCTION: The sodium-hydrogen exchanger (NHE) is integral to the processes that facilitate cell growth and may contribute to the development of left ventricular hypertrophy. The aim of this study was to examine the relationship between platelet sodium-hydrogen exchanger activity and left ventricular mass index (LVMI). METHODS: Twenty male untreated Caucasians (mean age +/- s.d.: 48 +/- 13; body mass index: 29 +/- 4 kg/m(2)) with a wide range of blood pressures were studied (mean BP: 152 +/- 22/93 +/- 15 mm Hg; range: 115-190/61-117 mm Hg). Sodium-hydrogen exchanger activity was determined as the rate of sodium-dependent recovery of intracellular pH in isolated platelets loaded with BCECF and acidified to pH 6.25 using nigericin. LVMI was calculated from measurements made by M-mode echocardiography. Associations between continuous variables were examined using parametric tests. RESULTS: The mean rate of pHi recovery was 0.15 +/- 0.03 dpHi/s (range: 0.09-0.21). Mean LVMI was 120 +/- 32 g/m(2) (range: 56-178) and was not significantly correlated with either systolic (r = 0.39, P = 0.09) or diastolic blood pressure (r = 0.27, P = 0.3). Platelet NHE activity was not significantly correlated with LVMI (r = 0.06; P = 0.8). Platelet NHE activity was not significantly different between subjects with (n = 7 with LVMI >131 g/m(2)) and without left ventricular hypertrophy (n = 13). CONCLUSIONS: The results of this study show that platelet NHE activity is not significantly correlated with LVMI. These data contrast with previously described correlations of LVMI with exchanger activity measured in leucocytes and erythrocytes; and indicate that the relationship between LVMI and exchanger activity may be specific to the cell type in which exchanger activity is measured.

Atrial natriuretic peptide mimetics and vasopeptidase inhibitors.

There is now substantial evidence supporting a role of the natriuretic peptides as a major defence mechanism against excess salt and water retention and high blood pressure. Because of this there has been considerable interest in the therapeutic potential of the natriuretic peptide system. Several approaches have been explored including the use of native peptides, the development of natriuretic peptides mimetics and targetting of endogenous clearance of natriuretic peptides. While ANP and BNP administration may be valuable in some circumstances, however, the limitations of the use of peptides especially for long-term treatment are well apparent. In view of this, considerable effort has been devoted to the development of orally active agents to enhance endogenous natriuretic peptides through inhibition of breakdown by neutral endopeptidase. This research has now led to the vasopeptidase inhibitors - dual inhibitors of both endopeptidase and angiotensin converting enzyme. These agents clearly provide a novel approach to enhance endogenous natriuretic peptide function on a background of reduced angiotensin II activity and may lead to an important advance in the treatment of hypertension and of conditions associated with overt salt and water overload.

T594M and G442V polymorphisms of the sodium channel beta 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 beta 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 > or =160 and/or 95 mm Hg 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.

Ethnic differences in erythrocyte membrane fluidity and the association with serum triacylglycerols.

The objectives of this study were to determine whether there are differences between black and white individuals with regard to the membrane fluidity of isolated erythrocytes, and/or in the relationships between membrane fluidity, gender and circulating lipids. Fluorescent polarization anisotropy, as an index of membrane fluidity, was determined using the fluorescent probe 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene (TMA-DPH) in 52 black and 52 white individuals, of whom 39 pairs were matched for age, sex and blood pressure. In the 39 matched pairs, the TMA-DPH anisotropy was significantly higher in the black (0.262+/-0.007) compared with the white (0.258+/-0.005) subjects (P<0.005). There was also a significant difference in serum lipids. Gender differences in TMA-DPH anisotropy were observed in the white but not in the black individuals. The associations between membrane fluidity and serum lipids were examined in the total group, separated according to ethnic group. Although the associations were in the same direction in both groups, the association was only significant in the white subjects (r= - 0.42; P<0.02). The ethnic difference in membrane fluidity was abolished when adjusting for serum triacylglycerols. In conclusion, ethnic differences in erythrocyte membrane fluidity, as determined by the use of TMA-DPH anisotropy, appear to be the result of ethnic differences in the level of serum triacylglycerols.

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) mmol/d in whites, 3.33 (0.12) in South Asians and 3.16 (0.13) in blacks (P < 0.001). a 100 mmol higher UNa predicted a 1.04 mmol higher daily UCa (P < 0.001), and a 20 mm Hg higher systolic BP predicted a 0.28 mmol 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] micromol/min in whites, 1.08 [0.06] in South Asians and 1.13 [0.06] in blacks; P < 0.001). 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.

Ethnic differences in fibrinogen levels: the role of environmental factors and the beta-fibrinogen gene.

Fibrinogen is a cardiovascular risk factor, but little is known about levels in ethnic groups that differ in their cardiovascular risk. Fibrinogen was measured in 479 Black individuals, 459 South Asian Indians, and 453 Whites aged 40-59 years living in south London, England, from March 1994 to July 1996. Genotype was determined at two sites in the promoter of the beta-fibrinogen gene (G-455-->A and C-148-->T). Plasma fibrinogen levels were lower in Blacks than in Whites by 0.22 g/liter (95% confidence interval (CI): 0.08, 0.36) in men and 0.11 g/liter (95% CI: -0.01, 0.23) in women. These differences were not explained by measured environmental variables, including smoking, or by genotypes. The fibrinogen levels of South Asians were not consistently different from those of WHITES: The A-455 and T-148 alleles were less common in Blacks than in either Whites or South ASIANS: In Whites and South Asians, but not in Blacks, there was complete allelic association between the two variants. In Blacks, the T allele rather than the A allele was associated with higher fibrinogen levels. The average fibrinogen-raising effect of the T-148 allele across all ethnic groups was 0.14 g/liter (95% CI: 0.02, 0.26 g/liter) in women and 0.15 g/liter (95% CI: 0.03, 0.27 g/liter) in men. Low fibrinogen levels in Blacks may partly explain their lower risk of ischemic heart disease in the United KINGDOM:

Variable effects of the APOC3-482C > T variant on insulin, glucose and triglyceride concentrations in different ethnic groups.

AIMS/HYPOTHESIS: The apolipoprotein C3-482C> T variant modulates insulin and glucose concentrations after an oral glucose tolerance test (OGTT) in young healthy white men. We evaluated the effect of this variant in different ethnic groups with different rates of Type II (non-insulin-dependent) diabetes mellitus and coronary heart disease. METHODS: We investigated the -482C > T in a population-based cross-sectional study of white subjects (n = 462), South Asians (n = 442) and subjects of West African and Afro-Caribbean origin (n = 462), whose OGTT and fasting plasma triglyceride concentrations had been measured. RESULTS: The -482T allele frequency differed between the three groups: 0.25 (95 % CI 0.22-0.28) in white subjects, 0.44 (0.41-0.47) in South Asians and 0.71 (0.68-0.74) in black subjects (p < 0.0001). A positive association was found between body mass index and genotype in black women (p = 0.009) and in black men (p = 0.056) but not in white subjects or South Asians. Associations between -482C > T and fasting insulin were found in white subjects, where -482T allele carriers had higher concentrations (adjusted for age and sex, p = 0.007, also including smoking and body mass index, p = 0.038). Higher triglyceride concentrations (p = 0.004 and p = 0.007 in the two models) but not glucose concentrations were also associated with -482C > T. In black subjects, decreased fasting insulin (p = 0.04) and fasting glucose (p = 0.004) were associated with -482C > T. No relation was observed between genotype and any post-load measured. CONCLUSIONS/INTERPRETATION. Allele frequencies of the -482C > T and associations with insulin, glucose and triglyceride concentrations vary considerably among ethnic groups. Although the results are consistent among white subjects across different studies, the associations among black subjects and South Asians differ.

Why is plasma renin activity lower in populations of African origin?

Plasma renin activity is significantly lower in black people compared with whites independent of age and blood pressure status. The lower PRA appears to be due to a reduction in the rate of secretion of renin but the exact mechanistic events underlying such differences in renin release between blacks and whites are still not fully understood. Nevertheless, given the paramount importance of the renin-angiotensin system in the control of sodium balance, a most likely explanation is that the lower renin is a consequence of differences in renal sodium handling between blacks and whites. The lower PRA does not reflect differences in dietary sodium intake but the evidence available suggests that the low PRA could be part of the corrective mechanisms designed to maintain sodium balance in the presence of an increased tendency for sodium retention in black people. While it is possible that several factors may contribute to the reduced PRA, more recent investigation at the molecular level suggests that the lower PRA may arise from gene variation in the renal epithelial sodium channel. The functional significance of the lower PRA in relation to the different pattern of cardiovascular and renal disease between blacks and whites remains unclear. Moreover, direct investigations of pre-treatment renin status in hypertensive blacks in relation to blood pressure response have demonstrated that the pre-treatment PRA is not a good index of subsequent blood pressure response to pharmacological treatment. Nevertheless, the blood pressure reduction to short term sodium restriction is greater in blacks compared with whites and, in the black subjects, the greater reduction in blood pressure to sodium restriction appears to be related, at least in part, to the decreased responsiveness of the renin-angiotensin system. Journal of Human Hypertension (2001) 15, 17-25

Urinary acid-base excretion in normotensives and hypertensives of african origin.

Abnormalities in acid-base regulation have previously been reported both in hypertensive humans and animals and a link between abnormalities in renal sodium handling and acid excretion may be particularly important in black hypertensives. The objectives of this study were to compare indices of urinary acid excretion (urinary pH, ammonium and titratable acid excretion) between normotensives and hypertensive people of African origin. Measurements were carried out in 86 black individuals of African origin in a case-control design (19 normotensive; 67 hypertensive). Of these, 17 normotensive and 17 patients with essential hypertension were matched for age, sex and weight. Group comparisons were carried out by unpaired t-tests or two-way analysis of variance and group values are given as means +/- s.d. Urinary pH was significantly higher in the hypertensives both in the unmatched groups and in the matched groups. In the 17 matched pairs: urinary pH in the hypertensive individuals was 6.36 +/- 0.54 and 5.84 +/- 0. 53 in the normotensives, respectively; P = 0.007. Additionally, urinary titratable acidity was significantly lower in the hypertensives than in the normotensives (25.4 +/- 13.7 vs16.7 +/- 10. 7 mmol/24 h; P = 0.047) but there were no significant differences in urinary ammonium excretion. The mechanisms for the apparent reduction in acid excretion in the hypertensives is not clear but these results highlight the possibility that hypertension in blacks is associated with abnormalities of renal sodium and hydrogen exchange with compensatory increases in renal ammonium production.

Frequency and allelic association of common variants in the lipoprotein lipase gene in different ethnic groups: the Wandsworth Heart and Stroke Study.

The lower serum triglyceride (Tg), higher high density cholesterol (HDL-C) levels and low coronary heart disease (CHD) mortality in black populations, contrast with that in whites. By comparison, South Asian populations display a higher mortality from CHD associated with increased Tg and low HDL-C levels. Lipoprotein lipase (LPL) plays a major role in Tg metabolism. To determine if variation in the LPL gene contributes to the differences in lipid levels, we studied the frequencies and allelic associations of five common variants in the lipoprotein lipase (LPL) gene (-93T/G, D9N, N291S, S447X, and the HinddIII RFLP in intron 8) with serum Tg and HDL-cholesterol concentrations in population samples of middle-aged men and women of whites, South Asians, and blacks of African origin co-resident in South London. Significantly higher frequencies of the H(-) (P < 0.00001), N9 (P < 0.001), and -93G (P < 10(-10)) alleles were seen in blacks compared to the other two groups. Allelic association between -93G and N9, and H(+) and X447 was strong in all three groups. However, no association was observed between serum Tg and HDL-cholesterol concentrations and these variants in the three ethnic groups. A single common polymorphism in the LPL gene is unlikely to account for the differences in fasting serum Tg in populations of different ethnic background. The importance of the differences in frequencies and the mechanism(s) whereby these may contribute towards a beneficial LPL genotype in black populations remain to be determined.

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.

Practical implications of current natriuretic peptide research.

Since the original discovery of atrial natriuretic peptide (ANP) nearly 20 years ago and the subsequent realisation of the existence of a family of natriuretic peptides, there has been considerable progress in the elucidation of the physiological and pathophysiological significance of these peptides. This review has examined two potentially important practical aspects arising from natriuretic peptide research - the significance of measurement of plasma levels of ANP and of brain natriuretic peptide BNP for cardiovascular disease and the therapeutic potential of targeting the natriuretic peptide system. Several situations where the measurement of plasma ANP and BNP may be of benefit in the overall assessment and prognosis of cardiac disease have been discussed. The measurement of plasma levels of these peptides appears to have limited value as a specific diagnostic tool and is unlikely to replace well-established procedures to assess cardiac function. Nevertheless, given the strong negative predictive value, the value of the measurement of plasma natriuretic peptides particularly BNPs, in people with suspected heart disease, rests on the evidence that a normal value indicates a low risk of cardiac impairment. Moreover, a consistently elevated plasma level of BNP after myocardial infarction is associated with a distinctly poor prognosis. In turn, this may help to select those with high plasma levels for subsequent detailed investigation of cardiac dysfunction. This may be an important option, especially where the facilities for the more invasive cardiological procedures are not available. Intriguingly, recent research also suggests the possibility that plasma levels of natriuretic peptides may have an important role in guiding more effective therapy for heart failure. The potent cardiovascular and renal effects of ANP and BNP provide an important therapeutic potential for hypertension and for conditions associated with volume overload. A number of approaches which have been used to enhance endogenous activity of these peptides have been highlighted. The use of the native peptides ANP and BNP may well be valuable in some circumstances, such as in critically ill individuals with congestive heart failure or renal failure. However, the limitations of the use of peptides, especially for long-term treatment, are obvious. In view of this, considerable effort has been devoted to the development of orally active agents to enhance endogenous natriuretic peptides by inhibition of breakdown by neutral endopeptidase. This research has led to the development of vasopeptidase inhibitors - dual inhibitors of both endopeptidase and angiotensin-converting enzyme - to enhance endogenous natriuretic peptide function on a background of reduced angiotensin II activity. The broad spectrum of action and the potentially important target-organ protection of these inhibitors offer potential benefits which may well go beyond existing treatment of hypertension and of conditions associated with overt volume overload.

Association between the C825T polymorphism of the G protein beta3-subunit gene and hypertension in blacks.

A polymorphism (C825T) of the G protein beta3-subunit gene has been associated with low renin hypertension in whites. The aim of this study was to examine the C825T polymorphism in relation to hypertension in a population-based study of black people of African origin who have high prevalence of low renin, salt-sensitive hypertension. A total of 428 men and women, aged 40 to 59 years (270 Caribbeans and 158 West Africans), who took part in a population-based survey were studied. All were blacks and first-generation immigrants. The C825T polymorphism was detected by polymerase chain reaction followed by restriction-enzyme digestion. The prevalence of hypertension (supine blood pressures >/=160 systolic and/or 95 mm Hg diastolic or on drug therapy) was 43%. The distribution of the genotypes (CC, CT, and TT) was in Hardy-Weinberg equilibrium with observed frequencies of 4.0% (n=17), 33.6% (n=144), and 62.4% (n=267), respectively. Allele frequencies were 20.8% for C and 79.2% for T. No difference was detected between Caribbeans and West Africans. A 3-fold higher risk of hypertension was found among the carriers of the T variant both as heterozygotes (odds ratio [OR], 3.43 [95% CI, 0.94 to 12.4]) and homozygotes (OR, 3.87 [95% CI, 1. 09 to 13.8]). The estimate of effect and the blood pressure values in the groups carrying the T variant suggested a dominant model for the T allele. This was confirmed by a significant association between the T allele and hypertension (OR, 3.71 [95% CI, 1.05 to 13. 1]), even when adjusted for age, sex, and body mass index (OR, 4.14 [95% CI, 1.11 to 15.4]). The study shows, for the first time, a high frequency of the 825T allele in black people, and it provides evidence that the T allele may be a susceptibility factor for the development of hypertension in blacks. Given the high frequency of the T allele, even a 2-fold increased risk of hypertension among the carriers of the T allele might account for 44% of the cases of hypertension in blacks.

Platelet sodium/hydrogen exchanger activity in normotensives and hypertensives.

Increased activity of sodium/hydrogen exchange provides a potentially important mechanism for the development of hypertension. The aims of this study were to compare platelet sodium/hydrogen exchanger activity and renal acid-base excretion in normotensives and hypertensives of Caucasian origin. Platelet intracellular pH (pHi) was measured using the fluorescent dye BCECF to monitor intracellular pH. Sodium/hydrogen exchanger activity was estimated from the recovery of pHi clamped to 6.25 with nigericin. Normotensives had supine blood pressures of < 140 and < 90 mmHg; those with essential hypertension had blood pressures > 150/95 mmHg with no known secondary cause. Measurements of platelet pHi and sodium/hydrogen exchanger activity were made on 26 normotensives (ten female, sixteen male) and 25 hypertensives (five female, twenty male). All subjects were on their usual dietary sodium intake. Statistical analysis was by two-way analysis of variance for gender and blood pressure status. Group values are expressed as means+/-SD and a P value of < 0.05 was taken as being statistically significant. There were no significant differences in platelet pHi between the normotensive (n = 26) and the hypertensive (n = 25) group: pHi 7.21+/-0.14 and 7.18+/-0.16, respectively. The pHi recovery after acidification was sodium-dependent and inhibited by N-hexamethylene amiloride. Comparison of kinetic constants showed no significant differences between the normotensive and the hypertensive groups: values for rate constants and initial velocities were 0.24+/-0.04 s(-1), 0.16+/-0.03 dpHi/s for the normotensives and 0.25+/-0.05 s(-1), 0.16+/-0.03 dpHi/s for the hypertensives, respectively; there were also no significant differences in proton fluxes. The inability to find raised platelet sodium/hydrogen exchanger in the hypertensives contrasts with previous observations using other methods for the measurement of this exchanger in platelets and this raises important methodological issues in the assessment of platelet sodium/hydrogen exchanger activity.

A population study of ethnic variations in the angiotensin-converting enzyme I/D polymorphism: relationships with gender, hypertension and impaired glucose metabolism.

BACKGROUND: The presence of the deletion allele of the angiotensin-converting enzyme (ACE) I/D polymorphism is associated with an excess risk of vascular disease and diabetic nephropathy. OBJECTIVE: To examine the importance of this polymorphism as a determinant of hypertension and impaired glucose metabolism in a population-based study of three ethnic groups and assess the potential modifying effect of gender. DESIGN: Population-based cross-sectional study in South London. The population-based sample of 1577 men and women, age 40-59 years, was obtained from stratified random sampling of general practice lists where 25% of the residents were born outside the UK. The ACE I/D polymorphism was determined for 1366 individuals (86.6%): 462 whites, 462 of African descent and 442 of South Asian origin. RESULTS: The genotype frequency within each ethnic group was in Hardy-Weinberg equilibrium. The frequencies were similar in whites and those of African descent (II, ID, DD: 18.4%, 49.6%, 32.0% for whites and 18.4%, 50.5%, 30.9% for those of African descent), but there was a much higher frequency of the II genotype in those of South Asian origin (39.8%, 41.8%, 18.3%; chi2 = 77.6; P < 0.0001). There was no association between the I/D polymorphism and impaired glucose metabolism in any ethnic group. There were also no significant associations between the I/D polymorphism and hypertension in whites and in those of South Asian origin. This contrasts with a highly significant association between the D allele and hypertension in women of African descent (OR = 2.54; 95% CI 1.38-4.65; P = 0.003) but not in men of African descent (0.79; 0.36-1.72) (test for differences between sexes P = 0.023). CONCLUSIONS: These observations provide estimates of the frequency distribution of the ACE I/D polymorphism in whites, in people of African descent and in people of South Asian origin. Moreover, these results highlight the potential importance of gender-dependent interactions between genetic background and expression of hypertensive phenotype.