Why Is Plasma Renin Activity Lower in Populations of African Origin?

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Journal of Human Hypertension (2001) 15, 17–25  2001 Macmillan Publishers Ltd All rights reserved 0950-9240/01 $15.00 www.nature.com/jhh REVIEW ARTICLE Why is plasma renin activity lower in populations of African origin?

GA Sagnella Blood Pressure Unit, St George’s Hospital Medical School, Cranmer Terrace, London SW17 ORE, UK

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

Keywords: African origin; plasma renin activity; sodium; renal; genetics

Introduction variability in candidate genes likely to influence renin release and activity especially because of early The possibility of differences in the renin-angioten- suggestions that genetic factors may have a strong sin-system between people of African origin (blacks) influence on PRA and urinary aldosterone.2,3 and Caucasians (whites) has been recognised since Indeed, the potential importance of polymorphic the late 1960s. In one of the first studies using a variation at the gene level is highlighted by the newly developed quantitative assay for the measure- identification of polymorphic variants in the angio- ment of plasma renin activity (PRA), Helmer and tensin-converting enzyme (ACE) gene known to 1 Judson reported a much higher frequency of low account for more than 50% of the variability in PRA in black hypertensives (52%) compared with plasma ACE activity4 and in genetic variants of the white hypertensives (31%). renin substrate gene (angiotensinogen) associated The main purpose of this review is to assess the with increased expression of angiotensionogen.5 differences in PRA between blacks and whites, to explore some of the reasons for the low PRA in blacks and, in particular, to examine to what extent Comparison of PRA between blacks and the available evidence supports the widely held whites view that it is a direct result of a greater extracellular Following the early work,1 numerous other investi- fluid volume due to increased renal sodium gators measured PRA in blacks and confirmed the retention. Moreover, in view of recent advances in presence of lower PRA in blacks compared with molecular biology, particular emphasis will also be whites. Some of these studies spanning a period of given to the potential importance of genetic nearly 25 years are summarised in Table 1. As can be seen, on average PRA in blacks is about 50% to that in whites and the differences are similar for Correspondence: GA Sagnella, Blood Pressure Unit, St George’s 15,16 Hospital Medical School, Cranmer Terrace, London SW17 ORE, men and women, however it is also relevant to UK note the wide variability indicating that the PRA in Received 22 June 2000; accepted 17 July 2000 a substantial proportion of blacks is likely to be in Why is PRA lower in populations of African origin? GA Sagnella 18 Table 1 Comparison of PRA in blacks and whites

Author Blacks Whites %

Levy SB et al (1977)6 normotensives 0.80 ± 0.85(8) 1.60 ± 1.10(13) 50 essential hypertensives 0.70 ± 0.20(7) 2.80 ± 4.67(18) 25 Sever et al (1978)7 essential hypertensives 0.34 ± 0.56(23) 0.97 ± 1.10(77) 35 Mitas JA et al (1979)8 normotensives 0.76 ± 0.11(14) 1.58 ± 0.48(15) 48 essential hypertensives 0.95 ± 0.26(9) 1.23 ± 0.16(27) 77 Veterans (1987)9 essential hypertensives 0.69 ± 0.82(407) 1.35 ± 1.27(216) 51 Hohn AR et al (1983)10 children 2.40 ± 1.70(36) 4.76 ± 2.8(33) 50 children with family history of hypertension 1.98 ± 1.50(18) 4.62 ± 3.5(41) 43 James GD et al (1986)11 normotensives 2.10 ± 1.60(112) 2.80 ± 2.0(124) 75 He F et al (1998)12 essential hypertensives 0.48 ± 0.46(33) 1.08 ± 0.76(71) 44 He J et al (1999)13 population-based study 0.92 ± 1.36(110) 1.26 ± 1.35(183) 73 Kotchen et al (2000)14 essential hypertensives 1.10 ± 1.07(29) 1.80 ± 1.15(33) 61

Values are means ± s.d. (n); PRA activity (ng/ml/hr); supine and for subjects on their normal sodium intake. % (ratio of PRA in blacks/whites expressed as %).

the range found in whites. Moreover, PRA distri- renin hypertension’ in blacks. However, ‘low renin butions are not normal, although there is no evi- hypertension’ is clearly an arbitrary definition and dence for a bimodal distribution in blacks. A lower the actual frequency in blacks has ranged widely plasma PRA has also been observed in some10,17 but depending on the cut-off value taken to delimit the not in every study18,19 of black children compared state of ‘low PRA’. Furthermore, suppressed PRA is with white children, however, it is apparent that the also present in both normotensive and hypertensive difference between black and white children blacks even when on a low salt diet6,12 and in becomes more pronounced with increasing age even response to loss of sodium as induced by admini- over an age range of 8–14 years.17 Interestingly, stration of diuretics.23,24 slightly lower PRA has also been reported in black The low PRA in blacks is also associated with a neonates.20 lower plasma angiotensin II independent of ACE While a lower PRA was originally defined in activity.12 Given the potent cardiovascular and renal relation to hypertension in blacks, lower PRA has effects of angiotensin II (Figure 1) this has led to also been found in normotensives6,8,9,11,13 suggesting that the lower PRA is not simply a consequence of the high blood pressure, at least in individuals with- out malignant hypertension and renal failure. That the lower PRA is a characteristic feature of blacks as a group is also supported by a lack of difference in PRA between normotensive and hypertensive blacks from rural African regions.21,22 A major criticism of some of the earlier studies was that they were limited by small numbers in clinic-based designs. However, lower PRA has also been found in population-based studies of blacks and whites in the absence of significant differences in blood pressure between the two groups.7,9,13 Nevertheless, in both whites and blacks, a weak but statistically significant inverse association between PRA and both systolic and diastolic blood pressure has been reported even after adjusting for age and gender13 (−2.4 mm Hg/1.24 ng/ml/hr renin for systolic and −1.5 mm Hg/1.24 ng/ml/hr renin for diastolic blood pressure, respectively). The regression coefficients

were slightly higher for the blacks and this could Figure 1 Systemic, renal and other effects of Angiotensin II (AT1 account for the apparently higher frequency of ‘low receptor). (See Taal and Brenner25 for further details).

Journal of Human Hypertension Why is PRA lower in populations of African origin? GA Sagnella 19 speculations about the functional significance of the Renin-angiotensinogen reaction lower PRA in blacks in relation to the physiological role of renin in the control of sodium balance; to the In humans, the concentration of angiotensinogen in pathophysiological significance for cardiovascular/ the plasma is less than that required for full satu- renal disease and to the treatment of hypertension ration and therefore even small changes in plasma in blacks. levels can influence the amount of angiotensin I produced.27 There is little information on the kinetics of the renin-angiotensinogen reaction in plasma from Possible reasons for lower PRA in black people, nor on the presence of endogenous blacks inhibitors of renin activity. But any effects are likely to be small as a lower PRA in blacks was also asso- The control of renin release into the circulation is ciated with a lower plasma concentration of renin.28 under the influence of many neural, haemodynamic A number of polymorphic variants have recently and hormonal factors.26 Renin release depends on been identified within the renin gene raising the both renal perfusion pressure and on tubular func- possibility that these variants might influence renin tion. Consistent with the physiological role of the activity,29 however, as yet, there is no evidence that renin-angiotensin system, renin release is increased these are associated with differences in plasma by several factors and mainly by: renin activity, in whites at least.30 Several polymorphic variants have also been (1) reduction in tension (pressure/stretch) within identified within the angiotensinogen gene; some of the walls of the afferent arteriole; these polymorphisms (eg the M235T polymorphism) (2) decreased load of sodium arriving at the macula are associated with increased levels of plasma angio- densa within the distal convoluted tubule; and tensinogen, and therefore could lead to increased (3) increase in activity of sympathetic renal afferent PRA.5 In blacks as in whites, the 235T variant is nerves, mainly beta adrenergic receptor. associated with raised levels of plasma angiotensin- Moreover, PRA is measured from the amount of ogen, however, as this variant is much more fre- angiotensin I produced from renin substrate quent in black people it is unlikely to provide an (angiotensinogen), hence PRA as usually reported explanation for the low PRA.31,32 depends not only on the concentration of active Differences in clearance and metabolism of renin renin within the circulation but also on the level of also represent a possible cause for the differences in plasma angiotensinogen and any factors likely to PRA between blacks and whites. The liver is a major affect the interaction between renin and its sub- site for metabolism of renin (and aldosterone),33,34 strate. Such a diversity of mechanisms which can and hence differences in hepatic elimination could influence renin release and the subsequent PRA pro- influence plasma levels. However, and even though vide a number of potential mechanisms for the no information is available on renin metabolism lower PRA in black people (Figure 2). between blacks and whites, differences in hepatic extraction appears unlikely especially as there are no major differences in plasma aldosterone between blacks and whites.12,28

Renin release and the sympathetic system Adrenergic receptors are found on JGA cells and there is considerable evidence demonstrating that even moderate increases in renal sympathetic activity leads to increases in renin release through ␤-adrenergic receptor stimulation; by contrast, there is still controversy on the role of ␣-adrenergic activation as both inhibition and activation of renin release have been reported.26 No major and consistent differences in circulating catecholamines between blacks and whites under basal conditions have been reported,35–37 though this does not exclude differences in sympathetic activity as plasma levels of catechoamines are not a good index of adrenergic activity. Reduced plasma levels of dopamine ␤-hydroxylase (DBH) have been described in both black adults and in children compared with whites.38,39 Although the interpretation of plasma DBH is controversial, these lower levels Figure 2 Possible reasons for decreased PRA in blacks. are consistent with reduced sympathetic tone.

Journal of Human Hypertension Why is PRA lower in populations of African origin? GA Sagnella 20 In fact, other investigations have recognised dif- effect in increasing PRA in the blacks.49,50 One ferences in autonomic reactivity in response to men- interpretation of these results is that potassium tal and physical stress in black children and black supplementation has a greater natriuretic effect in children tend to have lower heart rates.40 The lower blacks than in whites. Alternatively, a lower potas- heart rate appears to be due to a reduction in sym- sium intake may lead to a greater sodium retention pathetic activity rather than increased parasympa- in blacks. While these results suggest interactions thetic activity.40 Although there is still controversy between potassium intake, sodium balance and on whether there are differences in sympathetic PRA, differences in potassium intake are not the sole drive between white and blacks with essential answer as it is evident that lower PRA in blacks has hypertension, some studies suggest an attenuation also been observed in the absence of any differences ␤ 12 in 2-adrenergic responsiveness as a possible reason in urinary potassium excretion. for the higher peripheral vascular resistance in black people.41,42 Such a reduction in ␤ -mediated vasodi- 2 Renal sodium retention and extracellular fluid latation could provide a basis for a reduction in volume (ECFV) renin secretion. However, it is still unclear whether ␤ the reduced 2-adrenergic receptor-mediated vaso- To examine the possibility of an enhanced renal dilator response is associated with differences in sodium reabsorption in blacks which could lead to ␤ molecular properties of 2-adrenergic receptors at a greater degree of volume expansion, a number of the cellular level in blacks. More direct examination investigators measured renal sodium handling in of ␤ receptors, in isolated cells from blacks and response to a sodium load and plasma and total whites has provided conflicting results in terms of blood volume as an index of extracellular volume. whether there are any differences in receptor Luft et al51 monitored the amount of sodium density and/or affinity for adrenergic agonists. excreted up to 24 h after an infusion of 2 L of saline ␤ Molecular analysis of the 2 adrenergic receptor and found that blacks did not excrete the sodium gene has identified ethnic differences in the fre- load as rapidly as whites over the 24-h period. In quency distribution of polymorphic variants in this subsequent investigations Brier and Luft52 measured gene. The Gly 16 Arg polymorphism is of particular daily urine sodium excretion during alterations in interest as the Gly16 variant is associated with an dietary sodium intake in black and white normo- attenuated vasodilatory response to catechola- tensive subjects. Salt intake was varied from 10 to mines.43 The frequency of this variant is markedly 400 mmol/day. After 7 days, at the highest level of lower in blacks44,45 but whether the presence of this salt intake blacks retained much more sodium than variant is associated with differences in PRA whites (909 vs 385 mmols), demonstrating that remains to be seen. blacks have a reduced ability to excrete a sodium load compared with whites. Moreover, for both normotensives and hypertensives, the blood pressure of Dietary sodium and potassium intake blacks is also more salt-sensitive compared with Some of the earlier studies suggested that the lower whites.53–57 PRA in blacks could be explained by a higher Nonetheless, it has proved difficult to demonstrate sodium intake. However, several other studies of that blacks have a higher ECFV compared with renal function and electrolytes excretion of free- whites. While an early study58 in a small series of living black and white children revealed no differ- black hypertensives did report a significantly higher ences between the blacks and whites in sodium plasma volume in blacks compared with whites excretion.9,13,17,36 Similarly, lower PRA in blacks others have not been able to detect significant differ- compared with whites has also been reported even ences in either plasma and/or total blood volume when there were no significant differences in uri- between blacks and whites.8,12 Furthermore, nary sodium. Moreover, low PRA has also been Frohlich et al59 measured intravascular volume in found in blacks on diets where the intake of sodium black and white hypertensives and divided the has been carefully controlled and lower PRA has group into a ‘low volume’ and a ‘high volume’ been found on both low and high sodium intakes.6,12 group. Despite the differences in volume, they did By contrast, several studies9,13,46,47 have reported not find any significant differences in PRA between a lower urinary potassium excretion in blacks. And the two groups nor were there any differences in vol- although this has not been confirmed in every com- ume between the blacks and the whites. It is of inter- parative study,36,48 a lower potassium intake could est to note that no differences in volumes were be important as changes in potassium intake, though found between white subjects with ‘low renin’ to a smaller extent, can also influence renin release hypertension and age-matched subjects with ‘nor- largely through the impact on sodium balance. mal renin’ hypertension.60,61 To some extent, there- A possible link between potassium intake/balance fore, the inability to identify differences in and PRA in blacks has been highlighted in studies plasma/total blood volume between blacks and which have demonstrated a lower basal PRA in whites could simply reflect methodological aspects blacks than in whites and then demonstrated that such as the known imprecision of the measurement potassium supplementation had a more marked of blood/plasma volumes. Alternatively, it may

Journal of Human Hypertension Why is PRA lower in populations of African origin? GA Sagnella 21 relate to differential distribution of intravascular than Angiotensin II in the control of plasma aldo- volume with a more marked shift to the central sterone in blacks is still unclear but, a previous venous region in the blacks but as yet there is no study has demonstrated that the plasma aldosterone information on central blood volume between blacks response to a short-term infusion of Angiotensin II and whites. was lower in blacks compared with whites.68 Despite the blunted adrenal response in blacks compared with whites, within the blacks, the aldo- Hormones and PRA in whites and blacks sterone response to angiotensin II was independent Several hormones and in particular ANP and endo- of renin status suggesting a heightened sensitivity of thelin are potentially important modulators of renin the adrenal gland to Angiotensin II in blacks with secretion either by direct effect on renin secretion low PRA. It is not know whether this extends to or indirectly through their renal effects.26 However, other cells, but such enhanced sensitivity of the while both ANP and endothelin are known to angiotensin II receptor might be relevant for the low inhibit renin release,26 no information is, as yet, PRA in blacks given that angiotensin II is an available as to whether any differences in these sys- important feedback inhibitor of renin release. tems between blacks and whites may lead to a The effect of aldosterone on sodium excretion, reduction in renin release in the blacks. depends not only on its plasma levels but also on Renal kallikrein, however, may be relevant as the activity of the mineralocorticoid receptor there is evidence suggesting it may increase plasma through its effects on renal sodium transport path- renin activity directly by promoting the conversion ways.69 Indeed, inactivating mutations within the of inactive renin to active renin62 and it is well mineralocorticoid gene are known to cause auto- established that urinary kallikrein, an index of renal somal dominant pseudohypoladosteronism type 1, a kallikrein, is substantially lower in blacks compared mild sodium-losing condition associated with hypo- with whites, and this is independent of hyperten- tension.70 As yet, no information is available on the sion status.63,64 Renal kallikrein could also be presence of polymorphic variants in this gene in important as it generates the potent vasodilator and blacks likely to influence sodium excretion and natriuretic peptide bradykinin which may in turn thereby sodium balance. On the other hand, other influence renin release indirectly through its effect studies have addressed the question of whether on renal haemodynamics. In fact, in a comparative differences in renal sodium handling between study59 of blacks and whites matched for mean blacks and whites might be due to another mineralo- arterial pressure, at any level of blood pressure, corticoid produced in excess in blacks. Recently, renal vascular resistance was higher in the blacks Pratt et al71 compared plasma levels of aldosterone, and this was also associated with a significant cortisol, deoxycorticosterone and 18-hydroxycorti- reduction in renal blood flow. In turn this could sol excretion between blacks and whites. PRA was account for the lower PRA in the blacks in view of lower in the black group, however there was no evi- the inverse relationship between renal vascular dence that this was due to excess mineralocorticoid resistance and renin release.65,66 But whether the activity as the plasma levels of these steroids were reduced kallikrein is actually responsible for this significantly lower in the blacks. Measurement of remains to be established and moreover, other stud- salivary sodium/potassium ratio as an index of min- ies have demonstrated a lower PRA in blacks in the eralocorticoid excess also demonstrated a lack of absence of any differences in renal vascular resist- association with PRA in blacks.72 These results sug- ance between blacks and whites.14 gest that the increased sodium reabsorption in blacks may arise from differences in renal sodium ion transport mechanisms rather than increased pro- Aldosterone and other mineralocorticoids duction of mineralocorticoids. Paradoxically, despite the substantially low PRA and Angiotensin II, both plasma12,19,28 and urinary Intracellular sodium and calcium transport aldosterone67 in blacks is only slightly lower than mechanisms that found in whites; although lower plasma levels of aldosterone have been observed in blacks whilst It has been known for quite some time that intra- on a low sodium diet,12 possibly because of the slug- cellular sodium in cells, mainly peripheral blood gish response of the renin-angiotensin system to cells, isolated from black people is significantly sodium restriction. higher compared with cells isolated from white The reasons for the lack of differences in plasma people suggesting defects in cellular sodium trans- aldosterone in the presence of a markedly lower port mechanisms (reviewed in Aviv and Gardner73). PRA are not known but may relate to differences in Several transport mechanisms contribute to the aldosterone synthetic and stimulatory pathways overall control of intracellular sodium and signifi- between blacks and whites. While Angiotensin II is cant differences between blacks and whites have a major factor in the release of aldosterone, other been reported for a number of these transport mech- factors including plasma potassium and ACTH are anisms. Reduced activity of the sodium-potassium also important. The potential role of factors other ATPase has been found in erythrocyte membranes

Journal of Human Hypertension Why is PRA lower in populations of African origin? GA Sagnella 22 of blacks providing one possible mechanism for the molecular defect leading to increased activity of the higher intracellular sodium.73 The reduced activity renal epithelial sodium channel. The increased was also associated with reduced number of pump renal sodium reabsorption and sodium retention sites possibly due to an actual reduction of pump leads to high blood pressure and suppression of sites, but the possibility of a raised ouabain-like cir- plasma renin activity. culating inhibitor in blacks, could not be excluded. Hypertension in blacks shares some significant A lower efflux component of the Na-K-2Cl similarities with Liddle’s syndrome such as an cotransport in erythrocytes has also been reported apparent greater sodium sensitivity and low PRA. in erythrocytes from blacks compared with whites; This suggested the possibility that other mutations this was found in both blacks with hypertension and in subunits of the epithelial sodium channel leading in normotensive young blacks with a family history to less drastic disruption of channel activity could of hypertension.73 Similarly, reduced activity of provide a genetic basis for high blood pressure in sodium-lithium countertransport has been observed subgroups of black people. Working on this hypo- in blacks.73 But, whether the differences in these thesis Baker et al81 found that a mutation within the transport mechanisms provide a mechanistic basis sodium channel ␤-subunit, the T594M mutation, for a higher renal sodium absorption in blacks was significantly more common in hypertensive remains unresolved. Firstly, since the sodium po- black subjects (8.3%) than in normotensive black tassium ATPase is located within the basolateral controls (2.1%); moreover, the presence of this membranes74 it is difficult to see how inhibition in mutation was associated with lower PRA. While the this enzyme could lead to increased renal sodium frequency of this variant is relatively low, other reabsorption. Secondly, the functional significance studies have also provided evidence for distinct of the sodium-lithium countertransporter at least as molecular variants in this gene which appear to measured in erythrocytes, is still unknown, and influence renal sodium excretion in blacks.82 These thirdly, it is unclear whether the activity of the results, if confirmed on a more general basis, erythrocyte Na-K-2Cl is a direct index of the renal provide evidence that molecular variation within Na-K-2Cl cotransporter. tubular sodium transport mechanisms could influ- The concentration of cytoplasmic intracellular ence total sodium balance in blacks. calcium is also a potentially important factor in the regulation of renin secretion. In contrast with many Functional significance of lower PRA in other hormone secretion systems, renin release is inhibited by increases in intracellular calcium and blacks hence factors which increase intracellular calcium Apart from its well established effects on the control may also lead to reduction in renin release.26 Intra- of sodium excretion, some of the newly recognised cellular calcium has been compared in peripheral actions of Angiotensin II at the vascular and renal blood cells and skin fibroblasts from blacks and level (Figure 1) suggest that raised levels of Angio- whites.75–78 No significant differences in free tensin II could accelerate the atherosclerosis process intracellular cytoplasmic calcium have been and also enhance the progression to end-stage renal demonstrated; some studies have reported signifi- failure. However, there is as yet no consistent data cant differences in intracellular calcium fluxes but confirming this in epidemiologically-based studies. another study using platelets failed to find any dif- Indeed, although blacks have a lower rate of ferences in intracellular calcium mobilisation ischaemic heart disease, the incidence of end-stage between blacks and whites. Despite the attractive- renal disease in blacks with essential hypertension ness of this hypothesis, there is little evidence sug- is much higher compared with whites.83 The lower gesting that variation in intracellular calcium may rate of ischaemic heart disease in blacks may reflect be relevant for the lower PRA in blacks. the different pattern of other risk factors as apart from lower PRA, blacks also have a lower fibrinogen, serum cholesterol and triglyceride and a higher Renal epithelial sodium channel high-density lipoprotein (HDL).83 On the other The renal epithelial sodium channel, located within hand, the reasons for the greater susceptibility to the collecting duct, even though accounts for only a renal damage in blacks with essential hypertension small proportion of renal sodium reabsorption remain to be established but may be a consequence (ෂ5%) is one of the most important sodium transport of abnormalities in the renal haemodynamic adap- mechanisms in the overall control of sodium bal- tations to a high salt diet.84 ance as it is responsible for the final adjustments to The lower PRA in blacks and the sluggish the sodium content of the urine.79 The potential response to sodium restriction and diuretics raises importance of abnormal renal tubular sodium the question of the importance of the renin system reabsorption as a determinant of sodium balance in the blood pressure response to sodium restriction and of blood pressure has been highlighted by gen- or to pharmacological treatment in black hyperten- etic studies of renal sodium transporters in rare fam- sives. Previous work has shown that the blood ilial conditions.80 For example, Liddle’s syndrome pressure of blacks is more sensitive to diuretic is a rare autosomal dominant disorder caused by a monotherapy whereas other agents whose actions

Journal of Human Hypertension Why is PRA lower in populations of African origin? GA Sagnella 23 depends on the renin system (eg ␤-blocking agents References and ACE inhibitors) have a more limited effect85 and it has generally been assumed that these differences 1 Helmer OM, Judson WE. Metabolic studies on hyper- are related to the lower PRA in blacks. However, tensive patients with suppressed plasma renin activity more direct investigations of pre-treatment renin not due to hyperaldosteronism. Circulation 1968; 38: status in hypertensive blacks in relation to blood 965–976. 2 Grim CE et al. Genetic influences on renin, aldo- pressure response have demonstrated that the pre- sterone, and the renal excretion of sodium and potas- treatment PRA was not a particularly effective index sium following volume expansion and contraction in of subsequent blood pressure response to pharmaco- normal man. Hypertension 1979; 1: 583–590. logical treatment.24,86–89 Nevertheless, other studies 3 Manatunga AK, Reister TK, Miller JZ, Pratt JH. Genetic have demonstrated that the blood pressure influences on the urinary excretion of aldosterone in reduction to short term sodium restriction was children. Hypertension 1992; 19: 192–197. greater in blacks compared with whites; moreover, 4 Villard E et al. Identification of new polymorphisms of in the blacks, the greater reduction in blood pressure the angiotensin I-converting enzyme (ACE) gene, and was significantly related, at least in part, to the study of their relationship to plasma ACE levels by decreased responsiveness of the renin-angiotensin two-QTL segregation-linkage analysis. Am J Hum 12 Genet 1996; 58: 1268–1278. system. 5 Inoue I et al. A nucleotide substitution in the promoter of human angiotensinogen is associated with essential Conclusions hypertension and affects basal transcription in vitro. J Clin Invest 1997; 99: 1786–1797. There is little doubt about the presence of a lower 6 Levy SB, Lilley JJ, Frigon RP, Stone RA. Urinary kal- PRA in black people compared with white people. likrein and plasma renin activity as determinants of The lower PRA exists even in black children but the renal blood flow. The influence of race and dietary lower renin in adults is largely independent of blood sodium intake. J Clin Invest 1977; 60: 129–138. pressure status. The lower PRA appears to be due to 7 Sever PS et al. Are racial differences in essential a reduction in the rate of secretion of renin but the hypertension due to different pathogenetic mechanisms? Clin Sci (Suppl) 1978; 4: 383s–386s. exact mechanistic events underlying such differ- 8 Mitas JA, Holle R, Levy SB, Stone RA. Racial analysis ences in renin release between blacks and whites are of the volume-renin relationship in human hyperten- still not fully understood. The release of renin is sion. Arch Intern Med 1979; 139: 157–160. under the control of numerous cellular, hormonal 9 Veterans Administration Cooperative Study Group on and haemodynamic factors and this review has high- Antihypertensive Agents. Urinary and serum electro- lighted a number of systems which could account, lytes in untreated black and white hypertensives. J theoretically at least, for the differences in plasma Chronic Dis 1987; 40: 839–847. renin between blacks and whites. Nevertheless, 10 Hohn AR et al. Childhood familial and racial differ- given the paramount importance of the renin- ences in physiologic and biochemical factors related angiotensin system in the control of sodium balance, to hypertension. Hypertension 1983; 5: 56–70. 11 James GD et al. Renin relationship to sex, race and age a most likely explanation is that the lower renin is a in a normotensive population. J Hypertens (Suppl) consequence of intrinsic differences in renal sodium 1986; 4: S387–S389. handling between blacks and whites. The lower 12 He FJ, Markandu ND, Sagnella GA, MacGregor GA. PRA is not due to variation in dietary sodium intake Importance of renin system in determining blood but the evidence available is consistent with the pressure fall with salt restriction in black and white view that the lower PRA could be part of the correc- hypertensives. Hypertension 1998; 32: 820–824. tive mechanisms designed to maintain sodium bal- 13 He J et al. The renin-angiotensin system and blood ance in the presence of an increased tendency for pressure. Differences between blacks and whites. Am sodium retention in black people. To some extent, J Hypertens 1999; 12: 555–562. this is supported by more recent investigation at the 14 Kotchen TA et al. Glomerular hyperfiltration in hypertensive African Americans. Hypertension 2000; 35: molecular level suggesting that the lower PRA may 822–826. arise from gene variation in the renal epithelial 15 Meade TW, Imeson JD, Gordon D, Peart WS. The epi- sodium channel. This increased tendency for demiology of plasma renin. Clin Sci (Colch) 1983; 64: sodium retention may reflect an evolutionary adap- 273–280. tation for more efficient mechanisms to conserve 16 Grim CE et al. Racial differences in blood pressure in sodium in people originally inhabiting semitropical Evans County, Georgia: relationship to sodium and regions where sodium intake was traditionally low potassium intake and plasma renin activity. J Chronic and difficult to obtain. There is little evidence to Dis 1980; 33: 87–94. indicate that PRA levels in blacks could be used for 17 Berenson GS et al. Creatinine clearance, electrolytes, a more targeted pharmacological treatment of blacks and plasma renin activity related to the blood pressure of white and black children—the Bogalusa Heart with essential hypertension; however it is apparent Study. J Lab Clin Med 1979; 93: 535–548. that the more sluggish renin system in blacks pro- 18 Pratt JH et al. 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