Effects of isradipine or enalapril on blood pressure in salt-sensitive hypertensives during low and high dietary salt intake. MIST II Trial Investigators.

This large multicenter study, tested the antihypertensive effects of isradipine, a dihydropyridine calcium channel blocker and enalapril, an angiotensin-converting enzyme inhibitor, in salt-sensitive hypertensive patients under low and high salt intake diets. After a 3-week (weeks -9 to -6) of ad lib salt diet, those patients who had a sitting diastolic blood pressure (SDBP) of > or =95 but < or =115 mm Hg qualified to enter a 3-week (weeks -6 to -3) placebo run-in low salt diet (50 to 80 mmol Na+/day). Then high salt (200 to 250 mmol Na+/day) was added to the placebo treatment for 3 weeks (weeks -3 to 0). Those patients who demonstrated an increase in SDBP > or =5 mm Hg from the low to high salt diet were considered salt sensitive and were randomized into a 4-week (weeks 0 to 4) double-blind treatment period of either isradipine 2.5 to 10 mg twice a day, enalapril 2.5 to 20 mg twice a day, or placebo. Then they entered a 3-week (weeks 4 to 7) placebo washout phase of low salt diet (50 to 80 mmol Na+/day). After week 7 and while the low salt diet was continued the patients were restarted on their double-blind treatment for 4 more weeks (weeks 7 to 11) and the study was completed. Of 1,916 patients screened, 464 were randomized into the double-blind treatment phase and 397 completed the study. Both isradipine and enalapril decreased the sitting systolic blood pressure (SSBP) and SDBP during the high salt diet, to a similar degree, whereas enalapril caused a greater reduction in SSBP and SDBP than isradipine during the low salt diet (11.3 +/- 1.2/7.7 +/- 0.7 mm Hg v 7.7 +/- 0.9/4.8 +/- 0.6 mm Hg, mean +/- SEM, respectively, P < .02). Within drugs, the effect of isradipine on blood pressure (BP) was higher during the high than the low salt diet (14.9 +/- 1.5 v 7.6 +/- 1.3 mm Hg for SSBP and 10.1 +/- 0.6 v 4.8 +/- 0.9 mm Hg for SDBP, P < .001), but enalapril exerted a similar effect during both diets. Because salt restriction lowered both SSBP and SDBP, the lowest BP achieved with both drugs were during the salt restriction phase.

Lack of association between a biallelic polymorphism in the adducin gene and blood pressure in whites and African Americans.

Population-based candidate gene association analyses are becoming increasingly popular as a result of a greater number of genes and gene polymorphisms having been identified for which some functional information is available. Because many biochemical and physiologic systems impact blood pressure regulation and hypertension susceptibility, many of these identified genes and polymorphisms are candidates for population-level association studies involving blood pressure levels or hypertension status. Recent studies have suggested that the alpha-adducin gene may harbor polymorphisms that influence blood pressure level. Therefore, we embarked on a study to test one such polymorphism in two large US samples: one from an urban African American population (Maywood, IL) and another from a rural white population (Tecumseh, MI). We used both family-based association tests and tests that consider the impact of additional measured factors beyond adducin gene variation on blood pressure levels. We found no evidence for a significant effect of the chosen adducin polymorphism on blood pressure variation in either sample. We also found no association between Adducin genotypes and antihypertensive use. These facts, together with similar findings in companion studies, suggest that the alpha-adducin gene polymorphism does not have a pronounced effect on blood pressure variation in the populations studied. This does not suggest, however, that the alpha-adducin gene does not have a role in blood pressure regulation and hypertension susceptibility.

Office and laboratory blood pressures as predictors of daily blood pressure level in normotensive subjects and borderline and mild hypertensive subjects.

A series of standardized laboratory tests [10 min sitting and supine, 9 min standing, dynamic; cycle ergometer (ERG) and isometric exercise; handgrip (HG)] were performed during intra-arterial blood pressure (BP) recording in 97 healthy unmedicated men, initially classified as normotensive (NT, n = 34), borderline hypertensive (BHT, n = 29) or mildly hypertensive (HT, n = 34) by repeated office blood pressure (OBP) measurements. After testing, a 24-h intra-arterial ambulatory BP (IABP) recording was obtained while subjects performed their normal activities. Day and night periods were analysed as well as 24-h averages for systolic BP (SBP) and diastolic BP (DBP) using Pearson correlations and multiple linear regressions. In normotensive subjects, the supine SBP predicted IABP measurements best (r range 0.39-0.69, P < 0.05-0.001). In multiple regression, supine SBP explained 49% of 24-h SBP variance (F = 12.4, P = 0.001). For BHT, supine SBP was also the best predictor (r range 0.09-0.64, P NS to P < 0.001), and it explained 37% of 24-h SBP variance (F = 15.6, P = 0.0005). In HT, ERG DBP correlated best with IABP (r range 0.52-0.75, P < 0.01-0.001). ERG SBP explained 49% of 24-h SBP (F = 31.0, P = 0.0000) and ERG DBP explained 56% of 24-h DBP (F = 35.4, P = 0.0000) variance. Laboratory BP correlations were generally better with day than with night measurements. OSBP correlated moderately well with IABP in NT, and weakly in BHT and HT; ODBP instead correlated with IABP in NT and HT but not significantly in BHT. In conclusion, OBP is less closely related to IABP than laboratory BP, but even laboratory BP generally explains less than 50% of IABP variance. Stressors such as exercise are useful only in HT. For BHT, the prediction of IABP with laboratory measures was even weaker than in other groups, and thus ambulatory measurements cannot be replaced by short-duration laboratory measurements and stress tests.

Influence of race and dietary salt on the antihypertensive efficacy of an angiotensin-converting enzyme inhibitor or a calcium channel antagonist in salt-sensitive hypertensives.

Dietary salt restriction is a recommended adjunct with antihypertensive therapy. There may be racial differences in blood pressure response to salt restriction while on antihypertensive therapy. We performed a multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial (black, n=96; Hispanic, n=63; white, n=232). Participants were initially preselected for stage I to III hypertension and then further selected for salt sensitivity (> or = 5 mm Hg increase in diastolic blood pressure after 3 weeks of low salt [< or = 88 mmol/d Na+] and high salt [>190 mmol/d Na+] diet). We compared the antihypertensive effect of an angiotensin-converting enzyme inhibitor (enalapril 5 or 20 mg BID) or a calcium channel antagonist (isradipine 5 or 10 mg BID) during alternating periods of high and low salt intake. The main outcome measure was blood pressure change and absolute blood pressure level achieved with therapy. During the high salt diet (314.7+/-107.5 mmol/d urinary Na+) there was greater downward change in blood pressure with both enalapril and isradipine compared with the low salt diet (90.1+/-50.8 mmol/d Na+); however, the absolute blood pressure achieved in all races was consistently lower on a low salt diet for both agents. Black, white, and Hispanic isradipine-treated salt-sensitive hypertensives demonstrated a smaller difference between high and low salt diets (black, -3.6/-1.6 mmHg; white, -6.2/-3.9 mmHg; Hispanic, -8.1/-5.3 mm Hg) than did enalapril-treated patients (black, -9.0/-5.3 mm Hg; white, -11.8/-7.0 mm Hg; Hispanic, -11.1/-5.6 mm Hg). On the low salt diet, blacks, whites, and Hispanics had similar blood pressure control with enalapril and isradipine. On the high salt diet, blacks had better blood pressure control with isradipine than with enalapril, whereas there was no difference in the blood pressure control in whites and Hispanics treated with either drug. Dietary salt reduction helps reduce blood pressure in salt-sensitive hypertensive blacks, whites, and Hispanics treated with enalapril or isradipine. These data demonstrate that controlling for salt sensitivity diminishes race-related differences in antihypertensive activity.

There are no racial, age, sex, or weight differences in the effect of salt on blood pressure in salt-sensitive hypertensive patients.

BACKGROUND: This report is part of a larger, multicenter, placebo-controlled study designed to test the effects of low and high salt intake on the antihypertensive action of enalapril maleate or isradipine in salt-sensitive, hypertensive patients. OBJECTIVE: To present our findings with respect to the effects of race, age, sex, and weight on the blood pressure response to low and high salt intake in salt-sensitive hypertensive patients before randomization into the larger study. PATIENTS AND METHODS: After 3 week (weeks -9 to -6) of ad lib salt intake (100-200 mmol/d of sodium), 1916 patients whose sitting diastolic blood pressure was between 95 and 115 mm Hg entered a 3-week period (week -6 to -3) of low salt intake (50-80 mmol/d of sodium) and then a 3-week period (week -3 to 0) of high salt intake (200-250 mmol/d of sodium). Of the 1916 patients, 624 were identified as being sensitive to salt by demonstrating an increase in sitting diastolic blood pressure of equal to or more than 5 mm Hg from the low to high salt intake. Of these patients, 367 were white, 156 were black, 92 were Hispanic, 8 were Asian, and 1 was American Indian. Also, 315 were men and 309, women; 351 were 55 years or younger and 273 were older than 55 years; and 195 had a body mass index of 27 or less and 429 had a body mass index higher than 27. RESULTS: The sitting blood pressure decreased with salt restriction and increased with salt load in all groups of patients (P < .001). There were no statistically significant differences in the blood pressure changes to salt changes by race, age, sex, and weight. CONCLUSIONS: This large, multicenter study did not demonstrate any statistically significant effect of race, age, sex, and weight on blood pressure response to salt changes in salt-sensitive hypertensive patients.

Erythrocyte sodium-lithium countertransport in non-modulating offspring and essential hypertensive individuals: response to enalapril.

Non-modulators are a subset of essential hypertensive individuals in whom renal hemodynamic and adrenal aldosterone responses to angiotensin II fail to modulate appropriately during high dietary salt intake. The main aim of this study was to investigate the familial aggregation of non-modulation and several erythrocyte Na+ transport systems in normotensive and hypertensive individuals as well as offspring of hypertensive parents. An additional aim was to evaluate the effect of treatment with enalapril on erythrocyte Na+ transport. We studied 15 normotensive subjects (6 males, 27+/-6 years), 14 untreated modulating essential hypertensive subjects (7 males, 38+/-7 years), 12 untreated non-modulating essential hypertensive subjects (7 males, 38+/-6 years), 14 modulating offspring of hypertensive parents (8 males, 25+/-6 years), and 14 non-modulating offspring of hypertensive parents (8 males, 26+/-4 years). Blood pressure was recorded with an oscillometric device and renal plasma flow and glomerular filtration rate by clearances of para-aminohippurate and inulin, respectively. Non-modulating subjects were identified as individuals who failed to increase effective renal plasma flow by 30% and decrease filtration fraction by at least 30% 10 days after changing from a low (20 mmol/d) to a high (250 mmol/d) sodium intake. Erythrocyte Na+ transport was characterized by measurements of the Na+-K+ pump, Na+-Li+ countertransport, Na+-K+-Cl- cotransport, passive Na+ permeability, and Na+ content. After the initial studies, hypertensive individuals were treated with enalapril (20 mg/d P.O.) for 6 months, after which erythrocyte Na+ transport measurements were again made. The main findings were that Na+-Li+ countertransport is increased in non-modulating hypertensive subjects and non-modulating offspring of hypertensive parents, that the increase in blood pressure in response to high salt intake is greater in non-modulating than modulating hypertensive subjects, and that enalapril decreases Na+-Li+ countertransport activity to normal in non-modulating hypertensive subjects. These findings provide support for a possible genetic role in the development of salt sensitivity and suggest that Na+-Li+ countertransport and non-modulation are related phenotypes.

Does orthostatic testing have any role in the evaluation of the young subject with mild hypertension?: an insight from the HARVEST study.

The aim of the study was to assess the clinical significance of the blood pressure (BP) reaction to standing in 1029 stage I hypertensives. Office BP was measured six times in the supine position and six times after 2 min of standing. All subjects underwent 24-h ambulatory BP monitoring, and measurements of 24-h urinary epinephrine and norepinephrine excretion. Echocardiography was performed in 636 patients. With use of mixture analysis we could single out a population with abnormal diastolic BP response to standing (hyperreactors, n = 95). These subjects had a diastolic BP increase from lying to standing of >11 mm Hg. The other subjects were defined as normoreactors (n = 934). Office systolic BP was similar in the two groups. Diastolic BP was lower (91 +/- 6 mm Hg v 95 +/- 5 mm Hg, P < .0001) and heart rate was higher in the hyperreactors (77 +/- 10 beats/min v 75 +/- 9 beats/min, P = .004). After adjusting for age, gender, and smoking habits the statistical significance did not change. Adjusted 24-h systolic BP (P = .02) and diastolic BP (P = .02) were higher in the hyperreactors than in the normoreactors. Hyperreactors were characterized by higher cardiac index (3.2 +/- 0.8 L/min/m2 v 3.0 +/- 0.7 L/min/m2, P = .008 for adjusted values), lower total peripheral resistance (1420 +/- 330 dyne/sec/cm(-5) v 1600 +/- 380 dyne/sec/cm(-5), P = .003), and higher urinary norepinephrine output (114.9 +/- 80.3 microg/24 h v 90.6 +/- 78.5 microg/24 h, P = .03). Dimensional echocardiographic data and albumin excretion rate did not differ between the two groups. In conclusion, mixture analysis allowed us to identify a population of young mild hypertensives with exaggerated BP response to standing. Hyperreactors were characterized by higher whole-day BP and by a hyperkinetic hemodynamic pattern as a result of increased sympathetic tone.

Blood pressure and metabolic responses to moderate sodium restriction in isradipine-treated hypertensive patients.

This multicenter, randomized, controlled clinical trial assessed the influence of sodium chloride intake on the antihypertensive effect of the calcium channel blocker isradipine. Participants with uncomplicated hypertension controlled by isradipine entered a 4-week sodium-restricted (60 to 80 mmol/24 h) period. Participants with urinary sodium levels < 120 mmol/24 h (n = 99) were randomized to placebo or sodium chloride (100 mmol/24 h) for 4 weeks, and then crossed over to the alternative treatment for an additional 4 weeks. Mean baseline systolic blood pressure was 151.9 +/- 16.7 mm Hg (mean +/- SD). During open-label isradipine treatment, systolic blood pressures for ad libitum sodium chloride and restriction were 134.1 +/- 11.1 and 132.1 +/- 12.2 mm Hg respectively; for double-blind sodium chloride restriction and supplementation: 133.6 +/- 12.6 and 138.5 +/- 12.8 mm Hg (P < .01). Urinary sodium excretion values for open-label isradipine ad libitum versus restricted were 140.6 +/- 61.9 versus 76.9 +/- 32.4 mmol/24 h; for double-blind restricted versus supplemented, sodium excretion was 120.5 +/- 68.9 v 175.9 +/- 68.7 mmol/24 h (P < or = .0001). Changes in urinary sodium excretion were not predictive of variations in blood pressure. Urinary sodium excretion during sodium restriction correlated directly with HDL-cholesterol (P < .02) and inversely with total cholesterol:HDL-cholesterol (P = .02), despite decreased total and saturated fat intake (P < .01). Sodium restriction was associated with significant reductions (P < .01) in virtually all macronutrients and electrolytes, and thus had an adverse impact on overall nutrition. The antihypertensive action of isradipine was not enhanced by dietary sodium chloride restriction, and the lipoprotein profile was least favorable with sodium chloride restriction.

Sodium concentration of water from softeners.

OBJECTIVES: To determine whether water is safe for consumption after it has passed through a water softener and whether there are any health and environmental implications of cationic water softeners. METHODS: Sodium concentration was measured in 59 water samples that had passed through a water softener and was compared with the sodium concentration of 5 samples from 4 different local municipal sources. RESULTS: The mean +/- SD sodium concentration of softened well water was 278 +/- 186 mg/L (range, 46-1219 mg/L). There were 10 (17%) households with sodium levels greater than 400 mg/L. The mean +/- SD sodium concentration of municipal, nonsoftened water was 110 +/- 98 mg/L (range, 0-253 mg/L). CONCLUSIONS: Softened well water in our area on average contained a 2.5-times-higher concentration of sodium than local municipal water, comparable with previous reports. It is unlikely that the increased sodium from softened water would have any health risks for most people. This may not be true for people on severely sodium-restricted diets.

Blood pressure level and variability in the prediction of blood pressure after 5-year follow-up.

We compared mean intra-arterial ambulatory blood pressure (IAMB), blood pressure (BP) diurnal profiles are variability, and postural measurements with casual sphygmomanometric measurements for the prediction of future BP. We studied 97 healthy, ummedicated men classified as normotensive (NT, n = 34), borderline hypertensive (BHT, n = 29), or mildly hypertensive (HT, n = 34) by repeated casual measurements during the 2 months before IAMB. Five years later, we reassessed 79 subjects (81%) using casual BP measurements and noninvasive ambulatory 24-hour BP monitoring (NAMB). IAMB level generally correlated well with follow-up BP and slightly better with NAMB level than with casual measurements (24-hour IAMB versus follow-up NAMB systolic BP [SBP], r = .64, P < .001; versus diastolic' BP [DBP], r = .52, P < .001). NT and BHT subgroup correlations were of similar strength, but the relationship in the HT subgroup was not significant. Similarly, when we examined daytime and nighttime BP levels, nighttime BP correlated better with follow-up BP in NT and BHT but not in HT. The only measures that were significantly related to follow-up BP in HT were two BP variability measures, SD and the range of variability (RV80: 90th minus 10th percentile), (initial 24-hour IAMB SD and follow-up BP, r = .42 to r = .52, P < .05 to P < .01; RV80 versus follow-up BP, r = .43 to r = .52, P < .05 to P < .01). Correlations of follow-up BP with postural BP were generally weaker than with casual BP or IAMB level. Linear stepwise regressions for SBP and DBP separately (including all IAMB variables) demonstrated that the best single predictor for follow-up BP was 24-hour IAMB SBP level, which explained 41% of follow-up NAMB SBP level variance (F = 52.6, P < .001). However, in a second analysis including casual values, casual SBP alone explained 44% of follow-up NAMB SBP variance (F = 62.5, P < .001), whereas IAMB SBP added only 4% (F = 5.5, P < .05). Predictions of follow-up DBP were always poorer. After 5 years, 70% of NT and 86% of HT were still in their initial classification group, but 67% of BHT had become hypertensive. In these new HT (n = 16), initial IAMB level correlated most strongly with follow-up NAMB level (24-hour SBP, r = .70, P < .01; 24-hour DBP, r = .55, P < .05). The only other significant demographic variable predicting future BP was change in weight over 5 years, which added 10% to the explanation of future casual SBP variance (F = 12.5, P = .0007) and 15% to casual DBP variance (F = 18.0, P = .0001); for NAMB, the percentages were lower. In logistic regression, those NT and BHT who became hypertensive (n = 22) had a 75% probability of becoming hypertensive if they gained 11.7 kg or more during 5 years (X2 = 4.5, P = .03). To conclude, BP tended to increase in all groups, especially in BHT, during follow-up. Nominal differences were observed between casual measurements and BP level measures in the prediction of future BP, and their explanatory value for future BP was generally less than 50%. However, for BHT who became hypertensive, BP level and variability measurements somewhat improved the prediction of follow-up BP. Weight gain was an important additional predictor for future hypertension in both NT and BHT.

Effects of increased arterial epinephrine on insulin, glucose and phosphate.

The relationship between sympathetic nervous system activity and glucose and insulin metabolism is not fully understood. In the present study we therefore investigated the effect of raising arterial plasma epinephrine within the lower pathophysiological concentration range on insulin, glucose and phosphate in blood. Arterial plasma epinephrine was raised over 60 min by a stepwise increasing intravenous infusion in healthy men aged 20-40 years (n = 40). Compared with infusion of saline, epinephrine caused a small but significant rise in serum insulin of 10 +/- 26 pmol/L (p = 0.016), more than 70% increase in serum glucose (p < 0.0001) and a decrease in serum phosphate (p < 0.0001). The changes in serum insulin during epinephrine infusion correlated negatively with the changes in arterial plasma epinephrine (r = -0.46, p = 0.003) and the changes in serum phosphate correlated negatively with the changes in serum glucose (r = -0.42, p = 0.007). Thus, arterial plasma epinephrine raised within the lower pathophysiological concentration range over a rather short period of time (60 min) has pronounced effects on insulin, glucose and phosphate in blood. These results suggest that epinephrine when infused acutely may suppress the insulin response to raised glucose, and that the acute hypophosphatemic effect of epinephrine is related to the glucose production. Thus, when epinephrine is released into the circulation during various forms of daily stress, e.g. mental stress, it may significantly affect insulin and glucose metabolism.

The use of genetic information in large-scale clinical trials: applications to Alzheimer research.

A great deal of secondary, or covariable, information is often collected during the course of large-scale clinical trials. This information typically includes demographic and anthropometric data but often also includes more elaborate laboratory-based measures that might be used to screen for adverse reactions to the preventive agent or treatment being tested. This information can be and often is used to identify individuals or, more likely, subgroups of individuals who appear to respond better (or worse) to the compound of relevance. Such heterogeneity in response is to be expected, since the basic biological constitution of individuals differs widely and since it is well known from simple pharmacokinetic assays that such differences can affect drug responses. Since genes influence the biological constitution of individuals, it is easy to argue that genetic differences between individuals could explain differential responsiveness to certain drugs, as pharmacogeneticists have suggested for years. In this article, it is argued that by collecting relevant genetic data on participants in large-scale clinical trials as though these data merely provided additional covariables, one might not only be in a position to identify responders and nonresponders to the compound being tested but could also be in a position to address fundamental questions about the nature and pathogenesis of the disease for which the compound was designed. Although we exemplify this simple argument by referring to antihypertensive compounds and research, this reference is made merely for reasons of convenience, since there are numerous compounds designed expressly for the prevention and treatment of hypertension, but rather few for Alzheimer disease. It is hoped that by adopting some of the guidelines and principles outlined herein, better and more appropriate compounds for the prevention and treatment of Alzheimer disease will be tested and ultimately made available to the patients for whom they work best.

Effect of circulating epinephrine on platelet function and hematocrit.

We investigated the effect of raising arterial plasma epinephrine within the lower pathophysiological concentration range on various indicators of blood platelet function and hematocrit. Epinephrine was raised over 60 minutes by a stepwise increasing intravenous infusion in 40 healthy men aged 20 to 40 years. Platelet count increased progressively with increasing arterial epinephrine to a maximal change of 69 +/- 6 x 10(9)/L in EDTA-anticoagulated blood and a maximal change of 42 +/- 6 x 10(9)/L in acid-citrate-dextrose (ACD)-anticoagulated blood, and the weight of circulating platelets increased by 29% (P < .001). Platelet size increased significantly in EDTA and decreased in ACD, and the difference between EDTA and ACD was significant (P < .0001) for both count and size, suggesting that epinephrine not only recruits platelets into the circulation but also induces some microaggregation in vivo or adhesion ex vivo. Aggregation of platelets in vitro induced by epinephrine decreased (P < .003 for delta optical density and P = .038 for maximal optical density) after epinephrine infusion compared with saline but did not change when stimulated with ADP or collagen. These findings suggest a selective downregulation of the epinephrine-activating mechanisms concomitant with a rise in the platelet content of epinephrine by 81% (P < .001) and no change in the platelet sodium-proton membrane exchange. The release of granular content (beta-thromboglobulin and platelet factor 4) to the circulation in response to epinephrine was not significant. Thus, under acute conditions it seems that the platelets may protect themselves against inappropriate overstimulation by epinephrine. The importance of platelet epinephrine uptake is still unknown, but sodium-proton exchange does not seem to be involved in regulating the effects of circulating epinephrine on platelet function. Epinephrine has a pronounced effect on raising hematocrit (maximal change of 1.74 +/- 0.13 x 10(-2), P < .0001).

Sex-specific determinants of increased left ventricular mass in the Tecumseh Blood Pressure Study.

BACKGROUND: Left ventricular hypertrophy (LVH) defined by either ECG or echocardiographic criteria is a risk factor for cardiovascular morbidity and mortality. A number of determinants of LVH have been described in previous studies, principally male sex, hypertension, obesity, and aortic valvular stenosis. We examined the distribution of LV mass (LVM) in a population of 18- to 42-year-old normotensive men and women who were free of valvular heart disease to establish sex-specific normal values for LVM index (LVMI) and to determine the correlates of LVMI. METHODS AND RESULTS: LVM was derived from measurements obtained by M-mode echocardiography. Average LVMI is significantly greater in men (102.9 +/- 0.7 g/m2) than women (88.2 +/- 0.7 g/m2). By defining LVH as an LVMI greater than the 90th percentile, we developed sex-specific criteria for LVH: men, > 125.4 g/m2; women, > 110 g/m2. We found that LVH in men is associated with indices of enhanced sympathetic nervous system reactivity and with elevated fasting insulin and triglyceride levels, which may be caused by insulin resistance. In women, LVH was associated with higher body weight and obesity. CONCLUSIONS: Before the onset of hypertension, increased LVMI appears to have different determinants in men and women. We suggest that early LVH in young men is a manifestation of hyperkinetic borderline hypertension, a state previously shown to be associated with increased sympathetic nervous system activity and insulin resistance. The hyperkinetic state is less prevalent in young women, in whom increased adiposity seems to be the predominant factor associated with LVH.

Adaptation, allometry, and hypertension.

Essential hypertension is a "disease of civilization" but has a clear genetic component. From an evolutionary perspective, persistence in the human genome of elements capable of raising blood pressure presupposes their adaptive significance. Recently, two hypotheses that explicitly appeal to selectionist arguments, the "slavery" and "thrifty gene" theories, have been forwarded. We find neither completely successful, and we advance an alternative explanation of the adaptive importance of genes responsible for hypertension. We propose that blood pressure rises during childhood and adolescence to subserve homeostatic needs of the organism. Specifically, we contend that blood pressure is a flexible element in the repertoire of renal homeostatic mechanisms serving to match renal function to growth. The effect of modern diet and lifestyle on human growth stimulates earlier and more vigorous development, straining biologically necessary relationships between renal and general somatic growth and requiring compensation via homeostatic mechanisms preserved during evolution. Prime among such mechanisms is blood pressure, which rises as a compensation to maintain renal function in the face of greater growth. Since virtually all members of acculturated societies share in the modern lifestyle, the demands imposed by accelerated growth and development result in a populational shift to higher blood pressures, with a consequent increase in the prevalence of hypertension. We propose that hypertension is the product of maladaptation of highly genetically conserved mechanisms subserving important biological homeostatic needs. Elucidation of the mechanisms underlying hypertension will require approaches that examine the developmental processes linking growth to blood pressure.

Sympathetic nervous system involvement in essential hypertension: increased platelet noradrenaline coincides with decreased beta-adrenoreceptor responsiveness.

Platelet catecholamine content may reflect integrated plasma catecholamine concentrations over time. The present study aimed at examining sympathetic nervous system (SNS) involvement in essential hypertension by assessing platelet noradrenaline (NA) and typically beta-adrenoreceptor mediated responses to adrenaline (A) infusion as indices of sympathetic tone. Healthy white men were recruited by public advertising and screening (mean +/- SD): Hypertensives (n = 13, sitting blood pressure [BP] 153 +/- 13/106 +/- 7 mmHg, age 34 +/- 5 years, weight 83 +/- 10 kg) were compared to normotensives (n = 13, sitting BP 114 +/- 9/75 +/- 9 mmHg, age 30 +/- 6 years [n.s.], weight 82 +/- 9 kg [n.s.]). Loss of platelet granular contents (including NA) prior to analysis was minimized by studying young subjects (age range 20-40 years, minimal atherosclerosis), using arterial blood sampling, and processing blood immediately. These procedures resulted in plasma beta-thromboglobulin and platelet factor 4 levels which were not significantly different between groups. Sympathetic activation resulting from stress was minimized by not labelling subjects as either hypertensive or normotensive. Mean arterial platelet NA content was significantly higher in hypertensives (64 +/- 31 pg/mg of platelet weight) compared to normotensives (43 +/- 20 pg/mg, p < 0.05) both at baseline and following 35% expansion of the circulating platelet pool by A infusion (p < 0.05) and correlated with arterial NA in the hypertensives (r = 0.79, p < 0.002) but not in the normotensives (r = 0.04, n.s.). Similar increases in platelet and plasma A during infusion in both groups suggest unchanged platelet uptake capacity and plasma clearance in the hypertensive group.(ABSTRACT TRUNCATED AT 250 WORDS)