Abnormal Epinephrine Release in Young Adults With High Personal and High Parental Blood Pressures
Background Increased activity of the sympathetic nervous system has been proposed as a cause of high blood pressure (BP) and may be related to diet and body weight. To determine the role of these factors in predisposition to high BP, we studied 100 young adults with high or low BP from families in which both parents had either high or low BP.
Methods and Results Plasma catecholamine, glucose, and insulin levels were measured before and after an oral glucose load. There was a significant correlation between fasting plasma norepinephrine and mean arterial pressure (P=.001). Subjects with high BP, irrespective of parental BP, were heavier (P=.003) and fatter (P=.002) and had a greater rise in plasma insulin (P=.003) following glucose than those with low BP. Offspring with high BP whose parents also had high BP showed an unexpected rise in plasma epinephrine (P=.004) following glucose. This adrenal medullary response was not the result of high parental or high personal BP alone as it was not seen in offspring with low BP whose parents had high BP or in offspring with high BP whose parents had low BP.
Conclusions Irrespective of family history, high BP is associated with increased body weight and hyperinsulinemia and reflects personal environment and behavior. However, abnormal epinephrine release is characteristic of the combination of genetic, environmental, and behavioral factors that is associated with high personal BP and a familial predisposition to high BP.
High BP is associated with abnormalities of the sympathetic nervous system1 2 and insulin metabolism.3 4 Similar findings are reported in young people predisposed to high BP. Familial factors are important, and increased cardiovascular responses to mental stress5 and catecholamine responses to physical stress6 have been reported in subjects with a history of parental hypertension. Abnormal insulin metabolism, including hyperinsulinemia and/or insulin resistance, is also evident in the offspring of hypertensive parents.7 8 9 However, the relationship between familial patterns of sympathetic activity and insulin metabolism is not well understood.
In general, the metabolic effects of insulin and the sympathetic nervous system are opposite and part of normal homeostasis. For example, the hypoglycemic effects of insulin are antagonized by the sympathetically mediated release of EPI from the adrenal medulla. However, insulin may stimulate central activation of sympathetic nerves.10 In the long term, high energy intake and BMI may result in increased insulin levels,11 increased activity of the sympathetic nervous system,12 and increased BP.13 The nature of these links is not clear and may involve interactions between personal environment or behavior and genetic predisposition.14
This study aimed to examine the relationship between body composition and the responses of the sympathetic nervous system, adrenal medulla, and insulin to glucose ingestion in individuals predisposed to high BP. Predisposition was defined on the basis of both personal and parental BP levels. We used the four-corners method15 16 17 to select groups of healthy young adults from the general population with high or low personal and high or low parental BPs. This approach provides a method for finding correlates that are not apparent in studies based on personal or parental pressures alone because it is possible to compare and contrast correlates of raised BP in subjects with and without familial predisposition. This study was designed to examine in healthy young adults with high BP whether body size and composition, sympathetic nervous activity, or the physiological response to glucose depends on familial predisposition.
The four-corners design relies on BP data from both parents and children and has been described in detail.15 16 17 In brief, BPs were measured in 864 young adults, aged 16 to 24 years, from 603 families. Their parents had undergone BP measurements 8 years before as part of the screening phase of the Medical Research Council Mild Hypertension Trial. Individual BPs were adjusted for the effects of age, sex, and use of the oral contraceptive pill. The BPs of subjects being treated for hypertension were adjusted to place them in the top 5% of the distribution. Maternal and paternal BPs were combined to provide a single parental BP for each offspring.
The personal BPs of the offspring were plotted against their combined parental pressures in a scatter diagram (Fig 1⇓). High pressures were considered to be those in approximately the top 30% of personal or parental distributions. Low pressures were those in the bottom 30% of the distributions. These relatively broad epidemiological definitions were chosen to identify differences associated with contrasts in BP within the general population rather than with differences between normotensive subjects and patients with clinical hypertension. The divisions resulted in four corners, ie, offspring with high personal and low parental pressures, high personal and high parental pressures, low personal and low parental pressures, and low personal and high parental pressures. For this study we recruited ≈25 offspring from each group.
Subjects were admitted to the hospital on their normal diet, and written informed consent was obtained from all volunteers. To minimize potential bias, the BP categorizations of the parents and offspring were not revealed to either the participants or the clinical investigators. The studies were approved by the Western Infirmary ethics committee.
Measurements were obtained of participants’ height, weight, armspan, waist and hip circumferences, and skinfold thicknesses in the triceps, biceps, subscapular, and suprailiac regions. Body fat as a percentage of body weight was calculated from skinfold measurements.18 Total body fat was subtracted from body weight to calculate lean body mass.
At 7 am, after an overnight fast that began at 9 pm, intravenous cannulae were inserted into the subjects’ right and left cubital veins. A BP cuff was attached to the right arm, and BP and PR were measured automatically by a Copal UA251 autoinflation digital sphygmomanometer (Takeda Medical Corp) while subjects remained semisupine in bed. Three readings were taken every half hour for 2 hours and averaged at each time point to calculate the SBP, DBP, and PR.
Blood samples were taken at 8:30 am for estimation of glucose, insulin, NE, EPI, dopamine, glycosylated hemoglobin, and fructosamine levels and a lipid profile by methods used previously.12 All subjects then drank 75 g of glucose in water. Blood was taken every half hour for 2 hours for measurements of glucose, insulin, and catecholamine levels. Cortisol and aldosterone were measured 1 hour after glucose ingestion.
The effects of categorization according to parental and personal BPs were analyzed by using a 2×2 factorial ANOVA design with one factor being personal BP (high or low) and the other parental BP (high or low). Characteristics that were dependent on particular combinations of personal and parental BPs were identified in the ANOVA as those associated with a significant statistic for interaction between the two factors. Nonparametric correlation analysis was used to calculate Spearman rank correlation coefficients to examine relationships between variables in the combined group of 100 subjects. To detect and control for effects arising as a result of categorization according to personal and parental BPs in the combined group, we used multiple regression analysis. Pressure categories were entered into the regression models as dummy variables (low=0, high=1). To control for any sex-related differences in ANOVA and regression analyses, gender was also entered as a dummy variable (female=0, male=1). For variables measured several times, a repeated-measures ANOVA was used.19 The χ2 test was used to compare sex distribution and the use of the oral contraceptive pill between groups. In view of the number of comparisons, we accepted statistical significance as P<.005.
Baseline Characteristics: Hemodynamic and Anthropometric Variables
The four offspring groups comprised approximately equal numbers of individuals of similar average age (Table 1⇓). There were no significant differences in the male/female ratio (χ2 =2.31, df=3, P=.51) or the use of the oral contraceptive pill (χ2 =6.35, df=3, P=.10).
Mean arterial pressure was significantly different between the high and low groups (Table 1⇑), reflecting the original categorization made 3 years previously. The persistence of these differences with time indicates tracking of pressures and the robustness of the original classification. PR was higher in offspring with high personal pressures, and within this group, PR was higher in offspring whose parental pressures were also high.
Body weight, BMI, and body fat were significantly greater in offspring with high BPs irrespective of parental BPs (Table 2⇓).
Baseline Characteristics: Biochemical Variables
Fasting plasma NE was higher in those with high personal BPs (Table 3⇓) and correlated with mean arterial pressure (r=.343, P=.001). In offspring whose parents had high BP, plasma EPI was significantly higher (P=.01) in those with high as opposed to low personal BPs. No significant differences were seen between groups in fasting plasma dopamine, nor were there any significant differences between the groups in basal plasma glucose or insulin levels (Table 3⇓). Indices of time-averaged glycemia:fructosamine and glycosylated hemoglobin were also similar between groups (data not shown). Lipid profiles (total, HDL, LDL, and VLDL cholesterol and triglycerides) were the same in each group (data not shown) and were not associated with BP.
Changes After Glucose
The hemodynamic response to glucose (Fig 2⇓) comprised significant (P<.0001) increases in PR and SBP and reductions in DBP. There were no differences in these responses according to parental or personal BP groups. In the subsequent period both SBP and DBP returned toward fasting values (Fig 2⇓).
There were significant (P<.0001) rises in plasma glucose and insulin (Fig 3⇓) 30 minutes after glucose. Subsequently, subjects with high BPs had higher glucose and plasma insulin levels (P=.008) than subjects with low BPs irrespective of parental BPs. There was also a significant rise in plasma NE 30 minutes after glucose in all groups (P<.0001), but changes in plasma EPI were not uniform. Three groups showed no change or a slight fall in plasma EPI 30 minutes after glucose (Fig 4⇓) (P=.507). In contrast, subjects with both high personal and high parental BPs showed a significant increase in EPI (P<.004).
Plasma dopamine levels rose significantly in all groups 30 minutes after glucose (data not shown). In the subsequent period, plasma EPI fell slightly and nonsignificantly in all groups while plasma NE levels remained relatively stable throughout the postglucose period (Fig 4⇑).
Influence of BMI
Because differences in BMI per se may influence insulin levels, we performed two analyses of the insulin response to glucose, taking BMI into account. First, BMI was entered as a covariate in the ANOVA to correct for the association between BMI and insulin for the entire sample. Second, insulin levels were corrected for individual BMIs before being entered into the ANOVA. Neither approach showed a significant relationship between high BP and insulin adjusted for BMI.
In contrast, the rise in plasma EPI in those with high personal and parental BPs remained statistically significant after adjustment for BMI.
Studies of young people predisposed to high BP aim to identify physiological characteristics that may explain population variation in BP or precede the later development of clinical hypertension. Predisposition can be defined in two ways. High personal BPs predispose because of the tracking phenomenon. High parental BPs predispose because of genetic and/or shared behavioral or environmental factors within families. The physiological mechanisms underlying tracking and familial predisposition may differ and possibly interact. In this study we have identified phenotypes that associate with high personal BP irrespective of familial predisposition and a phenotype that is apparent only when high personal and parental BPs coincide.
In young adults with high BP, only those with high parental pressures showed a significant rise in plasma EPI in response to glucose ingestion. This phenotype is contrary to expectations, as EPI is normally released in response to insulin-induced hypoglycemia, and plasma EPI usually falls slightly during hyperglycemia.20 21 22 The physiological explanation for this unusual response is not obvious from these studies.
EPI is usually released in response to sympathetic stimulation of the adrenal medulla. Acetylcholine release by preganglionic nerves causes adrenal medullary chromaffin cells to secrete EPI. In our study, glucose ingestion and hyperinsulinemia resulted in stimulation of the sympathetic nerves20 23 24 as mirrored by increased PR and plasma NE. The magnitude of the generalized sympathetic response was not augmented in the subjects showing a rise in plasma EPI levels. Thus, higher EPI suggests a process involving the adrenal medulla specifically. Such a phenotype may be the result of greater regional sympathetic nerve traffic to the adrenal medulla or greater sensitivity of the adrenal medulla to sympathetic stimulation.25
The enzyme phenylethanolamine N-methyltransferase converts NE to EPI in the adrenal medullary chromaffin cells. The basal activity of this enzyme is modulated by the high levels of cortisol in blood flowing from the adrenal cortex.26 Therefore, increased adrenal cortical activity could enhance EPI production, storage, and release. The plasma cortisol levels obtained 30 minutes after glucose ingestion (9:30 am) were not significantly higher in the group showing the exaggerated EPI release. However, we have reported16 that afternoon cortisol levels are significantly higher in these subjects, suggesting a loss of the normal diurnal fall in afternoon cortisol. These higher average cortisol levels may induce phenylethanolamine N-methyltransferase activity and contribute to the abnormal EPI release.
The EPI response to glucose is not a consequence of high personal BP alone as it was not found in offspring with high personal but low parental BPs. Dependence on parental BP suggests the influence of familial factors associated with high BP. However, high parental BP alone is not a sufficient explanation for EPI release, as it was not seen when offspring had high parental but low personal BPs. Therefore, the phenotype depends on the combination of individual and familial factors. This suggests that individual environment or lifestyle may interact with the genetic or environmental factors that characterize families in which both parents have high BP.
High personal BP was also associated with increased body fat and plasma NE levels and hyperinsulinemia. Similar observations have been made by others, and their possible interrelationships have been discussed.13 14 27 28 However, our study reveals for the first time that these phenotypes are independent of familial predisposition as they were observed when parental BPs were either high or low. The association between high personal BP and increased BMI and insulin and NE concentrations could be explained by the influence of individual environment or lifestyle. For example, high dietary energy intake or low energy expenditure through a sedentary lifestyle might cause increased body fat, leading to elevated plasma insulin and NE levels and BP.
Clearly, there is a potentially synergistic interaction between personal behavior and familial predisposition. If eating stimulates the release of EPI in genetically predisposed subjects, then larger or more frequent meals may augment the adrenal medullary response as well as contribute to increased body fat. Other stimulants of the sympathetic nervous system such as smoking or sex may also augment the release of EPI. Such intermittent increases may be more important in physiological terms than prolonged increases in EPI, which can lead to receptor desensitization.29
Direct actions of EPI may contribute to the development or sequelae of hypertension. Through the β-adrenergic receptors, EPI results in inotropic and chronotropic stimulation of the heart and renin release. Stimulation of the α1-adrenergic receptors contracts the vasculature and may have trophic effects on cardiovascular muscle cells. EPI also has agonist effects on the α2-adrenergic receptors, which are numerous in organs relevant to long-term BP control such as the central nervous system and the kidneys, where the α2-adrenergic receptors mediate effects on neural vasomotor control and sodium resorption, respectively.30
This study is unique in that it is based on families selected from the general population and definitions of familial predisposition based on BP measurements in two generations. The participants in this study are a random subsample of offspring in the four corners who together comprise 55% of the total population. The results bear on why large numbers of people have BPs above and below the mean, rather than why a few people have values in the tail of the distribution (eg, patients with clinical hypertension). The abnormal adrenal medullary function that occurs with the combination of high personal and parental BPs exists in ≈14% of our population. This group comprises only 37% of all offspring with high BP and 46% of all offspring from families with high parental BPs. Studies based only on the presence or absence of a “positive family history of hypertension” without reference to personal BPs are unlikely to identify such phenotypes because of a dilution effect. The adrenal medullary phenotype would not have been identified in our study if we had selected on the basis of high personal BP or high parental BP alone. Our study has also shown that certain correlates of high BP, such as increased body weight, transcend familial predisposition and are likely, therefore, to have environmental or behavioral explanations. Such information from young adults before the development of clinical hypertension may be relevant to the development and targeting of prevention and treatment strategies.
Selected Abbreviations and Acronyms
|BMI||=||body mass index|
|DBP||=||diastolic blood pressure|
|SBP||=||systolic blood pressure|
This study was funded by the British Heart Foundation. Professor Harrap was supported as a Neil Hamilton Fairley Travelling Fellow of the National Health and Medical Research Council of Australia. We thank Drs D.W. Holton and H.V. Edwards of the Ladywell Medical Centre, Edinburgh, UK, for their valuable cooperation.
- Received August 20, 1996.
- Revision received February 3, 1997.
- Accepted February 11, 1997.
- Copyright © 1997 by American Heart Association
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