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Clinical Diabetes and Nutrition Section, National Institute of Diabetes Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona 85016
Address all correspondence to: E. Ravussin, Ph.D., NIH, 4212 N. 16th Street, Phoenix, Arizona 85016. E-mail: Eric_Ravussin{at}nih.gov
Abstract
The sympathetic nervous system controls cardiovascular homeostasis and regulates energy metabolism. Pima Indians, a population with a low prevalence of hypertension and a high prevalence of obesity, have low sympathetic nervous activity, compared with Caucasians. Preliminary findings suggest that they may also have a low ß-adrenergic sensitivity. We studied ß-adrenergic sensitivity in 87 nondiabetic normotensive individuals [52 Pima Indians (35 males/17 females) and 35 Caucasians (24 males/11 females)], matched for age and body weight. Chronotropic sensitivity to ß-adrenergic stimulation was assessed by the dose of isoproterenol necessary to increase heart rate by 25 beats per minute [chronotropic dose-25 (CD25)]. Despite a similar basal heart rate and arterial blood pressure, Pimas tended to have lower ß-adrenergic sensitivity than Caucasians (CD25 = 2.37 ± 2.27 vs. 1.57 ± 1.38 µg, P = 0.07; mean ± SD). This difference was significant in males (CD25 = 3.03 ± 2.39 vs. 1.85 ± 1.56 µg, P = 0.02) but not in females (CD25 = 1.01 ± 1.17 vs. 0.96 ± 0.61 µg, P = 0.99). In males only, CD25 was positively correlated to percent body fat (r = 0.36, P < 0.01). After adjustment for percent body fat, ß-adrenergic sensitivity was still significantly lower in Pima than in Caucasian males (CD25 = 3.44 ± 2.24 vs. 2.57 ± 1.60 µg, P = 0.05). In conclusion, our data suggest that increased adiposity is accompanied by decreased ß-adrenergic sensitivity in males only. However, at each level of adiposity, Pima Indian males have lower ß-adrenergic sensitivity than Caucasian males. In combination with a low sympathetic nervous system activity, a reduced ß-adrenergic sensitivity may contribute to the low prevalence of hypertension and the high prevalence of obesity observed in Pima Indians.
SEVERAL lines of evidence suggest that an altered sympathetic nervous system (SNS) activity not only perturbs cardiovascular homeostasis (1) but also plays a role in obesity (2, 3). In humans, SNS activity is positively associated with energy expenditure (4, 5, 6, 7, 8) and negatively associated with energy intake (9, 10, 11). Pima Indians have a low SNS activity, compared with Caucasians (8); and among Pimas, a low SNS activity is associated with body weight gain and development of central adiposity (12). Interestingly, the association between SNS activity and energy expenditure is only observed in Caucasians and not in Pima Indians (6, 8). Taken together, these findings suggest that Pima Indians may be characterized not only by low SNS activity but also by a reduced sensitivity to ß-adrenergic stimulation, as previously suggested by Christin et al. (7). Both a reduced SNS activity and a blunted response to its action may predispose Pima Indians to obesity (13) but may protect them from the cardiovascular complications of adiposity (14, 15).
The aim of the present study was to investigate whether Pima Indians have lower ß-adrenergic sensitivity than Caucasians, by measuring the chronotropic response of the heart to ß-adrenergic stimulation (isoproterenol). We studied 52 Pima Indians and 35 age- and weight-matched Caucasians, and we observed a reduced ß-adrenergic sensitivity in Pima males only.
Materials and Methods
Subjects
Fifty-two Pima Indians from the Gila River Indian Community and
35 Caucasians from the metropolitan Phoenix area participated in the
study [results in 10 Pimas and 10 Caucasians were previously reported
(7)]. The physical characteristics of the subjects are shown in Table 1
. Subjects were admitted, for 7–10
days, to the Clinical Diabetes and Nutrition Section of the National
Institute of Diabetes and Digestive and Kidney Diseases in Phoenix, and
they were fed a weight maintenance diet (50% carbohydrate, 30% fat,
and 20% protein). All subjects were sedentary individuals in good
health, with normal thyroid status and normal blood pressure. All were
nondiabetic, according to an oral glucose tolerance test administered
after at least 3 days on the diet (16). Body composition was estimated
by underwater weighing with simultaneous measurement of residual lung
volume (17, 18). Abdominal girth was measured at the umbilicus, with
the subjects lying; and thigh circumference was measured at the level
of the gluteal fold, with the subject standing. The waist-to-thigh
circumference ratio was used as an index of body fat distribution. The
study was approved by the ethics committee of the NIDDK and by the
Tribal Council of the Gila River Indian Community. All subjects gave
written informed consent.
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After at least 3 days on the diet and after an overnight fast,
the chronotropic sensitivity to ß-adrenergic stimulation was measured
using isoproterenol (a nonselective ß-adrenergic agonist) injections
(7, 19). With the subject lying comfortably on a bed, an antecubital
vein was cannulated and kept patent with isotonic saline. After a
20-min rest period, baseline systolic and diastolic blood pressure and
resting heart rate were recorded using a heart rate monitor with an
automated inflatable cuff (Escort 100, Medical Data Electronics,
Arleta, CA). Baseline systolic and diastolic blood pressure was the
mean of four determinations over 2 min. Baseline heart rate was
continuously recorded for 60 min and was measured as the mean of three
peak R-R intervals. Increasing bolus doses (0.10, 0.25, 0.50, 1.00,
2.00, and 4.00 µg) of isoproterenol (Elkins-Sinn, Cherry Hill, NJ; 1
mg/5 mL) were injected, at least 10 min apart (to allow the heart rate
to return to baseline values for 5 min). No additional dose was infused
if heart rate increased by 
35 beats per minute (bpm) over baseline.
The chronotropic dose-25 (CD25) was calculated from the regression line
between the increment in heart rate and the log dose of isoproterenol,
and it represents the dose of isoproterenol required to increase the
heart rate by 25 bpm over baseline (19). The experiment was well
tolerated by all subjects, and only a few of them experienced mild
palpitations and shortness of breath.
Respiratory chamber
Twenty-four-hour energy expenditure and respiratory quotient were measured in a respiratory chamber in only 32 Pima Indians and 27 Caucasians, as previously described (20). Briefly, the subject entered the respiratory chamber at 0800 h and remained inside until 0700 h the next day. No vigorous exercise was allowed in the chamber, and spontaneous physical activity was assessed by a radar system. Meals supplied from the metabolic kitchen provided approximately 80% of the energy requirements on the ward, to account for the decrease in physical activity in the chamber. Twenty-four-hour energy balance was calculated as the difference between daily energy intake and expenditure, and it was expressed as percent of energy intake.
Analytical determinations
Plasma glucose concentration was measured by the glucose oxidase method using a Beckman Glucose Analyzer (Beckman Instruments, Inc., Fullerton, CA). Plasma insulin concentration was determined by the modification made by Hebert et al. (21) to the RIA of Yalow and Berson (22).
Statistical analyses
Results are presented as means ± SD, unless otherwise indicated. Statistical analyses were performed using the procedures of the SAS Institute (Cary, NC). CD25 and plasma insulin concentrations were log10-transformed before parametric analysis to approximate normal distribution. Between-group differences were tested by unpaired Student’s t test. Correlations are Pearson’s product-moment correlations. Using multiple regression analyses, 24-h energy expenditure was adjusted for fat-free mass, fat mass, and age; and 24-h respiratory quotient was adjusted for percent body fat, energy balance, and age. In males only, linear regression analysis was used to adjust CD25 for percent body fat.
Results
The physical characteristics of the subjects are shown in Table 1
.
When compared with Caucasians, Pimas had higher percent body fat and a
more centrally distributed adiposity. Also, fasting plasma insulin was
significantly higher in Pimas than in Caucasians. Basal heart rate and
diastolic, systolic, and mean blood pressure were similar in Pimas and
Caucasians. However, the dose of isoproterenol necessary to increase
the basal heart rate by 25 bpm (CD25) tended to be higher in Pimas than
in Caucasians (2.37 ± 0.31 vs. 1.57 ± 0.23 µg,
P = 0.07). This difference was significant in males
(CD25 = 3.03 ± 0.40 vs. 1.85 ± 0.31 µg,
P < 0.02; Fig. 1, upper panel) but not in females (CD25 = 1.01 ±
0.28 vs. 0.96 ± 0.18 µg, P = 0.99;
Fig. 1, lower panel).
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CD25 was significantly lower in females than in males (P < 0.01). In females, no correlations were found between CD25 and body size, adiposity, body fat distribution, cardiovascular parameters, fasting plasma insulin and glucose concentrations, and adjusted energy metabolism variables.
Discussion
The results of the present study indicate that the chronotropic sensitivity to ß-adrenergic stimulation decreases with increasing adiposity in males. Also in males, ß-adrenergic sensitivity was lower in Pimas than in Caucasians, even after adjustment for percent body fat. In females, ß-adrenergic sensitivity was not correlated to adiposity and was not different between Pimas and Caucasians.
In agreement with other studies (7, 23, 24), we observed a reduction of ß-adrenergic sensitivity with increasing adiposity in males. This may be caused by the development of hyposensitivity to adrenergic stimulation and down-regulation of receptors in response to the increased SNS activity often observed with increasing adiposity (8, 25, 26). However, at each level of adiposity, Pima Indian males were more resistant to ß-adrenergic stimulation than Caucasian males. This is surprising, because Pima Indians have a low SNS activity, when compared with age- and weight-matched Caucasians (8), and therefore, one would expect a higher ß-adrenergic sensitivity. Because chronic hyperinsulinemia is known to desensitize ß-adrenergic receptors in adipocytes (27), it is possible that hyperinsulinemia contributes to the lower ß-adrenergic sensitivity observed in Pima Indians.
The reasons for the sex differences in CD25 and in the relationship between CD25 and adiposity are unclear. Also, the racial difference in CD25 between Pima and Caucasian was not seen in females. The rather small sample size and the lack of control for the phase of the menstrual cycle may account, at least in part, for these negative results in females. Alternatively, sex hormonal differences (estrogen and/or testosterone) may explain the lower heart rate responsiveness observed in females and the lack of racial difference among females.
The SNS is primarily involved in the regulation of cardiovascular homeostasis (1). Cardiac ß-adrenergic sensitivity is an important determinant of cardiovascular reactivity to stress (28), which in turn, determines blood pressure status later in life (29) and, therefore, predisposition to cardiovascular disease and stroke. It has previously been reported that increased adiposity is associated with increased SNS activity (8, 25, 26). As a consequence, blood pressure and the morbidity and mortality from cardiovascular disease are generally increased in obese individuals (30). Despite the high prevalence of obesity and diabetes, Pima Indians seem to have a lower prevalence of hypertension (14) and a lower incidence of fatal coronary heart disease (15) than the general USA population. The lower chronotropic sensitivity to ß-adrenergic stimulation in Pima males is consistent with these epidemiologic findings and may indicate that Pima Indians have reduced cardiovascular reactivity to stress.
It has been proposed that the adrenergically mediated thermogenic response to stimuli is related to stimulation of both ß1 and ß2 (31) (and probably ß3) adrenoceptors (32). In the present study, however, we did not find any association between CD25 and energy expenditure. Because ß2 adrenoceptors are more important in mediating thermogenic responses than ß1 receptors (24), the ß1-adrenergic resistance observed in Pima males may, therefore, not be the primary cause of the blunted thermogenic response to adrenergic stimulation observed in this population (6, 7, 8). In contrast, it has been suggested that the contribution of ß1-adrenoceptors may be important in modulating lipid metabolism, such as lipolysis and oxidation (24). The positive association between CD25 and 24-h respiratory quotient in Pima males seems to indicate that ß1-adrenergic resistance may explain, at least in some individuals, a reduced ability to oxidize lipids. This is of importance, because a high respiratory quotient, i.e. a low ratio of fat to carbohydrate oxidation, is a predictor of the development of obesity (33, 34, 35, 36).
In conclusion, our data indicate that the chronotropic sensitivity to ß-adrenergic stimulation declines proportionally to the increase in adiposity in males, but not in females. At each level of adiposity, Pima Indian males have lower ß-adrenergic sensitivity than Caucasian males. Lower SNS activity, in combination with a reduced chronotropic sensitivity to ß-adrenergic stimulation, may contribute to the lower prevalence of hypertension and higher prevalence of obesity observed in Pima Indians.
Received August 20, 1997.
Revised October 17, 1997.
Accepted December 15, 1997.
References
- and ß-adrenoceptors in sympathetically mediated
thermogenesis. Am J Physiol. 264:E11–E17.
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