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(Hypertension. 1996;27:1180-1186.)
© 1996 American Heart Association, Inc.
Articles |
Improvement of Insulin Sensitivity Contributes to Blood Pressure Reduction After Weight Loss in Hypertensive Subjects With Obesity
From the Medical Research Institute and Department of Nephrology, Nippon Telegraph and Telephone (NTT) Kanto Teishin Hospital, Tokyo, Japan.
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Abstract |
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Abstract To assess the role of insulin resistance in obesity hypertension, we examined the change of insulin sensitivity after weight loss in 24 obese hypertensive subjects by the euglycemic hyperinsulinemic glucose clamp method. The results of the 4-week calorie-restricted diet were a weight loss of 10.2% (from 74±12 to 67±11 kg, P<.01) and a decrease in mean blood pressure of 13.1% (from 124±7 to 107±9 mm Hg, P<.01). A decrease in plasma norepinephrine (from 208±74 to 142±52 pg/mL, P<.01) was associated with decreases in plasma renin activity (from 1.06±0.98 to 0.62±0.63 ng/mL per hour, P<.01) and serum aldosterone (from 70±28 to 57±24 pg/mL, P<.05). Glucose infusion rate increased significantly (42.9%), from 809±194 to 1155±251 µmol/m2 per minute. The insulin sensitivity index, which is a measure of the glucose infusion rate divided by plasma insulin, increased significantly (42.6%), from 10.8±3.5 to 15.4±4.4 (µmol/m2 per minute)/(µU/mL). Stepwise multiple linear regression analysis showed that changes of plasma norepinephrine, insulin sensitivity index, plasma renin activity, and age were significant predictive factors for the change of mean blood pressure after weight loss. These results indicate a distinct relation between an improvement of insulin sensitivity and a decrease in blood pressure after weight loss in obese hypertensive subjects. The decrease in blood pressure after weight loss is probably related to the suppression of sympathetic nervous activity.
Key Words: body mass index • diet • hypertension, obesity • insulin resistance • norepinephrine • renin-angiotensin system
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Introduction |
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The strong association between hypertension and obesity has been amply documented in a cross-sectional survey of the general population.1 2 3 The precise prevalence of hypertension associated with obesity varies with the definition for hypertension and obesity, but the risk for hypertension has been reported to be 50% to 300% higher in obese individuals than in those of normal weight.2 3 Although the association between obesity and hypertension has been firmly established, the underlying mechanisms involved in the development of obesity-related hypertension have not been identified. Some investigators have suggested that certain hemodynamic factors and neuroendocrine mechanisms play a role in the pathogenesis of this type of hypertension. Obese hypertensive patients tend to have a slightly elevated cardiac output and less-pronounced peripheral vasoconstriction compared with lean patients with essential hypertension.4 5 6 An increased sympathetic nervous activity and stimulation of the renin-angiotensin-aldosterone system have been postulated as predominant pathogenic factors in obesity hypertension.7 8 9 10 Recently, attention has been focused on the role of insulin resistance in the development of obesity hypertension.11 12 13 14 15 Blood pressure (BP) has been reported to correlate with basal and glucose-stimulated insulin levels.11 12 13 Plasma insulin levels rise in obese subjects secondary to resistance to insulin-mediated glucose disposal.14 There is a significant inverse relation between BP and whole-body glucose uptake measured by the euglycemic hyperinsulinemic glucose clamp technique.15 16 However, the relationship between hypertension and insulin resistance in obesity may be complex, because some studies have shown that lean hypertensive subjects also have insulin resistance, the same as obese hypertensive patients.16 17
In this study, we sought to determine whether the depressor effect of weight loss after a low-calorie regimen could be linked to the change of insulin sensitivity and to determine predictive factors that may contribute to the depressor response in obese hypertensive subjects.
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Methods |
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Subjects
This study was conducted on 24 untreated hypertensive subjects with moderate obesity (9 men and 15 women; mean age, 51.4 years) whose body mass index was more than 25 kg/m2 (range, 25.0 to 34.8; mean, 29.4). Hypertension was diagnosed when BP measured at the outpatient clinic had been higher than 160 mm Hg systolic and 95 mm Hg diastolic on three consecutive visits at least 1 week apart without antihypertensive medication. Subjects with any other cause of hypertension except obesity and with diabetes mellitus as diagnosed according to the glucose criteria of the World Health Organization (WHO) Study Group (fasting plasma glucose levels,
7.8
mmol/L; 2 hours after glucose load, 11.1 mmol/L)18 were
excluded from the study. Physical and laboratory examinations, chest
radiographs, electrocardiograms, and funduscopy were
performed for determination of any hypertensive organ damage. Our
subjects included 3 cases at stage I and 21 cases at stage II of the
WHO classification of hypertension by extent of organ
damage.19 Clinical information about the subjects was
obtained from their medical records, which included a family
history of hypertension and diabetes mellitus, daily alcohol intake,
and tobacco consumption. Nineteen subjects (79%) had a family history
of hypertension, but only 2 subjects exhibited a family history of
diabetes mellitus. Six subjects took alcohol every day and 7 subjects
were smokers. The nature of the study and potential risk associated with it were explained to all subjects, who gave their signed informed consent before participating in the study. The study protocol was approved by the Institutional Review Board on Human Investigations of NTT Kanto Teishin Hospital.
Study Protocol
All subjects were admitted to the clinical research ward and
placed on a normocaloric and low sodium diet to stabilize BP and sodium
balance. The daily diet contained 7890 kJ (1900 kcal) and consisted of
305 g carbohydrates, 50 g proteins, and 60 g fats. Sodium intake was 90
mmol/d. More than 7 days after hospitalization, insulin sensitivity in
the control period was examined by the euglycemic
hyperinsulinemic glucose clamp method. The study
started in the morning with the subjects fasting over 12 hours in a
temperature-controlled (25°C) and humidity-controlled (55%)
quiet room. Subjects rested in the supine position after voiding of
urine and measurement of body weight. BP and pulse rate values used for
analysis were averaged from five measurements taken every 3
minutes after subjects had rested for 30 minutes in the supine position
after more than 7 days of in-hospital stabilization. A
double-lumen catheter for glucose analysis was introduced
into the antecubital vein. The contralateral antecubital vein was
cannulated with a No. 18 plastic cannula for infusion of an insulin and
glucose solution. Thirty minutes after implantation of the catheter,
blood samples were taken for determinations of plasma glucose, insulin,
lipids, plasma renin activity (PRA), serum aldosterone, and
plasma norepinephrine. Twenty-four-hour urine
samples taken during the 3 days before the clamp study were collected
for determination of creatinine and sodium excretion.
Fractional excretion of sodium was calculated from the ratio of sodium
clearance to creatinine clearance.
Two days after the clamp study in the control period, subjects were placed on a low-calorie diet without change in the sodium content for 4 weeks. The daily diet contained 3360 kJ (800 kcal) and consisted of 110 g carbohydrates, 50 g proteins, and 20 g fats. Sodium intake was 90 mmol/d, the same as the control period. Subjects were instructed to keep their daily activity constant before and throughout the low-calorie regimen. After weight loss, the same recordings were carried out under the same conditions as during the control period.
Insulin Sensitivity Studies
Insulin sensitivity was examined by the euglycemic
hyperinsulinemic glucose clamp method according to
DeFronzo et al20 with an artificial endocrine pancreas
(model STG-22, Nikkiso). Glucose concentration monitoring was done in
blood samples that were continuously withdrawn at 2 mL/h through a
catheter after the venous blood was arterialized by
covering the puncture site of the arm with a heating mat. A priming
dose of short-acting human insulin (Humulin R, Shionogi) with a
total dose of 700 mU/m2 was administered during the initial
10 minutes in a logarithmically decreasing manner to quickly raise
plasma insulin to the desired level; this was followed by continuous
insulin infusion at a rate of 40 mU/m2 per minute for 110
minutes to achieve steady-state
hyperinsulinemia. The glucose clamp level was set
at 4.9 mmol/L during the 2-hour clamp study and was maintained by
measurement of plasma glucose every 5 minutes and adjustment of the
infusion rate of the 20% glucose solution. These procedures were done
automatically by the insulin and glucose algorithms controlled by a
computer system built into the artificial endocrine pancreas. The
glucose infusion rate (micromoles per meter squared per minute) was
estimated by the mean glucose infusion rate during the last 30 minutes
of the clamp study. The insulin sensitivity index was calculated by
dividing glucose infusion rate by plasma insulin concentration
(microunits per milliliter). Steady-state plasma glucose
concentration was calculated as the mean of all values between the 90th
and 120th minute of the clamp study. Blood sampling for measurement of
plasma insulin levels used for calculation of the insulin sensitivity
index was performed at the 90th and 120th minute of the clamp
study.
Analytic Methods
Plasma glucose was measured by the glucokinase method on an
automatic analyzer (model H 736, Hitachi). Glycosylated
hemoglobin A1c (HbA1c) was measured by
high-performance liquid chromatography.
Plasma insulin level was determined by competitive enzyme immunoassay
with a double antibody procedure using EIA Test Insulin II (BMY,
Boehringer). Cholesterol and
triglyceride levels were measured by the enzymatic
technique with an automatic analyzer. High-density
lipoprotein cholesterol was measured after precipitation of
low-density lipoprotein, very-low-density lipoprotein, and
chylomicrons with dextran sulfate, magnesium chloride, and polyethylene
glycol, respectively. Creatinine and sodium in serum and
urine were measured by an automatic analyzer. PRA was
determined by radioimmunoassay of generated angiotensin I
with a Gamma Coat (125I) PRA Radioimmunoassay Kit (Baxter
Healthcare). Serum aldosterone was measured by a
nonchromatographic, nonextraction radioimmunoassay
method with the Aldosterone RIA Kit (Dinabot). Plasma
norepinephrine was determined according to the modified
trihydroxyindole method with high-performance liquid
chromatography.
Statistical Analysis
All data in the text, tables, and figure are mean±SD.
Wilcoxon's ranked score test was used for analysis of
the differences of data between baseline and after weight loss. The
Pearson product moment formula was used for calculation of
coefficients of correlation between various parameters
studied. Multiple linear regression analysis was performed on
the basis a stepwise forward-backward procedure for determination
of significant predictive factors for the decrease in mean BP after
weight loss. The F value for the entrance of a variable
into or removal from the regression function was set at 3.0.
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Results |
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Anthropometric Measurements, BP, and Heart Rate
All subjects completed the low-calorie protocol successfully. Table 1
presents anthropometric, BP, and heart rate
data. The 4-week calorie-restricted diet caused weight to decline
by 7.5±1.9 kg (range, 5.0 to 11.2), which corresponded to an average
decrease of 10.2% of initial body weight. Body mass index was
29.4±3.0 kg/m2 at baseline and declined to 26.4±2.8
kg/m2 by the end of the low-calorie protocol. Weight
loss was associated with significant reductions in BP and pulse rate.
Decreases in systolic, diastolic, and mean BPs were
20.9±13.7, 14.2±8.9, and 16.4±9.5 mm Hg, respectively, which
represent average decreases of 12.4%, 13.6%, and 13.1%,
respectively, of initial values. Pulse rate decreased significantly, by
7.3±3.8 beats per minute, which corresponded to a 9.9% reduction of
the initial pulse rate.
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Metabolites, Hormone Levels, and Renal Sodium
Handling
Table 2 shows plasma levels of metabolites and
hormones and renal sodium handling. Fasting plasma levels of glucose
and HbA1c decreased by 8.0% (from 5.0±0.3 to 4.6±0.5
mmol/L, P<.01) and 5.6% (from 5.6±0.4% to 5.3±0.4%,
P<.01), respectively. Plasma insulin levels decreased
markedly, from 10.2±7.2 µU/mL at baseline to 5.5±4.3 µU/mL by the
end of the study. Plasma levels of total cholesterol and
triglycerides decreased by 19% and 56% of initial values
(P<.01), and high-density lipoprotein
cholesterol increased significantly, by 7.5% (from
1.07±0.22 to 1.15±0.25 mmol/L, P<.05). A decrease in
plasma norepinephrine (from 208±74 to 142±52 pg/mL,
P<.01) was associated with decreases in PRA (from
1.06±0.98 to 0.62±0.63 ng/mL per hour, P<.01) and serum
aldosterone (from 70±28 to 57±24 pg/mL,
P<.05). Urinary excretion of creatinine
decreased significantly, from 10.4±3.2 to 9.5±2.9 mmol/d
(P<.01). This caused a decrease in creatinine
clearance from 146.6±17.0 to 136.7±19.3 L/d. However,
creatinine clearance standardized for body surface area
showed no significant change. Urinary excretion of sodium was identical
under a normocaloric and low-calorie diet (85.5±19.8 versus
87.0±17.1 mmol/d). Fractional excretion of sodium at baseline was
0.417±0.103% and increased to 0.452±0.097% by the end of the
low-calorie protocol (P<.01).
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Insulin Sensitivity Studies
Steady-state plasma glucose concentration during the last 30
minutes of the glucose clamp study was 4.87±0.10 mmol/L at baseline
and 4.83±0.12 mmol/L after weight loss. The coefficient of variation
of plasma glucose during the glucose clamp study was less than 3% both
at baseline and after weight loss. The mean values of plasma insulin
determined at the 90th and 120th minutes of the glucose clamp study
were 78.1±13.5 µU/mL at baseline and 76.4±12.3 µU/mL after weight
loss. Insulin sensitivity, as measured by glucose infusion rate, during
the last 30 minutes of the glucose clamp increased significantly by
42.9% from 809±194 to 1155±251 µmol/m2 per minute. The
insulin sensitivity index, which is a measurement of glucose infusion
rate per unit of plasma insulin, increased significantly (42.6%), from
10.8±3.5 to 15.4±4.4 (µmol/m2 per minute)/(µU/mL)
(Figure).
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Factors Contributing to Decrease in BP After Weight
Loss
Table 3 shows the results of the stepwise multiple
linear regression analysis with the change of mean BP after
weight loss as a dependent variable. The variables selected as
candidates for the stepwise multiple regression function were subject
characteristics (age, sex, family history of hypertension and diabetes
mellitus, and daily use of alcohol and tobacco); anthropometric changes
(body weight, body mass index, and body surface area); and changes in
metabolites (fasting plasma glucose, HbA1c, and
insulin), hormone levels (PRA, serum aldosterone, and
plasma norepinephrine), renal function (urinary excretions
of creatinine and sodium, creatinine clearance,
and fractional excretion of sodium), and insulin sensitivity (glucose
infusion rate and insulin sensitivity index). Changes in plasma
norepinephrine, insulin sensitivity index, PRA, and age
were determined as significant predictive factors for a change in mean
BP after weight loss. The unstandardized coefficient (R)
calculated from the regression function with these four factors was
.892 and R2 was .752.
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Among the variables selected for predictive factors for change in mean BP after weight loss, change in plasma norepinephrine correlated with changes in insulin sensitivity index (r=-.575, P<.01) and PRA (r=.507, P<.02).
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Discussion |
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We found that a low-calorie regimen for 4 weeks resulted in a 10.2% decrease in body weight concomitant with a reduction in mean BP of 13.1% by the end of the study. Because urinary excretion of sodium did not change before and after the low-calorie regimen, it is possible to conclude that a low-calorie diet induces a sufficient reduction of BP in obese hypertensive subjects without restriction of sodium intake. These findings are in accordance with earlier reports.4 5 6 7 8 9 10 21 22 The studies in which sodium balance was kept constant during a low-calorie regimen7 8 9 showed that mean BP decreased by a mean of 11% (range, 9% to 13%), with a decrease in body weight by a mean of 13% (range, 10% to 16%). On the other hand, in those studies in which urinary excretion of sodium decreased to less than 50% of the initial value after a low-calorie diet,4 5 10 a mean weight loss of 18% (range, 16% to 19%) resulting in a 20% (range, 18% to 21%) reduction of mean BP was reported. The depressor effect of a low-calorie regimen seems to be greater when both energy and sodium intake are restricted. Maxwell et al21 performed a controlled prospective study to examine the hypotensive effect of calorie restriction in two groups placed on a low-calorie diet with different sodium intakes. One group was placed on a low-calorie diet of 1344 kJ (320 kcal) along with sodium intake restricted to 40 mmol/d. The other group received an additional salt supplement with salt tablets sufficient to maintain the baseline sodium intake of 210 mmol/d measured before the low-calorie regimen. They showed that the sodium-restricted group had a greater weight loss and a slightly greater decrease in BP only during the initial week of the low-calorie regimen. However, further substantial weight loss and decrease in BP under the condition of constant sodium balance were identical in both groups. They suggested that the initial reduction of BP during the first week of the low-calorie regimen may have been attributed to the negative salt and water balance, but the further decrease in BP during the period of constant sodium balance must have been caused by mechanisms directly connected to the weight loss per se. On the other hand, Fagerberg et al22 reported that the decrease in BP after a low-calorie diet was apparently greater in the group in which the sodium intake was restricted to 100 mmol/d compared with the group without restriction of sodium intake, even though both groups showed the same reduction of body weight. They emphasized that a decrease in salt intake was necessary for obtaining a sufficient depressor effect of the low-calorie diet. The results in the present study demonstrated the depressor effect of a low-calorie regimen without restriction of sodium intake. These data agree with the observations of Maxwell et al but are different from those of Fagerberg et al. Although the exact reason why the results of Maxwell et al and our results differ from those of Fagerberg et al is not clear, it may be due to a difference in the severity of energy restriction. The average reduction of body weight was 10.2% of the initial value after 4 weeks of a low-calorie regimen of 3360 kJ (800 kcal)/d in the present study. This is identical to the study of Maxwell et al, who used a low-calorie regimen of 1344 kJ (320 kcal)/d that induced an average decrease in body weight of 24% over 12 weeks. However, Fagerberg et al used a mildly energy-restricted diet of 5124 kJ (1220 kcal)/d, and the average decrease in body weight was only 8% of the initial value after 12 weeks of the low-calorie regimen. Further controlled prospective investigations concerning the effect of the different degrees of energy restriction on BP should be undertaken.
There seems to be a question whether the depressor effect seen in the present study after a low-calorie regimen is related to weight loss or starvation, because short-term fasting itself may directly influence sympathetic nervous activity via changes in insulin and norepinephrine production, which tend to reduce BP.23 24 However, two prospective case-control studies have shown that a decrease in BP after a low-calorie diet is mediated by the mechanism directly related to body weight reduction and is distinct from energy restriction itself.25 26 Andersson and coworkers25 clearly demonstrated that 3 days of semistarvation induced a slight decrease in body weight, without any change in BP or sympathetic muscle nerve activity in borderline hypertensive patients. However, after long-term energy intake restriction in the same patient group, they observed reductions of diastolic BP and sympathetic muscle nerve activity, along with a 7% reduction of body weight. These findings suggest that a fall in BP after weight loss with a negative energy balance is closely related to a reduction of sympathetic vasoconstrictor drive associated with body weight loss.
One of the most important findings in the present study was that an enhanced insulin sensitivity after weight loss was associated with a decreased BP. The enhanced insulin sensitivity was selected as one of the significant predictive factors for the depressor effect of weight loss. A highly significant positive relation between an improved insulin sensitivity and reduced mean BP indicates that the depressor effect of weight loss is at least partly correlated with the change of insulin sensitivity. The improvement of insulin sensitivity by weight loss was also associated with a decline of variables related to glucose metabolism, ie, fasting plasma levels of glucose, HbA1c, and insulin. The infusion of short-acting insulin during the glucose clamp study raised the plasma insulin level to approximately 76 µU/mL, which is well within the physiological range and sufficiently high enough to suppress hepatic glucose production to a negligible rate even in the presence of insulin resistance.17 27 28 Thus, the glucose infusion rate is equal to the glucose disposal in peripheral tissues, mainly in the muscle, which reflects the insulin sensitivity of each individual. The improvement of insulin sensitivity in terms of increased glucose infusion rate after weight loss was by a mean of 42.9% of that of baseline values. As the plasma insulin level during the insulin clamp study after weight loss was somewhat lower compared with that before weight loss, insulin sensitivity may have been underestimated for these conditions. The insulin sensitivity index calculated by dividing glucose infusion rate by plasma insulin level may be a more precise index for insulin sensitivity when plasma insulin levels are different during the glucose clamp study. In the present study, the insulin sensitivity index increased by 42.6% of the initial value after weight loss. Previous studies have shown that weight reduction results in an enhanced glucose disposal by euglycemic insulin clamp in both obese diabetic and nondiabetic subjects.29 30 31 Wolpert et al30 examined insulin sensitivity by euglycemic hyperinsulinemic glucose clamp before and after a 13.7% weight loss for 10 weeks in obese middle-aged women. The glucose infusion rate after weight loss increased by 50.6% of the initial value, and systolic BP decreased significantly (by 12 mm Hg), which represented 10% of the initial value. Franssila-Kallunki et al31 evaluated the change of insulin sensitivity estimated by the euglycemic insulin clamp after 6 weeks of low-calorie dieting in obese women with a normal oral glucose tolerance test. They showed that glucose disposal rate increased by 26.3% after a 10.6% weight reduction. Along with these two studies, our study may provide additional evidence for the hypothesis that a decrease in BP after a low-calorie diet is linked closely to an improvement of insulin sensitivity induced by weight loss in obese individuals.
Although a close link between elevated BP and reduced insulin sensitivity in obesity hypertension has been observed in many reports, the question of whether reduced insulin sensitivity has a cause-and-effect relationship with obesity hypertension remains to be clarified. Compensatory hyperinsulinemia occurring with insulin resistance has a stimulatory effect on the sympathetic nervous system23 24 32 33 34 and a direct antinatriuretic action.35 36 It seems unquestionable that insulin produces marked sympathetic activation. Short-term insulin infusion at rates that raised plasma concentrations to pathophysiological levels increased plasma norepinephrine concentrations23 24 32 33 34 and caused a marked increase in sympathetic nervous activity in skeletal muscle.33 34 Only two reports have suggested the pressor action of insulin in humans,32 36 but other studies in humans33 34 and dogs37 have failed to provide proof. On the other hand, in rats, acute and chronic increases in plasma insulin may elevate BP.38 39 40 These studies represent a serious challenge to the hypothesis that hyperinsulinemia and insulin resistance contribute to an increase in BP in humans. Sympathetic hyperactivity itself can cause hemodynamic and structural changes in the peripheral vessels and may promote insulin resistance by reducing skeletal muscle blood flow.41 42 Baron et al42 reported that insulin-mediated glucose uptake, as well as an insulin-mediated increase in skeletal muscle blood flow, was inversely proportional to basal BP in humans. They suggested that attenuated insulin-mediated skeletal muscle blood flow was a major cause of insulin resistance. Moan et al43 observed that insulin sensitivity index estimated by the euglycemic glucose clamp technique correlated with supine and stressed diastolic BP values and maximal plasma norepinephrine levels during stress in healthy young men. In the present study, we found a significant negative correlation between changes in insulin sensitivity index and plasma norepinephrine after weight loss. These lines of evidence seem to support the argument that the sympathetic nervous system may be a common regulator of both BP and insulin sensitivity. Despite the current surge of interest, it is not clear whether insulin resistance contributes to hypertension or is secondary to abnormal sympathetic and vascular mechanisms of skeletal muscle in obesity hypertension.
We found a significant decrease in fractional excretion of sodium after weight loss in obese hypertensive subjects. However, we could not find any significant relationship between the change in BP and fractional excretion of sodium. A considerable body of evidence, derived from studies in animals and humans, has indicated that hyperinsulinemia may have antinatriuretic effects on the kidneys that are expected to change the pressure-natriuretic relationship and could lead to elevated BP if sustained.35 36 However, Hall et al37 have reported that antinatriuretic effects of insulin on the kidney are not sustained and do not raise BP in insulin-treated dogs. It remains uncertain whether the change in renal sodium handling plays a role in the depressor effect of weight loss during a period of constant sodium balance.
Both PRA and aldosterone levels were reported to be higher in obese than nonobese subjects, whereas hypertensive obese subjects have inappropriately higher plasma aldosterone levels and PRA than normotensive obese subjects.4 5 7 8 9 10 Weight reduction decreases both PRA and aldosterone to normal values, and decreases in BP after weight reduction correlated with the decreases in PRA and/or aldosterone.7 9 10 In the present study, both PRA and plasma aldosterone levels decreased significantly after weight loss, along with the decrease in BP, without any change in sodium intake. Furthermore, a decrease in PRA correlated with a decrease in BP after weight loss. These results agree with previous reports that indicate the predictive role of suppression of the renin-angiotensin-aldosterone system in BP reduction after weight loss in obesity hypertension, regardless of sodium balance. However, a significant positive correlation was found between the changes of PRA and plasma norepinephrine after weight loss in this study. It is conceivable that the suppression of the renin-angiotensin-aldosterone system after weight loss may depend on the suppression of the sympathetic nervous system induced by weight loss in obese hypertensive subjects.
In obese normotensive subjects, total peripheral vascular resistance was decreased to compensate for the increased cardiac output.4 5 6 However, in obese subjects with hypertension, the total peripheral vascular resistance was inappropriately high.4 5 6 Jacobs et al44 clearly demonstrated that a reduction in peripheral vascular resistance was an important hemodynamic mechanism involved in BP reduction associated with weight loss in obese subjects. A decrease in BP after weight reduction in obese subjects was accompanied by a decrease in resting4 7 8 and stimulated7 8 plasma norepinephrine and directly recorded resting sympathetic muscle nerve activity.25 In the present study, we found that BP decreased after a low-calorie diet without concomitant sodium restriction. This was associated with decreases in plasma norepinephrine, PRA, and pulse rate, which are considered good indications of sympathetic discharge. These results agree with earlier studies in which semistarvation itself, regardless of sodium intake, caused reductions in plasma norepinephrine concentration and PRA.7 8 9 10 Moreover, a change in plasma norepinephrine was found to be a strong contributing factor for a change in mean BP after weight loss by stepwise multiple linear regression analysis. These findings provide additional evidence to confirm the hypothesis that the decrease in BP after weight loss is probably mediated by suppressed sympathetic nervous activity.
Concerning the change in plasma lipids after weight loss, serum levels of total cholesterol and triglycerides decreased and those of high-density lipoprotein cholesterol increased significantly after weight loss, as in previous reports.30 31 45 46 Abnormalities of lipid metabolism associated with obesity may be reversed with weight reduction. In view of the effect of weight reduction on lowering BP and reversing abnormal lipid metabolism, it is reasonable to suggest that weight reduction should be the first line of therapy in obese hypertensive patients.
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Footnotes |
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Reprint requests to Toshio Ikeda, MD, Medical Research Institute, NTT Kanto Teishin Hospital, 5-9-22 Higashigotanda, Shinagawa, Tokyo 141, Japan.
Received October 11, 1995; first decision November 14, 1995; accepted January 19, 1996.
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