Abstract

Adipocytes secrete several biologically active substances that are presumed to be involved in obesity-related hypertension. There are no reports that deal with the relationship between plasma adiponectin concentration and blood pressure (BP).

To evaluate the role of adiponectin in essential hypertension 33 patients with essential hypertensive (EHP) (12 women, 21 men) and 33 body mass index-matched normotensive healthy subjects (NHS) (13 women, 20 men) were studied.

In EHP plasma adiponectin concentration was significantly lower than in NHS (9.1 ± 4.5 v 13.7 ± 5.2 μg/mL, respectively). In all subjects a significant negative correlation was found between plasma adiponectin concentration and mean, systolic, and diastolic BP, suggesting that adiponectin contributes to the clinical course of essential hypertension. Am J Hypertens 2003;16:72–75 @ 2003 American Journal of Hypertension, Ltd.

High prevalence of arterial hypertension in obese humans seems to suggest that the adipose tissue may influence blood pressure (BP).1 There is growing evidence that the adipose tissue per se is a large endocrine organ secreting biologically active substances with systemic action.2 Among them plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor-α (TNF-α), leptin, and resistin are to be mentioned.2

Adiponectin is a recently discovered protein secreted by adipocytes.3 There is growing evidence that decreased adiponectinemia is involved in the pathogenesis of atherosclerosis and insulin resistance.4,5,6,7,8,9,10,11 This polypeptide exhibits binding ability to some matrix proteins such as collagen I, III, and V, but not collagen II and IV, laminin, or fibronectin.7 It was suggested that adiponectin might inhibit formation of initial atherosclerotic lesions by decreasing expression of adhesion molecules (vascular adhesion molecule-1 [VCAM-1], intercellular adhesion molecule-1 [ICAM-1], E-selectin) in endothelial cells in response to inflammatory stimuli such as TNF-α8 and suppressing cytokine (also TNF-α) production in macrophages.7 Moreover, adiponectin suppresses lipid accumulation in human monocyte-derived macrophages and inhibits macrophage-to-foam cell transformation.5 In animal models it was shown that adiponectin accumulates in the subendothelial space of catheter-injured vascular wall but not in intact vascular wall.7 Recently it was shown that adiponectin-deficient mice are characterized by insulin resistance and increase neointimal formation in response to external vascular cuff injury.9 These observations suggest strongly that adiponectin plays a protective role against insulin resistance and atherosclerosis.

Plasma adiponectin concentrations in humans are lower in obese than in nonobese subjects, more in men than in women, and in patients with coronary artery disease, and diabetes mellitus type 2 than in healthy subjects.4,10,11 Weight reduction in obese subjects is followed by an increase of plasma adiponectin concentration.10

Taking into account the antiatherogenic effect of adiponectin and its influence on insulin resistance, it was of interest to examine plasma adiponectin levels in patients with essential hypertension. The present study aimed to answer the following questions: 1) Do patients with essential hypertension (EHP) differ from normotensive healthy subjects (NHS) with respect to plasma adiponectin concentration? and; 2) Are plasma adiponectin concentrations and BP interrelated?

Methods

Blood samples were drawn from 33 EHP (12 women, 21 men) and 33 age-, gender-, and body mass index (BMI)-matched NHS (13 women, 20 men). The study protocol was approved by the Local Bioethical Committee. Mean age, BMI, and BP in EHP and NHS are enlisted in Table 1. The diagnosis of essential hypertension was established after exclusion of secondary forms of hypertension by careful clinical, biochemical, hormonal, and radiologic examinations performed in the Department of Nephrology, Endocrinology, and Metabolic Diseases, Silesian University School of Medicine in Katowice, Poland. Antihypertensive drugs were withdrawn at least 7 days before the study. Blood pressure was measured using mercury sphygmomanometer with an accuracy of 5 mm Hg. Biochemical parameters were estimated in blood samples drawn in the morning after overnight fasting. Plasma adiponectin concentration was assessed by ELISA as described by Arita et al.4 Plasma leptin concentration was estimated by radioimmunoassay using kits from Linco Research Inc., St. Charles, MO (coefficient of intra-assay and interassay variation was 7.1% and 10.8%, respectively). Other parameters were assessed by routine techniques.

Table 1

Clinical and biochemical data of patients with essential hypertension patients (EHP) and normotensive healthy subjects (NHS)

 EHP NHS 
 Whole group (n = 33) Women (n = 12) Men (n = 21) Whole group (n = 33) Women (n = 13) Men (n = 20) 
Age (y) 48 ± 16 50 ± 14 46 ± 18 50 ± 18 50 ± 18 50 ± 18 
BMI (kg/m228.5 ± 4.8 28.9 ± 4.8 28.2 ± 4.8 27.8 ± 3.8 28.1 ± 3.7 27.5 ± 3.9 
MAP (mm Hg) 116 ± 13 112 ± 8 118 ± 15 97 ± 9 95 ± 9 99 ± 9 
SBP (mm Hg) 145 ± 20 146 ± 15 145 ± 24 125 ± 7 122 ± 14 128 ± 11 
DBP (mm Hg) 94 ± 10 92 ± 6 97 ± 13 84 ± 7 81 ± 8 84 ± 7 
Plasma adiponectin (μg/mL) 9.1 ± 4.5 8.3 ± 3.1 9.5* ± 5.1 13.7 ± 5.2 14.8 ± 6.0 12.9 ± 5.1 
Plasma leptin (ng/mL) 13.9 ± 10.2 23.4 ± 9.5 8.1 ± 5.1 11.6 ± 5.1 19.0 ± 5.1 6.8 ± 4.5 
Serum creatinine (μmol/L) 81 ± 16 71§ ± 13 87 ± 15 85 ± 21 67 ± 22 96 ± 12 
Serum glucose (mmol/L) 4.7 ± 0.6 4.6 ± 0.7 4.8 ± 0.6 4.8 ± 0.9 4.7 ± 0.8 4.9 ± 1.0 
Serum cholesterol (mmol/L) 5.4 ± 1.0 5.4 ± 1.0 5.4 ± 1.0 5.7 ± 1.3 6.2 ± 1.4 5.4 ± 1.2 
Serum triglicerides (mmol/L) 1.6 ± 0.9 1.3 ± 0.8 1.8 ± 0.9 1.8 ± 1.1 1.6 ± 0.9 1.9 ± 1.3 
 EHP NHS 
 Whole group (n = 33) Women (n = 12) Men (n = 21) Whole group (n = 33) Women (n = 13) Men (n = 20) 
Age (y) 48 ± 16 50 ± 14 46 ± 18 50 ± 18 50 ± 18 50 ± 18 
BMI (kg/m228.5 ± 4.8 28.9 ± 4.8 28.2 ± 4.8 27.8 ± 3.8 28.1 ± 3.7 27.5 ± 3.9 
MAP (mm Hg) 116 ± 13 112 ± 8 118 ± 15 97 ± 9 95 ± 9 99 ± 9 
SBP (mm Hg) 145 ± 20 146 ± 15 145 ± 24 125 ± 7 122 ± 14 128 ± 11 
DBP (mm Hg) 94 ± 10 92 ± 6 97 ± 13 84 ± 7 81 ± 8 84 ± 7 
Plasma adiponectin (μg/mL) 9.1 ± 4.5 8.3 ± 3.1 9.5* ± 5.1 13.7 ± 5.2 14.8 ± 6.0 12.9 ± 5.1 
Plasma leptin (ng/mL) 13.9 ± 10.2 23.4 ± 9.5 8.1 ± 5.1 11.6 ± 5.1 19.0 ± 5.1 6.8 ± 4.5 
Serum creatinine (μmol/L) 81 ± 16 71§ ± 13 87 ± 15 85 ± 21 67 ± 22 96 ± 12 
Serum glucose (mmol/L) 4.7 ± 0.6 4.6 ± 0.7 4.8 ± 0.6 4.8 ± 0.9 4.7 ± 0.8 4.9 ± 1.0 
Serum cholesterol (mmol/L) 5.4 ± 1.0 5.4 ± 1.0 5.4 ± 1.0 5.7 ± 1.3 6.2 ± 1.4 5.4 ± 1.2 
Serum triglicerides (mmol/L) 1.6 ± 0.9 1.3 ± 0.8 1.8 ± 0.9 1.8 ± 1.1 1.6 ± 0.9 1.9 ± 1.3 

BMI = body mass index; MAP = mean arterial blood pressure; SBP = systolic blood pressure; DBP = diastolic blood pressure.

Mean values ± SD.

*

P < .05;

P < .01.

P < .001 v NHS.

§

P < .01.

P < .001 v men.

Statistical evaluation of the obtained results was performed using the Mann-Whitney U test. Correlation coefficient was calculated according to the Kendall τ correlation test. Multiple regression analysis with mean arterial pressure (MAP) as a dependent variable and BMI, plasma adiponectin concentration, and age as independent variables was also performed. All results are expressed as means ± SD.

Results

As shown in Table 1 and Fig. 1, plasma adiponectin concentration was significantly lower in EHP than in NHS (9.1 ± 4.5 v 13.7 ± 5.2 μg/mL, respectively), irrespective of gender. Plasma adiponectin concentration was of similar magnitude in women and men, both in EHP and NHS (Table 1).

Plasma adiponectin concentration in EHP and NHS (left). Correlation between plasma adiponectin concentration and MAP in all subjects (τ = −0.20; P = .02) (right). EHP = essential hypertensive patients; NHS = normotensive healthy subjects; MAP = mean arterial blood pressure.

In contrast to adiponectin, plasma leptin concentration was similar in EHP and NHS (Table 1). Women of both groups (hypertensive and normotensive) were characterized by significantly higher plasma leptin concentration as compared with respective values obtained in men (Table 1). Slightly lower serum creatinine concentrations were found in women than in men of both analyzed groups. Serum glucose, cholesterol, and triglyceride concentrations were similar in EHP and NHS (Table 1).

A significant negative correlation was found between plasma adiponectin concentration and BMI in the whole group (EHP and NHS) and in EHP analyzed separately (τ = −0.24; P < .05). Such a correlation did not reach statistical significance in NHS when analyzed separately (τ = −0.18; P = .13). A significant negative correlation was found between plasma adiponectin concentration and MAP (τ = −0.20; P = .02) (Fig. 1), systolic BP (τ = −0.19; P = .02) and diastolic BP (τ = −0.23; P = .007), respectively, when the results obtained in EHP and NHS were analyzed as one group (n = 66). A significant negative correlation was found between plasma adiponectin and leptin concentration when the results obtained in EHP and NHS were analyzed as one group (n = 66, τ = −0.19; P = .02) and in male EHP and NHS (n = 41, τ = −0.35; P = .001). Such a correlation did not reach statistical significance in female EHP and NHS (n = 25, τ = −0.19; P = .88). A significant negative correlation was also found between plasma adiponectin and serum triglyceride concentration when the results obtained in EHP and NHS were analyzed as one group (n = 66, τ = −0.25; P = .008) and in NHS (n = 33, τ = −0.30; P = .01). Such a correlation did not reach statistical significance in EHP (n = 33, τ = −0.26; P = .11). We did not found any significant difference in heart rate between EHS and NHS (respectively, 74 ± 9 and 76 ± 9 beats/min; P = not significant) and any significant correlation between plasma adiponectin concentration and heart rate both in EHS (τ = 0.08; P = .60) and NHS (τ = 0.14; P = .25).

Multiple regression analysis performed for the whole group, with MAP as the dependent variable and BMI, plasma adiponectin concentration, and gender as independent variables, did not show any significant relationship between MAP and independent variables analyzed in this model. It should be emphasized that two independent variables (BMI and plasma adiponectin) were significantly interrelated (which was shown by correlation analysis) and this fact might influence the results of the regression analysis.

Discussion

As was shown in this study, plasma adiponectin concentration was significantly lower in EHP than in NHS. Plasma adiponectin concentration was lower in hypertensive subjects irrespective of gender (Table 1). Moreover, using univariate correlation analysis, a significant negative correlation was found between BP and plasma adiponectin concentration (Fig. 1).

Our data are not consistent with preliminary results published by Mallamaci et al.12 They noticed higher plasma adiponectin concentrations exclusively in hypertensive men. However in this study, glomerular filtration rate was lower in hypertensive than normotensive subjects and there was a significant negative relationship between glomerular filtration rate and plasma adiponectin concentration. Therefore, it seems likely that impaired renal function in this group of hypertensive subjects may participate in the increase of plasma adiponectin concentration. This is probably a cause of discordance between results presented in current study and those published by Mallamaci et al.12

The mechanism of lower plasma adiponectin concentration in patients with essential hypertension remains to be clarified. However, recently, Fasshauer et al13 showed that β-adrenergic stimulation inhibited adiponectin gene expression in 3T3-L1 adipocytes. Taking into account that the increase of sympathetic nervous activity is one of several mechanisms that initiates and maintains BP elevation in humans,14 one may hypothesized that sympathetic nervous overreactivity participates, at least partially, in the pathogenesis of decreased adiponectin plasma concentration in patients with essential hypertension. We did not measure directly sympathetic nervous activity. However, we measured resting heart rate and did not find any significant correlation with plasma adiponectin. Taking into account that the resting heart rate depends on several factors (for review, see Ref. 15), we are aware that this parameter is of limited value in the assessment of sympathetic nerve activity. Thus, the relationship between adiponectinemia and sympathetic nerve activity needs further studies.

Because our patients were only moderately overweight it seems almost unlikely that fat distribution may influence adiponectin secretion. Nevertheless, further studies on the relationship between fat distribution and adiponectinemia are necessary to solve this until now unresolved problem. This seems even more urgent, because an overlap of adiponectin plasma levels between EHS and NHS was found.

Experimental studies showed that adiponectin may be a protective factor against atherosclerosis.4,5,7,8,9 Adiponectin may inhibit formation of atherosclerotic lesions by decreasing expression of adhesion molecules (VCAM-1, ICAM-1, E-selectin) in endothelial cells in response to inflammatory stimuli (like TNF-α),8 suppressing cytokine (also TNF-α) production in macrophages7 and suppressing lipid accumulation in human monocyte-derived macrophages (therefore inhibiting macrophage-to-foam cell transformation).5 In animal models it was shown that adiponectin accumulates in the subendothelial space of a catheter-injured but not in intact vascular wall.7 Low plasma adiponectin concentration in EHP might be the result of increased deposition of this peptide in the injured arterial wall induced by elevated BP. In the current study we have found a significant negative correlation between adiponectinemia and triglyceridemia. A similar correlation was previously observed in a group of patients with type 2 diabetes.10 In a recently published experimental study, Yamauchi et al6 suggested that adiponectin in skeletal muscle increased the expression of molecules involved in fatty acid transport, combustion, and energy dissipation such as CD36, acyl-CoA oxidase, and uncoupling protein 2. These alterations decreased tissue triglyceride content, associated with decreased serum triglyceride concentration.6 This beneficial effect of adiponectin on serum triglyceride level may be a protective factor against atherosclerosis. Taking into account results of these experimental studies one may speculate that insufficient adiponectin secretion in EHP may promote proatherogenic processes in these patients. However, this hypothesis needs more studies.

It cannot be excluded that adiponectin exerts a direct or indirect effect on BP.

A limitation of our study is that we did not measure insulin resistance, which is a known factor influencing plasma adiponectin concentration.11 However, it should be stressed that none of the studied subjects were diabetic. Another limitation of our study is that we did not measured body composition. Therefore, we cannot exclude that EHP had greater body fat mass than NHS, and that increased body fat mass is the cause of decreased plasma adiponectin concentration in EHP.

In summary, we found that essential hypertensive patients are characterized by 1) a lower plasma adiponectin concentration than age-, BMI-, and gender-matched normotensive healthy subjects, and 2) presence of a significant negative relationship between plasma adiponectin level and BP.

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Author notes

*
This study was supported by the Polish Committee for Scientific Research.