Effects of Angiotensin-Converting Enzyme Inhibition on Leptin and Adiponectin Levels in Essential Hypertension

Activation of the renin‐angiotensin‐aldosterone system (RAAS) and abnormal adipokine levels are biological alterations that affect blood pressure regulation and interact to link hypertension, obesity and metabolic diseases. While imbalanced levels of hormones produced by adipocytes including hypo‐adiponectinaemia and hyperleptinaemia were reported in hypertension, little is known about how antihypertensive therapy affects these alterations. This study aimed to evaluate the effects of enalapril on plasma adiponectin and leptin levels in hypertensive individuals. Thirty‐seven untreated hypertensive patients were prospectively treated with enalapril for 8 weeks. Blood samples were collected at baseline and after the treatment with enalapril. Plasma adiponectin and leptin levels were measured by enzyme‐linked immunoassay. We found significant increases in adiponectin levels after enalapril treatment (5.4 ± 3.7 versus 6.0 ± 4.5 μg/mL, mean±S.D., p = 0.04). Conversely, leptin levels were unchanged (18.0 ± 14.7 versus 18.4 ± 14.8 ng/mL, mean ± S.D., p = 0.31). Multiple linear regression revealed that baseline leptin is a significant predictor of systolic blood pressure reduction (β=0.269, p = 0.01) in hypertensive individuals treated with enalapril. While enalapril increases adiponectin levels in hypertensive individuals, baseline leptin levels predict blood pressure reduction in response to this therapy. These findings support the idea of an important relationship between RAAS and adipose tissue in hypertension and suggest that enalapril improves the adipokine profile, possibly allowing beneficial effects to overweight or obese hypertensive individuals.

Hypertension, obesity and metabolic abnormalities share common physiopathological mechanisms including activation of the renin‐angiotensin‐aldosterone system (RAAS) and alterations in adipokine levels [1] . Adiponectin and leptin are hormones produced by adipocytes [2] and imbalanced levels of these hormones have been shown in hypertensive patients compared with normotensive controls [3] . An inverse relationship between adiponectin and blood pressure (BP) levels was reported, and hypo‐adiponectinaemia has been suggested as a risk factor for hypertension [3] . The cardiovascular protective effects of adiponectin are mediated by anti‐inflammatory, insulin‐sensitizing and antiatherogenic mechanisms [4] , [5] , [6] . On the other hand, hyperleptinaemia promotes cardiovascular remodelling [7] , [8] mainly by increasing sympathetic nervous system activity [9] . Indeed, increased leptin levels may predict development of hypertension, independent of BMI and insulin resistance [10] .

Increasing evidence suggests that RAAS and adipose tissue are interplayers in BP regulation [11] , [12] , [13] . It has been suggested that angiotensin‐converting enzyme inhibitors (ACEi) may offer advantages as monotherapy in the treatment of obese hypertensive individuals, particularly in the prevention of metabolic disorders [14] . Moreover, some studies demonstrated that drug interfering with RAAS can improve adipokine profile in healthy and hypertensive individuals [15] , [16] , [17] , [18] , [19] , [20] . This is the first prospective study to evaluate the effect of enalapril monotherapy on leptin and adiponectin levels in mild‐ and moderate‐hypertensive individuals.

A total of 37 grade 1 or grade 2 hypertensive patients – systolic blood pressure ≥140 and ≤179 mmHg and diastolic blood pressure ≥90 and ≤109 mmHg [21] – from Cardiology Division of the Araçatuba Health Center (Araçatuba, SP, Brazil) were enrolled in this prospective study. The classification was performed according to the average of three BP readings on at least two office visits with the individuals in the seated position. Office systolic BP (SBP) and diastolic BP (DBP) were recorded with a semi‐automatic BP monitor (OMRON® ‐ HEM‐433 INT, Bannockburn, IL, USA) at the enrolment and after 8 weeks of the treatment. Patients with secondary hypertension, diabetes, hepatic or renal dysfunction were excluded from this study.

This study was approved by the Research Ethics Committee at the Faculty of Medicine of Ribeirão Preto, University of São Paulo, Brazil. Study individuals provided written informed consent, and the present work was performed in accordance with the ethics standards of the Helsinki Declaration.

Never‐treated hypertensive individuals received enalapril monotherapy for 8 weeks. Patients who were using antihypertensive agents received enalapril after a 2‐week washout period. Enalapril doses were prescribed according to the judgement of the physician and ranged from 10 to 30 mg daily. ACE activity was determined in plasma samples before and after the treatment with enalapril in order to assess the adherence to the treatment according to previously described [22] .

Peripheral blood samples were collected into heparin tubes (Becton‐Dickinson Sao Paulo, Brazil) by venipuncture after 8 hr of fasting at baseline and 8 weeks of treatment. The blood samples were centrifuged at 1000 × g for 10 min., and plasma fractions were immediately stored at −70°C until used for biochemical measurements. Plasma levels of adiponectin and leptin were measured with commercially ELISA kits (R&D Systems, Minneapolis, MN, USA), according to the manufacturer's instructions. Intra‐assay and the interassay coefficients of variance were less than 5.6% for adiponectin ELISA kits and below 4.8% for leptin ELISA kits.

The baseline clinical and laboratorial characteristics were expressed as mean ± standard deviation (SD). Adiponectin and leptin levels at baseline and after 8 weeks of treatment were compared by Wilcoxon signed rank test using GraphPad Prism V 5.0 for Windows. Multiple linear regression was performed to evaluate whether baseline adiponectin and leptin were predictors of changes in systolic BP (baseline SBP minus treatment SBP) using SigmaPlot v 12.0 for Windows. The regression model was further adjusted for age, gender, BMI, baseline SBP and enalapril dose. All those factors might affect blood pressure reduction. The level of significance accepted was 0.05.

Baseline characteristics of hypertensive individuals are listed in Table [NaN] . The mean age of study individuals was 47 years, predominantly male (62%) and overweight or obese (BMI, 29.7 ± 5.6 kg/m2, mean ± S.D.). No gender differences were found in baseline leptin and adiponectin levels. We found significant decreases in office systolic (148 ± 11 versus 131 ± 11 mmHg, p < 0.001; fig. [NaN] A) and diastolic blood pressures (93 ± 9 versus 82 ± 9 mmHg, p < 0.001; fig. [NaN] A) after 8 weeks of treatment with enalapril. Also, a significantly reduced ACE activity was observed after treatment with enalapril (25.5 ± 11.1 versus 8.0 ± 9.0 nmol/min/mL, p < 0.001; fig. [NaN] B).

Baseline clinical and laboratorial characteristics of untreated hypertensive individuals

1 BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate. Values are the mean ± S.D.

A significant increase in adiponectin levels was shown after the treatment with enalapril compared with baseline (5.4 ± 3.7 versus 6.0 ± 4.5 μg/mL, mean ± S.D., p = 0.04, fig. [NaN] A). However, no changes were observed in plasma leptin after the treatment compared with baseline levels (18.0 ± 14.7 versus 18.4 ± 14.8 ng/mL, mean ± SD, p = 0.31, fig. [NaN] B).

Multiple linear regression analysis revealed that baseline leptin levels (β = 0.269, p = 0.01) – but not baseline adiponectin levels (β = −0.685, p = 0.11) – were independent predictor of SBP reduction after enalapril treatment (table [NaN] ).

Multiple linear regression for systolic blood pressure reduction after treatment with enalapril

2 Multiple linear regression adjusted for age, gender and enalapril dose. SBP, systolic blood pressure; BMI, body mass index. *p < 0.05.

This study investigated the effects of enalapril monotherapy on plasma adiponectin and leptin levels in hypertensive patients. Treatment with enalapril for 8 weeks increased adiponectin levels by approximately 11%, whereas no significant changes in leptin levels were found. Interestingly, the reduction in systolic BP after enalapril treatment was predicted by baseline leptin, but not by adiponectin levels.

Beyond BP down‐regulation, ACEi exert important metabolic effects that result in insulin sensitivity improvement and adipocyte size and body weight reduction [23] , [24] . Previous studies have shown that low plasma adiponectin levels are significantly associated with hypertension [3] , [25] , [26] . Indeed, a recent meta‐analysis showed that a 1 μg/mL increase in adiponectin levels corresponds to a 6% reduction in the risk of hypertension [3] . The protective effects of adiponectin may be explained by cross talk between adipose tissue hormones and RAAS. In fact, previous studies reported that angiotensin II infusion or ACEi administration evoked significant increases in adiponectin levels in healthy individuals [27] . Moreover, diet‐induced obese mice treated with enalapril showed reduction in energy intake and body mass associated with higher serum adiponectin and insulin sensitivity improvement [28] . Also, enalapril treatment showed the most pronounced effect on adiponectin levels compared with angiotensin receptor 1 antagonist and direct renin inhibitor, thus indicating that the ACEi are more effective in up‐regulating adiponectin [28] . It has been described that adiponectin is up‐regulated in response to physical activity and weight loss [29] . Those potential confounders may interfere with our results because we did not control for physical activity and diet in studied individuals.

Conflicting results were reported in human studies. While no changes in adiponectin levels were observed with perindopril treatment [30] , increased levels were found with enalapril [27] , ramipril [18] or temocapril [15] . As ACE inhibitors reduce angiotensin II production and prevent bradykinin degradation, both mechanisms may be involved in the changes in adiponectin levels. Furthermore, there is evidence that adiponectin increases vasodilation by improving eNOS coupling [31] , [32] . In this study, we found significant increases in adiponectin levels in hypertensive patients treated with enalapril during 8 weeks compared with baseline. Although we found a modest effect of enalapril on adiponectin levels (mean difference of 0.6 μg/mL), this may have important clinical impact in long‐term treatment with enalapril. Moreover, pharmacological strategies to increase adiponectin levels may be beneficial in preventing vascular damage and metabolic abnormalities in hypertensive patients.

An earlier study showed reduced leptin levels after 3 months of treatment with quinapril [33] . However, we did not observe any differences in leptin levels after the treatment with enalapril in hypertensive individuals. Baseline plasma leptin levels significantly predict SBP reduction after treatment with enalapril. It is well known that leptin increases BP by activating the sympathetic nervous system [12] , [34] . Interestingly, leptin and angiotensin II act synergistically to control BP homeostasis by interfering with both peripheral and central mechanisms [11] , [13] . In agreement with this idea, animal studies showed that leptin administration enhances the effects of angiotensin II on BP [34] . Moreover, a recent study showed lower plasma and lung ACE activity in leptin‐deficient mice, which show an attenuated reduction in BP after treatment with enalapril. Additionally, leptin infusion restored ACE activity in those animals [11] . Together, those findings suggest that leptin activates RAAS, probably by increasing ACE expression/activity, and that the antihypertensive effects of ACEi depend on leptin levels. Our results showing that leptin levels are significant predictors of SBP reduction in response to enalapril agree with those previous findings.

The main limitation of this study is the uncontrolled and non‐randomized design; thus, definitive conclusions cannot be drawn. Whether the increases in adiponectin observed are mediated by direct effect of enalapril or by blood pressure reduction remains unanswered. Furthermore, it is possible that the relatively short time of follow‐up may underestimate the long‐term effects of enalapril on adiponectin and leptin levels. The main strength of this study is that the individuals were not taking other drugs, including statins and other cardiovascular agents.

In summary, our data support the idea that ACEi affect adipokine levels and may activate protective mechanisms, particularly in overweight or obese individuals, possibly resulting in improved metabolic profile. Additional prospective studies are warranted to clarify whether the changes in adipokine levels associated with ACEi result into lower incidence of clinically relevant events.

This work was supported by Sao Paulo Research Foundation (FAPESP) and National Council for Scientific and Technological Development (CNPq).

Graph: Blood pressure and angiotensin‐converting enzyme ( ACE ) activity at baseline and after enalapril treatment in hypertensive patients. (A) Systolic and diastolic blood pressure at baseline and after enalapril treatment. (B) Plasma ACE activity at baseline and after treatment with enalapril. * p  < 0.001.

Graph: image_n/bcpt12195-fig-0001.png

Graph: Plasma adipokine levels in hypertensive individuals at baseline and after treatment with enalapril. (A) Plasma adiponectin levels at baseline and after 8 weeks of enalapril treatment. (B) Plasma leptin levels at baseline and after 8 weeks of enalapril treatment. * p  < 0.05.

Graph: image_n/bcpt12195-fig-0002.png