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Effect of nifedipine on adiponectin in hypertensive patients with type 2 diabetes mellitus

Abstract

Nifedipine, a dihydropyridine calcium antagonist, improves endothelial function in patients with hypercholesterolaemia by enhancing nitric oxide (NO) activity, and increases endothelial NO bioavailability by antioxidant mechanisms. We administered a long-acting nifedipine formulation (controlled release (CR) nifedipine: 20 mg/day) to hypertensive patients for 6 months. There were no other changes of drug treatment during therapy with CR nifedipine. Clinical and biochemical data obtained before and after CR nifedipine administration were compared. All markers were measured by enzyme-linked immunosorbant assay. The levels of soluble markers (soluble CD40 ligand, soluble P-selectin, and soluble E-selectin), microparticles (MP) (platelet-derived MP, monocyte-derived MP, and endothelial cell-derived MP), and adiponectin differed between the control group and the hypertension group. The levels of these markers were also different in hypertensive patients with and without type 2 diabetes compared with the control group. In the hypertensive patients with type 2 diabetes, all markers except adiponectin decreased significantly after 3 months of CR nifedipine treatment. In contrast, markers were unchanged in the hypertensive patients without type 2 diabetes. Adiponectin was increased after 6 months of CR nifedipine treatment in hypertensive patients with type 2 diabetes. The effects of CR nifedipine on platelet/monocyte activation and adiponectin levels demonstrated in the present study indicate the potential effectiveness of calcium antagonist therapy for hypertensive patients with type 2 diabetes.

Introduction

Diabetes mellitus is often associated with a hypercoagulable state,1 and increases of platelet adhesion and aggregation have been reported in many patients.2 Platelet-derived microparticles (PDMP) are released after the activation or physical stimulation of platelets under various conditions.3, 4 PDMP have procoagulant activity, and some studies have assessed the potential role of PDMP in diabetic complications.4, 5, 6, 7, 8 Monocytes also can synthesize procoagulants, which are largely tissue factors,9, 10 and monocyte vesiculation is a possible mechanism for the dissemination of membrane-associated procoagulant activity.11 We previously reported that a high level of monocyte-derived microparticles (MDMP) may be a marker of vasculopathy in diabetic patients.12, 13, 14, 15, 16

Adiponectin is the most abundant fat-specific hormone, being exclusively expressed by and secreted from adipose tissue.17 The plasma adiponectin concentration is decreased in obese individuals17, 18 and patients with type 2 diabetes,19 and its level is closely related to whole-body insulin sensitivity.20 This protein is abundant in the circulation18 and suppresses attachment of monocytes to endothelial cells.21 Adiponectin also stimulates the production of nitric oxide (NO) by vascular endothelial cells, resulting in the improvement of endothelial dysfunction.22, 23 These data suggest that adiponectin has antiatherogenic properties, so that hypoadiponectinaemia might be associated with a higher incidence of vascular disease in diabetic subjects.24

Nifedipine is a dihydropyridine calcium antagonist that improves endothelial function in patients with hypercholesterolaemia by enhancing NO activity,25 and it also increases endothelial NO bioavailability by antioxidant mechanisms.26 In addition, nifedipine influences platelet function and the activity of some chemokines, resulting in this drug showing an antiatherosclerotic effect in hypertensive patients with type 2 diabetes. To our knowledge, few studies on the relationship between adiponectin and calcium antagonist have been published. Therefore, we investigated the effects of long-term treatment with nifedipine on several procoagulant markers (PDMP, MDMP and endothelial cell-derived microparticles (EDMP)) and adiponectin in patients with type 2 diabetes mellitus.

Materials and methods

Patients

The study group included 43 normotensive controls and 73 hypertensive patients. The controls were recruited from among our hospital staff and students of Kansai Medical University. The protocol of this study was approved by the Institutional Review Board (IRB) of the medical institution, and written informed consent was obtained from each subject prior to the start of the trial in accordance with the guidelines for Good Clinical Practice (GCP). Between April 2002 and August 2004, hypertensive patients were selected from among outpatients and inpatients receiving treatment for hypertension and diabetes mellitus. None of them had suffered from inflammatory conditions, coronary artery disease or cerebrovascular disease within the previous 3 months before enrolment or had clinically detectable renal dysfunction, hepatic dysfunction, infections or malignancy. Those who had been treated with antithrombotic agents, except aspirin, were excluded from this study. There were 12 patients receiving aspirin and the dosage level of this medication was kept unchanged after nifedipine treatment. Forty of the hypertensive patients had type 2 diabetes and 33 did not. The criteria for diagnosis of hypertension were a recumbent systolic blood pressure >150 mm Hg and a recumbent diastolic pressure >90 mm Hg on two or more occasions.27 Type 2 diabetes was defined according to the American Diabetes Association Criteria.28 We performed power calculations on the subjects and, consequently, the normotensive controls were divided into 28 non-diabetics and 15 diabetics (Table 1). Table 2 shows clinical characteristics of the hypertensive and control subjects.

Table 1 Power calculation of subjects
Table 2 Demographic and clinical characteristics of the patients with hypertension and normotensive controls

Study design

We administered long-acting nifedipine (controlled release (CR) nifedipine; Bayer Pharmaceutical, Tokyo, Japan) at a dose of 20 mg/day to the hypertensive patients for 6 months. There were no other changes to their current regimens during nifedipine treatment. Clinical and biochemical data obtained before and after nifedipine administration were compared.

Assessment of microparticles

PDMP

PDMP were detected using a modification of the previously reported method.4, 5, 6, 7 An aliquot (10 μl) of platelet suspension (3 × 108/ml) was added to 100 μl of 2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulphonic acid (HEPES)-Tyrode's buffer containing 5 mmol/l ethylene glycol-bis-(2-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA), and both intact and aggregated platelets were removed by centrifugation at 1000 g for 15 min to obtain a supernatant that only contained microparticles. Then washed intact platelets (10 μl, 3 × 108/ml) were added to the supernatant, and incubation with KMP-9 (a fluorescein isothiocyanate (FITC)-labelled monoclonal antibody for platelet glycoprotein (GP) IX was performed for 30 min in the dark at room temperature. After incubation, samples were diluted 1:10 with HEPES-Tyrode's buffer containing 5 mmol/l EGTA and were analysed with an Ortho Cytoron Absolute Analyzer (Ortho Diagnostic Systems, Tokyo, Japan). Only cells and particles positive for GPIX were gated in order to distinguish platelets and PDMP from electronic noise. To differentiate between platelets and PDMP, the lower limit of the platelet gate was set at the left limit of the forward-scatter profile of resting platelets. Ten thousand FITC-positive particles in the PDMP gate were then counted to determine the number of microparticles released per 10 000 platelets, and the concentration of microparticles was calculated per μl of whole blood.

MDMP and EDMP

MDMP and EDMP were detected by using the previously reported method with some modifications.12, 15 A 10 μl aliquot of washed intact platelets (3 × 108/ml) was added to plasma, and the mixture was incubated with FITC-labelled Annexin V (FITC-Ann V) and phycoerythrin (PE)-labelled CD14 (PE-CD14) to detect MDMP or PE-CD51 (αvβ3) to detect EDMP for 30 min in the dark at room temperature. Samples were diluted 1:10 with HEPES-Tyrode's buffer containing 5 mmol/l EGTA and analysed with a Cytoron Absolute Analyzer that was set to detect only particles bound to FITC-Annexin V and PE-CD14 or PE-CD51. This method was designed to only detect procoagulant MDMP or EDMP. Then the concentrations of these microparticles were calculated per μl of whole blood.

Measurement of sCD40L, sP-selectin, sE-selectin and adiponectin

Blood samples from patients and healthy controls were collected into tubes containing sodium citrate or tubes without any anticoagulant and the blood was allowed to clot at room temperature for a minimum of 1 h. Then serum or citrated plasma was isolated by centrifugation for 20 min at 1000 g at 4°C and stored at −30°C until analysis. As positive controls for each assay, we used the recombinant products and standard solutions provided with the commercial kits. Soluble CD40 ligand (sCD40L) was measured with an enzyme-linked immunosorbant assay (ELISA) kit from Chemicon International Inc. (Temecula, CA, USA). Plasma sP-selectin and sE-selectin were measured with a monoclonal antibody-based ELISA kit from BioSource International Inc. (Camarillo, CA, USA), while adiponectin was measured with an Adiponectin ELISA kit from Otsuka Pharmaceuticals Co. Ltd (Tokyo, Japan). All kits were used according to the manufacturer's instructions. The intre- and intra-assay CVs for all laboratory assays and their lower limits of detection are shown in Table 3.

Table 3 Reproducibility of assays

Statistics

Data are presented as the mean±s.d. The significance of differences among variables was determined by analysis of variance (ANOVA). Student's t-test was used for statistical comparisons, and P-values of less than 0.05 were considered significant.

Results

There were no cardiovascular events and no cerebral infarction. In addition, there were no cases of renal dysfunction. Three non-diabetic patients and seven diabetic patients showed abnormal laboratory data (renal failure and infections) and two diabetic patients changed hospital. Thus, data collected from 30 non-diabetic patients and 31 diabetic patients were used for analysis.

The levels of sCD40L, sP-selectin, PDMP and MDMP were higher in the hypertensive patients without diabetes than in the normotensive and non-diabetic controls (Table 4: sCD40L: 6.7±3.2 vs 9.3±2.2 ng/ml, P<0.01; sP-selectin: 112±22 vs 138±26 ng/ml, P<0.05; PDMP: 6690±1147 vs 8455±1362/μl, P<0.05; MDMP: 352±71 vs 433±81/μl, P<0.05). However, there were no significant differences between the levels of sE-selectin and EDMP in either group. The levels of all markers, except adiponectin, were also significantly higher in the hypertensive patients with diabetes than in the normotensive and non-diabetic controls (Table 4: sCD40L: 6.7±3.2 vs 16.4±3.9 ng/ml, P<0.001; sP-selectin: 112±22 vs 185±33 ng/ml, P<0.01; sE-selectin: 41±11 vs 68±19 ng/ml, P<0.01; PDMP: 6690±1147 vs 10873±2262/μl, P<0.01; MDMP: 352±71 vs 525±150/μl, P<0.01; EDMP: 318±95 vs 485±146/μl, P<0.05). Before nifedipine CR therapy, the adiponectin level of the hypertensive patients with diabetes was significantly lower than that of the normotensive and non-diabetic controls (Table 4) (8.3±3.2 vs 5.1±2.3 μg/ml, P<0.01).

Table 4 Soluble factors, microparticles and adiponectin in normotensive controls and hypertensive patients

Both systolic and diastolic blood pressure were decreased significantly by CR nifedipine administration in the diabetic and non-diabetic subjects (Figure 1: 0 vs 6 months: non-diabetic: 178±17 vs 153±16 mm Hg, P<0.01; diabetic: 175±13 vs 148±11 mm Hg, P<0.01; Figure 2: 0 vs 6 months: non-diabetic: 98±10 vs 91±8 mm Hg, P<0.01; diabetic: 104±11 vs 88±9 mm Hg, P<0.001).

Figure 1
figure1

Systolic pressure before and after CR nifedipine administration in hypertensive patients with and without type 2 diabetes. Systolic pressure before and after administration was similar in the patients with (n=31) or without (n=30) diabetes. Data are shown as the mean±s.d. P-value: Student's t-test, ANOVA: non-diabetic vs diabetic.

Figure 2
figure2

Diastolic pressure before and after CR nifedipine administration in hypertensive patients with and without type 2 diabetes. Diastolic pressure before and after administration was similar in the patients with (n=31) or without (n=30) diabetes. Data are shown as the mean±s.d. P-value: Student's t-test, ANOVA: non-diabetic vs diabetic.

The levels of all markers remained unchanged in the hypertensive patients without diabetes after nifedipine CR treatment (Table 5). In contrast, all of the markers, except adiponectin, decreased significantly in the hypertensive patients after 3 months of nifedipine CR treatment (Table 5). The hypertensive patients with type 2 diabetes displayed a significant increase in adiponectin after nifedipine CR treatment, compared to the hypertensive patients who did not have diabetes (Table 5). However, total cholesterol, triglycerides, haemoglobin A1c, fasting glucose and body weight did not demonstrate any differences after CR nifedipine administration (data not shown).

Table 5 Changes of soluble factors and microparticles with nifedipine treatment

Discussion

Normalization of hypertension is a key goal of treatment to achieve renal protection and possibly cardioprotection in hypertensive patients with type 2 diabetes.29 Inhibition of the renin–angiotensin system either by treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II antagonists has been shown to decrease structural renal damage.30 However, prospective clinical trials have revealed that calcium channel blockers are almost as effective as ACE inhibitors for preventing the progression of renal failure.31 In fact, calcium channel blockers have demonstrated diverse effects on glomerular haemodynamics in spontaneously hypertensive rats.32 The STONE study was a large-scale clinical trial that demonstrated a decline in the incidence of cardiovascular events and stroke with nifedipine treatment.33 Among our patients, there were no cardiovascular events during 6 months of CR nifedipine treatment. In addition, CR nifedipine was shown to improve platelet activation markers and microparticles, which have some influence on vasculopathy in hypertensive patients with type 2 diabetes. This suggests that CR nifedipine may have a beneficial effect on the vascular system beyond its antihypertensive effect.25, 26, 34, 35, 36 In patients with essential hypertension, platelets appear to be preactivated or hyper-responsive to vasoactive agents.37 In addition, the activation of platelets contributes to vascular structural changes and the development of atherosclerosis.38, 39 Therefore, antihypertensive agents should modulate platelet function as well as reducing blood pressure for better cardiovascular protection. The antiplatelet effects of various classes of calcium antagonists, including the dihydropyridine derivatives, have been well established by in vitro experiments, and some studies using ex vivo techniques have also shown inhibition of platelet activity.40, 41 In the present study, levels of some platelet activation markers such as sCD40L, sP-selectin and PDMP were higher in the hypertensive patients with type 2 diabetes than in hypertensive patients without diabetes. These results suggest that diabetes may have an influence on the levels of procoagulant markers. The recent Hypertension Optimal Treatment (HOT) study demonstrated that antiplatelet therapy with low-dose aspirin could reduce the incidence of primary cardiovascular events, especially myocardial infarction, in patients with essential hypertension.42 The antiplatelet effect of CR nifedipine observed in the present study supports the findings of the HOT study.

In the present study, we observed a significant decrease of the plasma adiponectin level in patients with type 2 diabetes, and this finding agrees with the report of Hotta et al.19 Abnormalities of lipid metabolism and haemostatic factors, as well as the presence of insulin resistance, are thought to contribute to atherosclerotic vascular damage in diabetes. Insulin resistance induces hyperinsulinaemia and alters the secretion by adipose tissue of various proteins that are regulated by insulin. Thus, the elevated plasma insulin level in diabetic subjects is responsible for the decrease of plasma adiponectin.43 Interestingly, treatment with CR nifedipine caused an increase of adiponectin levels in the present study. The exact mechanisms by which CR nifedipine therapy achieved an increase of circulating adiponectin levels remain unclear. However, one reason for this increase may have been the suppression of monocyte activation by CR nifedipine. Adiponectin suppresses the attachment of monocytes to endothelial cells21 and plays a role in protection against vascular damage. Thus, it is possible that continuous monocyte activation depletes adiponectin in type 2 diabetes. We recently reported that the level of MDMP, one of the markers of monocyte activation, is particularly high in diabetic patients12 and nifedipine has been shown to inhibit MDMP generation.44 In the present study, MDMP also decreased significantly after 3 months of CR nifedipine treatment, while there was a significant increase of adiponectin after 6 months (Table 5).

Another mechanism underlying the increase of circulating adiponectin after treatment with CR nifedipine may be the inhibition of platelet activation. In the present study, platelet activation markers such as sCD40L, sP-selectin and PDMP were significantly improved after 3 months of CR nifedipine treatment (Table 5). These results suggest that CR nifedipine can improve endothelial function and increase the activity of NO, which regulates platelet activation.25, 26, 35, 45 It is possible that inhibition of platelet activation improves blood flow in skeletal muscle and thus reduces insulin resistance, resulting in an elevation of circulating adiponectin.46 The ability of CR nifedipine to inhibit MDMP generation provides additional evidence for the antiatherosclerotic action of this drug.47, 48 However, further studies are required to elucidate the mechanism by which hypoadiponectinaemia is improved by CR nifedipine.

In conclusion, CR nifedipine directly or indirectly improved platelet activation markers, microparticles and adiponectin levels in hypertensive patients with diabetes. These results suggest that the long-acting calcium antagonist CR nifedipine may have a beneficial antiatherosclerotic effect in patients with type 2 diabetes in addition to its antihypertensive action.

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Acknowledgements

This study was partly supported by a grant from the Japan Foundation of Neuropsychiatry and Hematology Research, a Research Grant for Advanced Medical Care from the Ministry of Health and Welfare of Japan, and a Grant (13670760 to SN) from the Ministry of Education, Science and Culture of Japan.

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Nomura, S., Inami, N., Kimura, Y. et al. Effect of nifedipine on adiponectin in hypertensive patients with type 2 diabetes mellitus. J Hum Hypertens 21, 38–44 (2007). https://doi.org/10.1038/sj.jhh.1002100

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Keywords

  • procoagulant markers
  • adiponectin
  • type 2 diabetes mellitus
  • hypertension
  • long-acting nifedipine

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