DIAB-6211; No. of Pages 7 diabetes research and clinical practice xxx (2014) xxx–xxx
Contents available at ScienceDirect
Diabetes Research and Clinical Practice journ al h ome pa ge : www .elsevier.co m/lo cate/diabres
Effects of cilnidipine on sympathetic nerve activity and cardiorenal function in hypertensive patients with type 2 diabetes mellitus: Association with BNP and aldosterone levels§ Masami Tanaka a,*, Risa Sekioka a, Takeshi Nishimura a, Atsuhiro Ichihara b, Hiroshi Itoh a a
Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan b Department of Endocrinology and Hypertension, Tokyo Women’s Medical University, Tokyo, Japan
article info
abstract
Article history:
Aims: Hypertension stimulates the sympathetic nervous system and this phenomenon is
Received 22 March 2014
exacerbated by diabetes mellitus. We investigated the effects of cilnidipine, an N/L-type
Received in revised form
calcium channel blocker, on aspects of this system in patients with type 2 diabetes mellitus.
1 August 2014
Methods: In 33 hypertensive patients with type 2 diabetes mellitus treated with a calcium
Accepted 14 September 2014
channel blocker other than cilnidipine, we evaluated the influence of switching to cilnidi-
Available online xxx
pine on blood pressure, heart rate, catecholamine, plasma renin and aldosterone concentration, brain natriuretic peptide, urine liver-type fatty acid binding protein, and urinary
Keywords:
albumin excretion ratio in the same patients by a cross-over design. Other biochemical
Cilnidipine
parameters were also evaluated.
Diabetes mellitus
Results: Switching to cilnidipine did not change blood pressure but caused reduction in
Hypertension
catecholamine concentrations in blood and urine and plasma aldosterone concentration,
Renin–angiotensin–aldosterone
accompanied by significant reduction in brain natriuretic peptide, urine liver-type fatty acid
system
binding protein, and albumin excretion ratio. These parameters other than brain natriuretic
Sympathetic nervous system
peptide were significantly increased after cilnidipine was changed to the original calcium channel blocker. Conclusions: In 33 hypertensive patients with type 2 diabetes mellitus, compared to other calcium channel blockers, cilnidipine suppressed sympathetic nerve activity and aldosterone, and significantly improved markers of cardiorenal disorders. Therefore, cilnidipine may be an important calcium channel blocker for use in combination with renin–angiotensin–aldosterone system inhibitors when dealing with hypertension complicated with diabetes mellitus. # 2014 Elsevier Ireland Ltd. All rights reserved.
§ Redundant or duplicate publication: This paper was presented at the 2012 Conference of the International Society of Hypertension. However, there is no redundant or duplicate publication. * Corresponding author. Tel.: +81 3 5363 3797; fax: +81 3 3359 2745. E-mail addresses: [email protected], [email protected] (M. Tanaka). http://dx.doi.org/10.1016/j.diabres.2014.09.056 0168-8227/# 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Tanaka M, et al. Effects of cilnidipine on sympathetic nerve activity and cardiorenal function in hypertensive patients with type 2 diabetes mellitus: Association with BNP and aldosterone levels. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/ j.diabres.2014.09.056
DIAB-6211; No. of Pages 7
2
diabetes research and clinical practice xxx (2014) xxx–xxx
1.
Introduction
Hypertension is often accompanied by type 2 diabetes mellitus [1,2]. It has been reported that the sympathetic nervous system is stimulated in cases of hypertension and that sympathetic nervous activity is further elevated if hypertension is complicated by type 2 diabetes mellitus [3]. Hypertension and diabetes mellitus are components of metabolic syndrome. Metabolic syndrome is considered to begin with obesity based on disturbed daily habits. Obesity can result in blood pressure elevation and insulin resistance, leading to diabetes mellitus and eventually resulting in major vascular events. The sympathetic nervous system seems to play an important role as a factor accelerating the progression of metabolic syndrome [3,4]. Stimulation of the renin–angiotensin–aldosterone system (RAAS) is also observed in patients with hypertension complicated by diabetes mellitus [5]. Stimulation of both RAAS and the sympathetic nervous system forms a vicious cycle, and influences pathologic complexity in hypertensive patients [6]. Guidelines recommend active antihypertensive drug therapy using combinations of multiple drugs when dealing with cases of patients with hypertension complicated by diabetes mellitus, with RAAS inhibitors serving as the first-line drugs to be used in combination with calcium channel blockers (CCBs) and diuretics [7]. CCBs are among the most useful agents in respect of antihypertensive effect without crucial adverse effects. There are several types of CCB, blocking different calcium channels. Many are L type CCBs that exert hypotensive activity by blocking the L-type calcium channel of vascular smooth muscles. This CCB type has been reported to cause a reactive stimulation of the sympathetic nervous system. Cilnidipine, on the other hand, is a CCB blocking both L- and N-type calcium channels, and the blockade of N-type calcium channels at sympathetic nerve endings prevents reactive stimulation of the sympathetic nervous system [8]. Generally, blood pressure lowering by CCB leads to activation of the RAAS. Studies in rat models of hypertension and in patients with essential hypertension revealed that RAAS activation was less intense with cilnidipine than with L-type CCBs [9,10]. In patients with hypertension complicated by diabetes mellitus, stimulation of the sympathetic nervous system and RAAS occurs, and it seems likely that N/L-type CCB is more useful than L-type CCBs in the treatment of organ failure. With this possibility, the present study evaluated the influence on blood pressure, heart rate, sympathetic nervous activity, indicators of RAAS, brain natriuretic peptide (BNP), urinary biomarkers and other biochemical parameters in the same patients when the currently used CCB other than cilnidipine was switched to cilnidipine in a cross-over design in patients with hypertension complicated by type 2 diabetes mellitus.
2.
Methods
The study included outpatients with hypertension complicated by type 2 diabetes mellitus managed at the Department of Endocrinology, Metabolism and Nephrology of the Keio
University Hospital, who received a CCB other than cilnidipine for 3 months or more. The study excluded patients with malignant hypertension, and pregnant or possibly pregnant women. This study, approved in advance by the Ethical Committee of Keio University School of Medicine, was carried out in compliance with the Declaration of Helsinki. Informed consent in writing was obtained from each subject prior to the start of the study. With reference to the published report [11], the sample size was calculated based on the assumption of a 20% reduction in urinary microalbumin level on average following switching of CCB to cilnidipine, with a standard deviation (SD) of 40%, a minimum statistical power of 80% and a significance level of 0.5%. The number of subjects needed for this study was thus estimated to be 34. For each patient enrolled to this study, their current CCB was switched to cilnidipine (10 to 20 mg/day). The goal of office blood pressure reduction was set at less than 130/80 mmHg. Cilnidipine was administered for 3 months, with the dose level increased up to 20 mg/day in cases in which the hypotensive effect was insufficient. Subsequently, cilnidipine was switched to the original CCB, which was then administered for 3 months (observation of each patient for 6 months in total). For patients concomitantly using RAAS inhibitors and anti-diabetic drugs, their dose level was kept unchanged during the study period. Measurement was conducted on blood pressure, heart rate, blood/urinary catecholamines, plasma renin, aldosterone and BNP, urinary liver-type fatty acid binding protein (L-FABP) level and urinary albumin excretion before and after CCB switching. Urinary albumin excretion was shown as albumin creatinine ratio (ACR), was calculated from the values of albumin and creatinine in spot urine. The effects of cilnidipine were evaluated by switching cilnidipine to the original CCB again. Measurement was conducted in a similar way also on blood glucose control, hepatic function, renal function, serum sodium level, serum potassium level, creatine phosphokinase (CPK), uric acid, and lipid parameters.
3.
Statistical analysis
Data were expressed as mean SD. The test data before and after CCB switching were compared using paired-t test; p < 0.05 was regarded statistically significant. The correlations between change in aldosterone, BNP, L-FABP and albumin levels, and change in catecholamines were analyzed by the Spearman rank order correlation. Analyses were performed using SPSS 17.0 (SPSS; Chicago, IL, USA).
4.
Results
4.1.
Baseline characteristics of patients
Thirty-four patients were enrolled to this study. Informed consent was obtained in writing from all these patients. One patient cancelled participation in the study after providing consent, due to relocation. Thirty-three patients were therefore included. During the study period, 2 patients complained
Please cite this article in press as: Tanaka M, et al. Effects of cilnidipine on sympathetic nerve activity and cardiorenal function in hypertensive patients with type 2 diabetes mellitus: Association with BNP and aldosterone levels. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/ j.diabres.2014.09.056
DIAB-6211; No. of Pages 7
3
diabetes research and clinical practice xxx (2014) xxx–xxx
of dizziness and 1 patient complained of hot flush, but all of these complaints were minimal, allowing all patients to remain in the study until the end. Thirty-three patients with hypertension complicated by type 2 diabetes mellitus (26 males and 7 females) visiting the outpatient clinic between February 28 and October 3, 2011, were evaluated. Their mean age (SD) was 68.2 7.8 (range: 52–81). The patients were followed until Jun 23, 2012. Their mean body mass index was 25.2 4.4 kg/m2 and the mean duration of diabetes mellitus was 15.5 8.9 years. The diabetic complications observed were neuropathy in 21 cases, retinopathy in 14 cases and nephropathy in 12 cases. The major vascular events were cerebral infarction in 10 cases and angina pectoris/myocardial infarction in 4 cases. Concomitantly used anti-diabetic medication included oral hypoglycemic drugs (15 cases), insulin (10 cases) and oral hypoglycemic drug + insulin (3 cases). The CCB used before switching to cilnidipine was amlodipine in 26 cases, benidipine in 6 cases, and azelnidipine in 1 case (Table 1).
4.2.
Changes in office blood pressure and heart rate
Neither systolic blood pressure nor diastolic blood pressure changed following switching of the current CCB to cilnidipine, however, blood pressure rose significantly after cilnidipine switched back to the original CCB (SBP; was 137.6 12.4 ! 134.0 15.1 (ns) ! 141.0 15.2 (P < 0.01), DBP; 77.8 9.3 ! 74.8 10.3 (ns) ! 79.3 10.6 (P < 0.05)). Heart rate tended to be lower during the cilnidipine treatment period than the other CCB treatment period although this difference was not statistically significant (HR; 80.6 15.7 ! 78.2 14.6 (ns) ! 80.6 11.3 (ns)).
4.3.
Changes in blood/urinary catecholamines
Blood catecholamine levels tended to be lower during the cilnidipine treatment period than during the other CCB treatment period, and this difference in blood noradrenaline
level was statistically significant. The urinary level of each catecholamine was significantly lower during the cilnidipine treatment period, and both urinary normetanephrine level and metanephrine + normetanephrine level were significantly higher after switching from cilnidipine to the other CCB (Fig. 1).
4.4.
Changes in renin, aldosterone and BNP
Plasma renin concentration tended to rise following switching to cilnidipine although this change was not statistically significant. Plasma aldosterone level significantly decreased during the cilnidipine treatment period, and significantly increased after switching from cilnidipine to the original CCB. BNP level decreased significantly following switching to cilnidipine (Fig. 2).
4.5.
Changes in urinary biomarkers
Urinary L-FABP level was significantly lower during the cilnidipine treatment period than during the other CCB treatment period, and urinary albumin level was also significantly lower during the cilnidipine treatment period (Fig. 3).
4.6.
Changes in biochemical parameters
No significant change was noted following switching to cilnidipine in any of the other biochemical parameters (related to blood glucose control, hepatic function, renal function, serum sodium level, serum potassium level, CPK, uric acid level, and lipid level) (Table 2).
4.7. Relationship between blood aldosterone and urinary catecholamines The changes in blood aldosterone level by cilnidipine were positively and significantly correlated with the changes in
Table 1 – Baseline characteristics of the patients (n = 33). Gender (n)
Males: 26 Females: 7
Age (years) Body mass index (kg/m2) Duration of diabetes (years) Diabetic complications (n) Neuropathy Retinopathy Nephropathy Macroangiopathy (n) Cerebral infarction Angina/myocardial infarction
68.2 7.8 (52 81) 25.2 4.4 15.5 8.9
Other calcium channel blocker (n) Amlodipine Benidipine Azelnidipine
21 14 12 10 4
26 6 2
Diabetic medication (n) Oral hypoglycemic drugs Insulin Oral hypoglycemic drug + insulin Non-calcium blocker antihypertensives (n) ARB ACEI Diuretic drug a-Blocker b-Blocker Dyslipidemia medication (n) Statins Fibrates Antiplatelet drug (n) Aspirin Clopidogrel Warfarin
15 10 3
25 6 3 1 3 8 5 5 1 1
Gender, age, body weight and duration of diabetes are expressed in mean SD. Abbreviation: ARB; angiotensin receptor blocker. ACEI, angiotensine converting enzyme inhibitor
Please cite this article in press as: Tanaka M, et al. Effects of cilnidipine on sympathetic nerve activity and cardiorenal function in hypertensive patients with type 2 diabetes mellitus: Association with BNP and aldosterone levels. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/ j.diabres.2014.09.056
DIAB-6211; No. of Pages 7
4
diabetes research and clinical practice xxx (2014) xxx–xxx
ng/ml 0.14
Blood adrenaline
0.12 0.10 0.08 0.06 0.04 0.02 0
ng/ml 0.18 0.16 0.14 0.12 0.10 0.08 0.06 0.04 0.02 0
Other Cilnidipine Original CCB CCB
Urine metanephrine P
Contents available at ScienceDirect
Diabetes Research and Clinical Practice journ al h ome pa ge : www .elsevier.co m/lo cate/diabres
Effects of cilnidipine on sympathetic nerve activity and cardiorenal function in hypertensive patients with type 2 diabetes mellitus: Association with BNP and aldosterone levels§ Masami Tanaka a,*, Risa Sekioka a, Takeshi Nishimura a, Atsuhiro Ichihara b, Hiroshi Itoh a a
Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan b Department of Endocrinology and Hypertension, Tokyo Women’s Medical University, Tokyo, Japan
article info
abstract
Article history:
Aims: Hypertension stimulates the sympathetic nervous system and this phenomenon is
Received 22 March 2014
exacerbated by diabetes mellitus. We investigated the effects of cilnidipine, an N/L-type
Received in revised form
calcium channel blocker, on aspects of this system in patients with type 2 diabetes mellitus.
1 August 2014
Methods: In 33 hypertensive patients with type 2 diabetes mellitus treated with a calcium
Accepted 14 September 2014
channel blocker other than cilnidipine, we evaluated the influence of switching to cilnidi-
Available online xxx
pine on blood pressure, heart rate, catecholamine, plasma renin and aldosterone concentration, brain natriuretic peptide, urine liver-type fatty acid binding protein, and urinary
Keywords:
albumin excretion ratio in the same patients by a cross-over design. Other biochemical
Cilnidipine
parameters were also evaluated.
Diabetes mellitus
Results: Switching to cilnidipine did not change blood pressure but caused reduction in
Hypertension
catecholamine concentrations in blood and urine and plasma aldosterone concentration,
Renin–angiotensin–aldosterone
accompanied by significant reduction in brain natriuretic peptide, urine liver-type fatty acid
system
binding protein, and albumin excretion ratio. These parameters other than brain natriuretic
Sympathetic nervous system
peptide were significantly increased after cilnidipine was changed to the original calcium channel blocker. Conclusions: In 33 hypertensive patients with type 2 diabetes mellitus, compared to other calcium channel blockers, cilnidipine suppressed sympathetic nerve activity and aldosterone, and significantly improved markers of cardiorenal disorders. Therefore, cilnidipine may be an important calcium channel blocker for use in combination with renin–angiotensin–aldosterone system inhibitors when dealing with hypertension complicated with diabetes mellitus. # 2014 Elsevier Ireland Ltd. All rights reserved.
§ Redundant or duplicate publication: This paper was presented at the 2012 Conference of the International Society of Hypertension. However, there is no redundant or duplicate publication. * Corresponding author. Tel.: +81 3 5363 3797; fax: +81 3 3359 2745. E-mail addresses: [email protected], [email protected] (M. Tanaka). http://dx.doi.org/10.1016/j.diabres.2014.09.056 0168-8227/# 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Tanaka M, et al. Effects of cilnidipine on sympathetic nerve activity and cardiorenal function in hypertensive patients with type 2 diabetes mellitus: Association with BNP and aldosterone levels. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/ j.diabres.2014.09.056
DIAB-6211; No. of Pages 7
2
diabetes research and clinical practice xxx (2014) xxx–xxx
1.
Introduction
Hypertension is often accompanied by type 2 diabetes mellitus [1,2]. It has been reported that the sympathetic nervous system is stimulated in cases of hypertension and that sympathetic nervous activity is further elevated if hypertension is complicated by type 2 diabetes mellitus [3]. Hypertension and diabetes mellitus are components of metabolic syndrome. Metabolic syndrome is considered to begin with obesity based on disturbed daily habits. Obesity can result in blood pressure elevation and insulin resistance, leading to diabetes mellitus and eventually resulting in major vascular events. The sympathetic nervous system seems to play an important role as a factor accelerating the progression of metabolic syndrome [3,4]. Stimulation of the renin–angiotensin–aldosterone system (RAAS) is also observed in patients with hypertension complicated by diabetes mellitus [5]. Stimulation of both RAAS and the sympathetic nervous system forms a vicious cycle, and influences pathologic complexity in hypertensive patients [6]. Guidelines recommend active antihypertensive drug therapy using combinations of multiple drugs when dealing with cases of patients with hypertension complicated by diabetes mellitus, with RAAS inhibitors serving as the first-line drugs to be used in combination with calcium channel blockers (CCBs) and diuretics [7]. CCBs are among the most useful agents in respect of antihypertensive effect without crucial adverse effects. There are several types of CCB, blocking different calcium channels. Many are L type CCBs that exert hypotensive activity by blocking the L-type calcium channel of vascular smooth muscles. This CCB type has been reported to cause a reactive stimulation of the sympathetic nervous system. Cilnidipine, on the other hand, is a CCB blocking both L- and N-type calcium channels, and the blockade of N-type calcium channels at sympathetic nerve endings prevents reactive stimulation of the sympathetic nervous system [8]. Generally, blood pressure lowering by CCB leads to activation of the RAAS. Studies in rat models of hypertension and in patients with essential hypertension revealed that RAAS activation was less intense with cilnidipine than with L-type CCBs [9,10]. In patients with hypertension complicated by diabetes mellitus, stimulation of the sympathetic nervous system and RAAS occurs, and it seems likely that N/L-type CCB is more useful than L-type CCBs in the treatment of organ failure. With this possibility, the present study evaluated the influence on blood pressure, heart rate, sympathetic nervous activity, indicators of RAAS, brain natriuretic peptide (BNP), urinary biomarkers and other biochemical parameters in the same patients when the currently used CCB other than cilnidipine was switched to cilnidipine in a cross-over design in patients with hypertension complicated by type 2 diabetes mellitus.
2.
Methods
The study included outpatients with hypertension complicated by type 2 diabetes mellitus managed at the Department of Endocrinology, Metabolism and Nephrology of the Keio
University Hospital, who received a CCB other than cilnidipine for 3 months or more. The study excluded patients with malignant hypertension, and pregnant or possibly pregnant women. This study, approved in advance by the Ethical Committee of Keio University School of Medicine, was carried out in compliance with the Declaration of Helsinki. Informed consent in writing was obtained from each subject prior to the start of the study. With reference to the published report [11], the sample size was calculated based on the assumption of a 20% reduction in urinary microalbumin level on average following switching of CCB to cilnidipine, with a standard deviation (SD) of 40%, a minimum statistical power of 80% and a significance level of 0.5%. The number of subjects needed for this study was thus estimated to be 34. For each patient enrolled to this study, their current CCB was switched to cilnidipine (10 to 20 mg/day). The goal of office blood pressure reduction was set at less than 130/80 mmHg. Cilnidipine was administered for 3 months, with the dose level increased up to 20 mg/day in cases in which the hypotensive effect was insufficient. Subsequently, cilnidipine was switched to the original CCB, which was then administered for 3 months (observation of each patient for 6 months in total). For patients concomitantly using RAAS inhibitors and anti-diabetic drugs, their dose level was kept unchanged during the study period. Measurement was conducted on blood pressure, heart rate, blood/urinary catecholamines, plasma renin, aldosterone and BNP, urinary liver-type fatty acid binding protein (L-FABP) level and urinary albumin excretion before and after CCB switching. Urinary albumin excretion was shown as albumin creatinine ratio (ACR), was calculated from the values of albumin and creatinine in spot urine. The effects of cilnidipine were evaluated by switching cilnidipine to the original CCB again. Measurement was conducted in a similar way also on blood glucose control, hepatic function, renal function, serum sodium level, serum potassium level, creatine phosphokinase (CPK), uric acid, and lipid parameters.
3.
Statistical analysis
Data were expressed as mean SD. The test data before and after CCB switching were compared using paired-t test; p < 0.05 was regarded statistically significant. The correlations between change in aldosterone, BNP, L-FABP and albumin levels, and change in catecholamines were analyzed by the Spearman rank order correlation. Analyses were performed using SPSS 17.0 (SPSS; Chicago, IL, USA).
4.
Results
4.1.
Baseline characteristics of patients
Thirty-four patients were enrolled to this study. Informed consent was obtained in writing from all these patients. One patient cancelled participation in the study after providing consent, due to relocation. Thirty-three patients were therefore included. During the study period, 2 patients complained
Please cite this article in press as: Tanaka M, et al. Effects of cilnidipine on sympathetic nerve activity and cardiorenal function in hypertensive patients with type 2 diabetes mellitus: Association with BNP and aldosterone levels. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/ j.diabres.2014.09.056
DIAB-6211; No. of Pages 7
3
diabetes research and clinical practice xxx (2014) xxx–xxx
of dizziness and 1 patient complained of hot flush, but all of these complaints were minimal, allowing all patients to remain in the study until the end. Thirty-three patients with hypertension complicated by type 2 diabetes mellitus (26 males and 7 females) visiting the outpatient clinic between February 28 and October 3, 2011, were evaluated. Their mean age (SD) was 68.2 7.8 (range: 52–81). The patients were followed until Jun 23, 2012. Their mean body mass index was 25.2 4.4 kg/m2 and the mean duration of diabetes mellitus was 15.5 8.9 years. The diabetic complications observed were neuropathy in 21 cases, retinopathy in 14 cases and nephropathy in 12 cases. The major vascular events were cerebral infarction in 10 cases and angina pectoris/myocardial infarction in 4 cases. Concomitantly used anti-diabetic medication included oral hypoglycemic drugs (15 cases), insulin (10 cases) and oral hypoglycemic drug + insulin (3 cases). The CCB used before switching to cilnidipine was amlodipine in 26 cases, benidipine in 6 cases, and azelnidipine in 1 case (Table 1).
4.2.
Changes in office blood pressure and heart rate
Neither systolic blood pressure nor diastolic blood pressure changed following switching of the current CCB to cilnidipine, however, blood pressure rose significantly after cilnidipine switched back to the original CCB (SBP; was 137.6 12.4 ! 134.0 15.1 (ns) ! 141.0 15.2 (P < 0.01), DBP; 77.8 9.3 ! 74.8 10.3 (ns) ! 79.3 10.6 (P < 0.05)). Heart rate tended to be lower during the cilnidipine treatment period than the other CCB treatment period although this difference was not statistically significant (HR; 80.6 15.7 ! 78.2 14.6 (ns) ! 80.6 11.3 (ns)).
4.3.
Changes in blood/urinary catecholamines
Blood catecholamine levels tended to be lower during the cilnidipine treatment period than during the other CCB treatment period, and this difference in blood noradrenaline
level was statistically significant. The urinary level of each catecholamine was significantly lower during the cilnidipine treatment period, and both urinary normetanephrine level and metanephrine + normetanephrine level were significantly higher after switching from cilnidipine to the other CCB (Fig. 1).
4.4.
Changes in renin, aldosterone and BNP
Plasma renin concentration tended to rise following switching to cilnidipine although this change was not statistically significant. Plasma aldosterone level significantly decreased during the cilnidipine treatment period, and significantly increased after switching from cilnidipine to the original CCB. BNP level decreased significantly following switching to cilnidipine (Fig. 2).
4.5.
Changes in urinary biomarkers
Urinary L-FABP level was significantly lower during the cilnidipine treatment period than during the other CCB treatment period, and urinary albumin level was also significantly lower during the cilnidipine treatment period (Fig. 3).
4.6.
Changes in biochemical parameters
No significant change was noted following switching to cilnidipine in any of the other biochemical parameters (related to blood glucose control, hepatic function, renal function, serum sodium level, serum potassium level, CPK, uric acid level, and lipid level) (Table 2).
4.7. Relationship between blood aldosterone and urinary catecholamines The changes in blood aldosterone level by cilnidipine were positively and significantly correlated with the changes in
Table 1 – Baseline characteristics of the patients (n = 33). Gender (n)
Males: 26 Females: 7
Age (years) Body mass index (kg/m2) Duration of diabetes (years) Diabetic complications (n) Neuropathy Retinopathy Nephropathy Macroangiopathy (n) Cerebral infarction Angina/myocardial infarction
68.2 7.8 (52 81) 25.2 4.4 15.5 8.9
Other calcium channel blocker (n) Amlodipine Benidipine Azelnidipine
21 14 12 10 4
26 6 2
Diabetic medication (n) Oral hypoglycemic drugs Insulin Oral hypoglycemic drug + insulin Non-calcium blocker antihypertensives (n) ARB ACEI Diuretic drug a-Blocker b-Blocker Dyslipidemia medication (n) Statins Fibrates Antiplatelet drug (n) Aspirin Clopidogrel Warfarin
15 10 3
25 6 3 1 3 8 5 5 1 1
Gender, age, body weight and duration of diabetes are expressed in mean SD. Abbreviation: ARB; angiotensin receptor blocker. ACEI, angiotensine converting enzyme inhibitor
Please cite this article in press as: Tanaka M, et al. Effects of cilnidipine on sympathetic nerve activity and cardiorenal function in hypertensive patients with type 2 diabetes mellitus: Association with BNP and aldosterone levels. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/ j.diabres.2014.09.056
DIAB-6211; No. of Pages 7
4
diabetes research and clinical practice xxx (2014) xxx–xxx
ng/ml 0.14
Blood adrenaline
0.12 0.10 0.08 0.06 0.04 0.02 0
ng/ml 0.18 0.16 0.14 0.12 0.10 0.08 0.06 0.04 0.02 0
Other Cilnidipine Original CCB CCB
Urine metanephrine P
