http://informahealthcare.com/ceh ISSN: 1064-1963 (print), 1525-6006 (electronic) Clin Exp Hypertens, Early Online: 1–5 ! 2015 Informa Healthcare USA, Inc. DOI: 10.3109/10641963.2015.1025959

Cilnidipine but not amlodipine suppresses sympathetic activation elicited by isometric exercise in hypertensive patients Yumi Koike1,2, Tetsuya Kawabe1, Kanami Nishihara1, Naomi Iwane1,3, and Takuzo Hano1 Medical Education and Population-Based Medicine, Graduate School of Medicine, Wakayama Medical University, Wakayama, Japan, 2Department of Rehabilitation Medicine, School of Medicine, Wakayama Medical University, Wakayama, Japan, and 3School of Health and Nursing Science, Wakayama Medical University, Wakayama, Japan

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Abstract

Keywords

Pupillometry was used to evaluate the effects of the calcium channel blockers cilnidipine (CL) and amlodipine (AM) on changes in autonomic nervous activity induced by isometric exercise in patients with hypertension. After handgrip exercise, the velocity of miosis increased in both the CL and AM groups. However, the velocity of mydriasis increased in only the AM group. Velocity slopes of miosis and mydriasis were smaller in the CL group than in the AM group. The low-to-high frequency ratio obtained from pulse wave analysis increased in only the AM group. Sympathetic activation elicited by isometric exercise was suppressed more effectively by CL than by AM.

Hypertension, miosis, mydriasis, pulse wave, pupillary function, sympathetic nerve activity

Introduction The sympathetic nervous system is an important regulator of cardiovascular homeostasis. Its basal activity is determined by genetic and other factors, such as physical activity and salt intake. Sympathetic nerve activity (SNA) is stimulated by mental stress, cold, pain (1) and physical stress (2,3), and in line with this, essential hypertension and accelerated hypertension have been shown to accompany sympathetic activation (4,5). Calcium channel blockers (CCBs), in particular, long-acting dihydropyridine CCBs, are the most prevalent agents for treating hypertension in Japan (6,7). However, administration of CCBs can cause reflex tachycardia via activation of the sympathetic nervous system. Although longacting dihydropyridine CCBs such as amlodipine (AM) and cilnidipine (CL) can reduce the sympathetic activation compared with short-acting dihydropyridine CCBs (8–12), it remains controversial as to whether AM acts to reduce sympathetic activation. Reports have shown that AM does not result in sympathetic activation in patients with essential hypertension (8,12,13). However, others suggest that AM increases heart rate (HR) and SNA in patients with hypertension (7,14,15). Although CL, as well as AM (16), exhibits inhibitory effects on both L-type calcium channels directly associated with vascular contraction and N-type calcium channels related to sympathetic nerve activation (17–20), Correspondence: Takuzo Hano, Medical Education and PopulationBased Medicine, Graduate School of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama City, Wakayama 641-8509, Japan. Tel: +81 73 441 0813. Fax: +81 73 441 0814. E-mail: [email protected]

History Received 16 October 2014 Revised 18 November 2014 Accepted 6 December 2014 Published online 6 May 2015

experimental and clinical studies have consistently shown that CL does not elicit an increase in HR or sympathetic activation (10,18,21–26). That is, these studies suggest that CL perhaps blocks N-type calcium channels more effectively compared with other CCBs. Pupillometry is a valid, safe, straightforward and costeffective method to evaluate autonomic nerve activity (27–29). The pupil is a suitable end organ for studying autonomic function because the parasympathetic and sympathetic nervous systems innervate constrictor pupillae and dilator pupillae muscles of the iris, respectively. Therefore, the pupillary function test, which uses light stimulus, allows independent evaluation of both types of autonomic nerve activity (27,30,31). Pupillometry is thus a useful tool in analysis of sub-clinical defects in autonomic function associated with various diseases (32). To date, the pupillary reflex has been assessed in patients with heart failure (33), diabetes (34), Alzheimer’s disease (28), Parkinson’s disease (35) and myasthenia gravis (36). However, no report has documented use of pupillometry for assessing autonomic activity in patients with essential hypertension. As mentioned earlier, several reports have documented the suppressive effect of CL on reflex tachycardia and/or sympathetic activation in studies comparing with other CCBs (10,18,24) or results before and after its administration (21–23,25,26). However, the effect of CL on autonomic responses to isometric stress in hypertensive patients has yet to be determined. Using pupillometry, this study examines the hypothesis that CL reduces sympathetic activation elicited by isometric handgrip (IHG) exercise more effectively than AM in patients with hypertension.

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Methods

Statistical analysis

Participants

Group differences in age, height, weight, body mass index (BMI) and MVC of handgrip were examined by Student’s unpaired t-test. Male to female ratio and number of patients administered angiotensin II receptor antagonists or diuretics were compared between the groups by chi-squared test. Student’s paired t-test was used for comparisons of BP, PR, VC, VD and LF/HF ratio between before and after IHG within groups. The amplitude of changes in VC and VD between the two groups was assessed by two-way analysis of variance (ANOVA). Data are expressed as means ± SEM, with p50.05 taken to indicate a significant difference.

A total of 37 consecutive outpatients with mild essential hypertension who had been administered AM (n ¼ 18) or CL (n ¼ 19) for at least 6 months at Wakayama Medical University Hospital were enrolled in the study. Those with secondary hypertension, diabetes, cataract or other medical problems requiring specific treatments were excluded. All the participants provided written, informed consent prior to participation. The study conformed to the principles of the Declaration of Helsinki and was approved by the Ethics Committee of Wakayama Medical University.

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Experimental protocol

Results

All the participants completed a medical history and physical activity questionnaire, and were familiarized with the testing procedures. Height and weight were measured. All the tests were performed under similar environmental conditions between 09:00 and 12:00. After resting for 15 min, each patient underwent pupil function tests, blood pressure (BP) and pulse rate (PR) measurements, and acceleration pulse wave measurements within 2 min. IHG was then performed for 1 min. These parameters were again measured within 2 min after completion of IHG.

Baseline characteristics Table 1 shows the baseline characteristics of the patients. No significant differences were found in male to female ratio, age, BMI or handgrip MVC between the AM and CL groups. In some cases, the CCBs were administered in combination with angiotensin II receptor antagonists and/or diuretics, and the number of patients administered these drugs in combination with CCBs did not differ between the groups.

Isometric handgrip exercise Maximal voluntary contraction (MVC) of the right hand was determined in seated patients using a JAMAR hydraulic hand dynamometer (Patterson Medical Holdings Inc., Bolingbrook, IL). Isometric contraction was maintained for 1 min at 70% of the MVC load and measured using a hand dynamometer. Patients were instructed to breathe naturally during isometric contraction to avoid a Valsalva maneuver and their respiratory profiles were observed throughout the tests. Measured parameters Circulation and autonomic nervous function were evaluated before and after IHG as follows. BP and PR were monitored using a COLIN 203i autonomic sphygmomanometer on the left radial artery (OMRON, Tokyo, Japan). Parameters of the pupillary light reflex were examined using pupillometry in low light conditions before and after IHG. Patients rested for 15 min to allow their eyes to adjust to the low light levels, and experimental conditions were explained to each patient in detail prior to pupillometry of both eyes. The diameter of the pupil was measured using an Iriscorder Dual C10641 pupillometer (Hamamatsu Photonics, Hamamatsu, Japan). The velocity of pupil constriction (VC) and dilation (VD) was determined from the total of pupillary function. Figure 1 shows the index of pupillary tests calculated from successive changes in pupil diameter per second in response to light stimulus. Maximum values of VD and VC were used as indices of sympathetic function and parasympathetic function, respectively. The low-to-high frequency (LF/HF) ratio was calculated from total pulse wave acceleration monitored via the left middle finger using an acceleration pulse wave measurement system (Artett C, U-Medica Inc., Osaka, Japan). The LF/HF ratio was then used as an index of SNA.

Figure 1. Analysis of pupillary light reflex parameters using pupillometry. AC, maximal acceleration of pupil constriction; D1, initial pupil diameter; D2, minimal pupil diameter; VC, maximal velocity of pupil constriction (velocity of miosis); VD, maximal velocity of pupil re-dilation (velocity of mydriasis).

Table 1. Baseline characteristics of patients.

Male/female (n) Age (years) Height (cm) Weight (kg) BMI (kg/m2) Grasping power (kg) Combined drugs ARB (n) Diuretic (n)

Amlodipine n ¼ 18

Cilnidipine n ¼ 19

6/12 67.9 ± 3.0 157.1 ± 1.8 59.8 ± 2.6 24.1 ± 0.8 24.7 ± 1.5

5/14 68.7 ± 2.6 156.6 ± 2.1 54.4 ± 2.3 22.3 ± 2.8 23.0 ± 0.6

11 1

8 2

Values are expressed as means ± SEM. ARB, angiotensin II receptor blockade; BMI, body mass index.

Effects of cilnidipine on autonomic activation

DOI: 10.3109/10641963.2015.1025959

BP and PR Systolic and mean BP and PR significantly (p50.01) increased after IHG in both the groups. IHG significantly (p50.001) increased diastolic BP in the AM group but not the CL group (Table 2).

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Pupillary function Initial pupil diameter (D1) remained unaltered after IHG in both the AM and CL groups. D1 before and after IHG was 4.58 ± 0.22 and 4.58 ± 0.20 mm, respectively, in the AM group and 4.77 ± 0.19 and 4.74 ± 0.18 mm, respectively, in the CL group. Minimal pupil diameter (D2) also remained unchanged after IHG in both the groups. D2 before and after IHG was 3.39 ± 0.16 and 3.29 ± 0.18 mm, respectively, in the AM group and 3.50 ± 0.71 and 3.48 ± 0.17 mm, respectively, in the CL group. VC was significantly increased after IHG in both the groups. VC before and after IHG was 3.66 ± 0.27 and 4.74 ± 0.46 mm/s, respectively, in the AM group (p50.05) and 3.54 ± 0.23 and 3.84 ± 0.27 mm/s, respectively, in the CL group (p50.05) (Figure 2A). The velocity slope (change in velocity after IHG relative to before IHG) of miosis was significantly (p50.05) higher in the AM group than in the CL group. VD was significantly increased after IHG in the AM group but not in the CL group. VD before and after IHG was 1.84 ± 0.17 and 2.74 ± 0.25 mm/s, respectively, in the AM group (p50.01) and 1.74 ± 0.10 and 1.73 ± 0.11 mm/s, respectively, in the CL group (p40.05) (Figure 2B). The velocity slope of mydriasis was significantly (p50.05) smaller in the CL compared to the AM group.

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elicited by isometric exercise in patients with essential hypertension. Emotional and physical stress can elevate BP through sympathetic activation in healthy individuals and in patients with hypertension (1–3). It has been reported that sympathetic and pressor responses elicited by IHG are augmented in hypertensive humans compared to normotensive subjects (37). Accelerated sympathetic function is also known to be an important cause of hypertension (4,5). In particular, increased

LF/HF ratio The LF/HF ratio, as an index of SNA, was significantly increased after IHG in only the AM group. The LF/HF ratio before and after IHG was 1.93 ± 0.48 and 4.66 ± 1.10 mm/s, respectively, in the AM group (p50.05) and 3.03 ± 0.94 and 2.82 ± 0.50 mm/s, respectively, in the CL group (p40.05) (Figure 3).

Discussion The most significant findings of this study were that CL but not AM inhibited increases in SNA, as assessed by pupillometry and pulse wave analysis, and diastolic BP

Figure 2. Comparison of changes in velocities of miosis (A) and mydriasis (B) induced by isometric handgrip exercise in the cilnidipine group (filled circles) and the amlodipine groups (unfilled circles). Values are expressed as means ± SEM. Significant differences from baseline (resting) values: *p50.05, yp50.01. Significant difference between groups: zp50.05 (two-way ANOVA). IHG, isometric handgrip exercise; SEM, standard error of the mean.

Table 2. Changes in blood pressure and pulse rate by isometric handgrip exercise in cilnidipine and amlodipine groups. Amlodipine

SBP (mmHg) MBP (mmHg) DBP (mmHg) PR (per min)

Cilnidipine

Before IHG

After IHG

Before IHG

After IHG

134.66 ± 2.59 99.66 ± 1.85 75.88 ± 2.04 67.05 ± 1.90

145.83 ± 3.06y 110.83 ± 3.21y 84.22 ± 2.65z 71.88 ± 2.25z

128.12 ± 3.12 95.62 ± 2.32 78.00 ± 3.04 67.88 ± 1.88

147.8 ± 3.18z 111 ± 2.92z 83.43 ± 2.48 74.44 ± 2.73*

Values are expressed as means ± SEM. DBP, diastolic blood pressure; IHG, isometric handgrip exercise; MBP, mean blood pressure; PR, pulse rate; SBP, systolic blood pressure. Significantly different from baseline (resting) values: *p50.05; yp50.01, zp50.001 (before IHG versus after IHG).

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Figure 3. Comparison of changes in the LF/HF ratio induced by isometric handgrip exercise in the cilnidipine (filled circles) and amlodipine groups (unfilled circles). Values are expressed as means ± SEM. Significant difference from baseline (resting) values: *p50.05. Significant differences between groups: yp50.05. IHG, isometric handgrip exercise; LF/HF, low-to-high frequency; SEM, standard error of the mean.

renal SNA (RSNA) is known to be involved in development of hypertension (38). Although it is not clear whether pupillary sympathetic activity is accelerated in patients with hypertension compared with normotensive subjects, pupil diameter was previously shown to increase during IHG as a result of sympathetic activation (39). Since RSNA is also enhanced by isometric exercise (40), pupillary and renal sympathetic activities may change in a parallel manner at least during this form of exercise. As mentioned earlier, although pupil diameter was shown to increase during IHG due to sympathetic activation mediated via metaboreflex of skeletal muscles, the increase was not observed during the recovery period following exercise (39). The present study also found no significant difference in pupil diameter between before and after IHG in either the AM or CL group. However, VC as an index of parasympathetic nerve activity increased in both the groups and VD as an index of SNA increased in the AM group even after the exercise. VC and VD may be more sensitive than pupil diameters in measurement of pupillary autonomic activity. The increases in VC elicited by IHG in the AM group can be explained as a counteraction against sympathetic activation. The increases in VC in the CL group may have been the direct effect of parasympathetic nervous system activation since CL was previously shown to ameliorate parasympathetic nerve activity both in an animal model (19) and in hypertensive patients (25). Changes in VC and VD elicited by IHG were reduced in the CL compared to AM group. In particular, CL completely inhibited the changes in VD with IHG, suggesting that CL exhibits a potent inhibitory effect even on sympathetic activation induced by the exercise. The difference in changes in the LF/HF ratio between groups supports these findings. The cause of systolic BP and HR elevation in both the groups remains unclear, but may be explained by adrenal gland activation as a result of IHG. SNA is generally evaluated using plasma catecholamines and HR variability. However, pain elicited during blood

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sampling can alter levels of plasma norepinephrine and epinephrine. Moreover, measurement of continuous SNA using plasma catecholamines is difficult because not only is continuous blood sampling challenging but a time lag exists between the imposition of stress and elevation of blood catecholamine. HR variability is affected both by secretion of catecholamines from the adrenal glands and by autonomic activity. Therefore, in this study, we used pupillometry to evaluate autonomic activity. Fotiou et al. (27,28) showed that pupillometry using light stimuli is a non-invasive and reproducible method for independent assessment of sympathetic and parasympathetic function. Furthermore, it has also been suggested that the contribution of the adrenal gland can be essentially excluded from pupillary function (27,28). N-type calcium channels have been shown to be located at sympathetic nerve terminals where they regulate norepinephrine release (41). The N-type channels influence 85% of all the Ca2+ currents in sympathetic neurons (17). It has also been reported that CL inhibits SNA at the level of vascular sympathetic innervation (42) and dorsal root ganglion neurons (43). Unlike AM, CL does not cross the blood– brain barrier (44,45), and therefore, the effects of CL on pupillary autonomic function observed in this study were not likely to have been mediated via the central nervous system. One possibility is that CL blocks N-type channels located at sympathetic nerve endings distributed on the dilator pupillae. AM inhibits both N-type and L-type calcium channels as well as CL (16). However, unlike CL, AM did not inhibit the increase in pupillary SNA elicited by IHG, possibly because AM has a lesser blocking effect on N-type channels compared to CL. This possibility is supported by another literature (18).

Limitations A limitation of this study is that only patients treated with anti-hypertensive drugs were enrolled. Our Ethics Committee did not permit inclusion of individuals with untreated hypertension because pressor responses elicited by IHG can be greater in hypertensive patients compared to normotensive subjects (37), and such augmented pressor responses may be a risk for onset of cardiovascular events.

Conclusions Cilnidipine distinctly inhibited autonomic activation induced by IHG among patients with essential hypertension compared with AM. This inhibitory effect was more apparent with sympathetic than parasympathetic activation. To our knowledge, this is the first study to use dynamic pupillary function measurements as a tool for assessing autonomic activities in patients with essential hypertension.

Declaration of interest The authors report no conflicts of interest, and they alone were responsible for the content and writing of the article. This study was supported by a Grant-in-Aid for Scientific Research (C) (#26460915) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan.

DOI: 10.3109/10641963.2015.1025959

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Cilnidipine but not amlodipine suppresses sympathetic activation elicited by isometric exercise in hypertensive patients.

Pupillometry was used to evaluate the effects of the calcium channel blockers cilnidipine (CL) and amlodipine (AM) on changes in autonomic nervous act...
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