International Journal of Hypertension

International Journal of Hypertension / 2020 / Article

Research Article | Open Access

Volume 2020 |Article ID 6653851 | https://doi.org/10.1155/2020/6653851

Yutaka Kawabata, Takeshi Soeki, Hiroyuki Ito, Tomomi Matsuura, Kenya Kusunose, Takayuki Ise, Koji Yamaguchi, Takeshi Tobiume, Shusuke Yagi, Daiju Fukuda, Hirotsugu Yamada, Tetsuzo Wakatsuki, Mitsuhiro Kitani, Kazuhiro Kawano, Yoshio Taketani, Masataka Sata, "Effects of L-/N-Type Calcium Channel Blockers on Angiotensin II–Renin Feedback in Hypertensive Patients", International Journal of Hypertension, vol. 2020, Article ID 6653851, 7 pages, 2020. https://doi.org/10.1155/2020/6653851

Effects of L-/N-Type Calcium Channel Blockers on Angiotensin II–Renin Feedback in Hypertensive Patients

Academic Editor: Fulvio Morello
Received04 Nov 2020
Accepted10 Dec 2020
Published22 Dec 2020

Abstract

Objectives. Cilnidipine, an L-/N-type calcium channel blocker (CCB), has unique organ-protective properties due to suppression of hyperactivity in the sympathetic nervous system and renin-angiotensin system (RAS). In this study, we hypothesized that cilnidipine might exert a renoprotective effect by suppressing the RAS. Methods. A total of 25 hypertensive patients receiving a RAS inhibitor were randomly assigned to a cilnidipine (n = 12) or amlodipine (n = 13) group. The effects of cilnidipine on proteinuria and angiotensin II–renin feedback were assessed. Results. After 6 months of treatment, both systolic and diastolic blood pressures were significantly reduced to a similar extent in both groups. The urine albumin-to-creatinine ratio was significantly lower in the cilnidipine group () than in the amlodipine group. Amlodipine increased plasma angiotensin I and angiotensin II levels (), whereas cilnidipine did not. Interestingly, the cilnidipine group had a higher ratio of angiotensin-(1–7) (Ang-(1–7)) to angiotensin II in plasma than the amlodipine group (). Conclusions. The L-/N-type CCB cilnidipine, but not amlodipine, decreased urinary albumin excretion in hypertensive patients. Cilnidipine also increased the ratio of Ang-(1–7) to angiotensin II in plasma, which might be one factor underlying its beneficial effects.

1. Introduction

Patients with chronic kidney disease have been shown to have a higher risk of developing cardiovascular diseases and end-stage renal failure as their blood pressure increases [1]. Therefore, it is crucial to adequately control their blood pressure, initially either with angiotensin-converting enzyme inhibitors or angiotensin II (Ang II) type 1 receptor blockers (ARBs). However, in clinical practice, these drugs are often used in combination with a calcium channel blocker (CCB) to achieve a sufficient antihypertensive effect. There are several types of CCBs that differ according to their duration of action and the calcium channel subtype that they inhibit. The major CCBs exert a strong antihypertensive effect through vasodilation mediated by L-type Ca inhibition, but they can cause reflex stimulation of the sympathetic nervous system and renin-angiotensin system (RAS) by their abrupt hypotensive action. Cilnidipine, a dihydropyridine CCB, is an antihypertensive drug with both L-type and N-type calcium channel antagonist activities [2, 3]. Since cilnidipine suppresses hyperactivity of the sympathetic nervous system, it exerts a slow and sustained antihypertensive effect without causing reflex tachycardia during hypotension.

Previous studies showed that cilnidipine demonstrates unique organ-protective properties as a result of its effects on the sympathetic nervous system [46]. In addition, we reported that cilnidipine exerts a greater renoprotective effect than amlodipine due to its antioxidative properties [7]. Furthermore, previous studies demonstrated that cilnidipine is unique in that it suppresses the RAS. Some previous studies reported that cilnidipine has no effect on plasma renin activity or plasma Ang II levels, while amlodipine, an L-type CCB, significantly increases both parameters [8, 9]. Another study showed that cilnidipine but not amlodipine, suppressed the ARB-induced increase in plasma renin activity and plasma Ang II levels [10].

Angiotensin-(1–7) (Ang-(1–7)), a heptapeptide member of the RAS, has attracted attention in recent studies as an antagonist of Ang II. Ang-(1–7) binds to Mas receptors, seven transmembrane proteins also known as the G-protein-coupled receptors via different signaling pathways. Ang-(1–7) exerts antiproliferative, antigrowth, and cardiorenal protective effects in vascular smooth muscle cells, cardiac myocytes, and fibroblasts. These actions contrast with the Ang II-mediated proliferative effects on smooth muscle cells and fibroblasts [1113]. Ang-(1–7) is formed by two pathways. In one pathway, Ang I is converted to Ang II by angiotensin-converting enzyme (ACE), and then Ang II is converted to Ang-(1–7) by Ang II-converting enzyme (ACE2). In the other pathway, Ang I is converted to angiotensin-(1–9) (Ang-(1–9)) by ACE2, and then Ang-(1–9) is converted to Ang-(1–7) by ACE [14]. However, the precise mechanism of the renoprotective effect of cilnidipine via Ang-(1–7) remains unknown in hypertensive patients. Therefore, in this study, we hypothesized that cilnidipine might exert a renoprotective effect by the activation of the ACE2-Ang-(1–7) pathway and suppression of the ACE-Ang II–angiotensin II type 1 receptor (AT1R) pathway.

2. Methods

2.1. Study Design

In this 6-month, multicenter, prospective, randomized, open-label clinical trial named the Tokushima Antioxidation Clinical Trial in Hypertensives, Cilnidipine vs. Amlodipine (TACTICAL2) study (UMIN ID: 00006544), 25 hypertensive patients receiving ARB treatment at four hospitals in Japan between August 2013 and June 2016 were enrolled. The study was approved by the Institutional Review Board of The University of Tokushima Clinical Research Center and the review boards of the four hospitals. The study protocol was in accordance with the Declaration of Helsinki. Written informed consent was obtained from all patients included in the study. The enrollment criteria were as follows: (1) hypertension defined as a blood pressure (BP) of ≥140/90 mmHg and (2) treatment with ARBs for 3 months or more before the administration of cilnidipine or amlodipine. The exclusion criteria were as follows: (1) age <45 years or >85 years, (2) hypertensive emergency, (3) severe liver failure, (4) pregnancy, and (5) a history of severe adverse effects due to CCBs or ARBs.

The overview of the study design is shown in Figure 1. Subjects were randomly assigned to two groups at the time of registration. To achieve the target BP level of 130/85 mmHg, patients received either 10 mg per day of cilnidipine, which was titrated upward to a daily dose of 20 mg, or 5 mg per day of amlodipine, which was titrated upward to a daily dose of 10 mg. The doses of ARBs were not altered during the study period. BP was measured according to the Japanese Society of Hypertension Guidelines for the Measurement of Hypertension.

During the first 3 months of the study, patients received their initial (baseline) assigned drug combination. However, if cilnidipine or amlodipine in combination with the ARB failed to reduce BP to the target level within 3 months, additional antihypertensive medications, such as diuretics, were administered until the target was reached.

2.2. Measurement of the Urinary Parameters

Morning spot urine samples were obtained. The urinary levels of albumin and creatinine were measured using a turbidimetric immunoassay and enzyme assay, respectively (LSI Medience Corporation, Tokyo, Japan).

2.3. Measurement of RAS

The levels of Ang I, Ang II, and Ang-(1–7) concentrations in human plasma were measured by liquid chromatography (LC)/mass spectrometry (MS)/MS (SRL, Tokyo, Japan).

2.4. Statistical Analysis

The data in this study are expressed as the mean ± SD. Differences between the two groups were analyzed by Student’s unpaired t-test for continuous variables and the chi-square test for categorical variables. Changes before and after treatment administration were assessed by Wilcoxon’s signed-rank test.

3. Results

3.1. Baseline Characteristics

The baseline characteristics of the subjects are shown in Table 1. There were no significant differences between the two groups in terms of age, sex, systolic and diastolic BP, heart rate, HbA1c, or total cholesterol level. There was no additional use of diuretics in either group during the study period.


Cilnidipine group (n = 12)Amlodipine group (n = 13) value

Age (years)68.5 ± 8.862.9 ± 11.1NS
Sex (male/female)6/65/8NS
Systolic BP (mmHg)162.1 ± 19.4149.9 ± 18.7NS
Diastolic BP (mmHg)86.2 ± 9.888.6 ± 12.8NS
Heart rate (bpm)76.6 ± 11.684.8 ± 12.7NS
HbA1c (%)6.0 ± 0.46.2 ± 0.8NS
Total cholesterol (mg/dL)194.0 ± 43.8194.9 ± 31.6NS

Values are the mean ± standard deviation.
3.2. Safety

No adverse effects related to the antihypertensive treatments occurred during the study period.

3.3. Changes in BP and Heart Rate

The systolic and diastolic BP values were significantly lower in both the cilnidipine and amlodipine groups at 6 months after the initiation of therapy than at baseline (). However, there were no significant differences in BP values between the two groups at either time point (shown in Figure 2). Moreover, the heart rate showed no changes over time in either group (shown in Figure 3).

3.4. Changes in Urinary Albumin

While the urine albumin-to-creatinine ratio did not change over time in the amlodipine group, it decreased significantly after 6 months of treatment in the cilnidipine group (; shown in Figure 4).

3.5. Changes in Plasma Ang I and Ang II Levels

After 6 months of treatment, the plasma Ang I and Ang II levels were significantly increased in the amlodipine group () but not in the cilnidipine group (shown in Figure 5).

3.6. Plasma Aldosterone Levels and Plasma Renin Activity (PRA)

Although neither plasma aldosterone levels nor PRA differed significantly between the two groups, there was a nonsignificant increase in both measurements from pre- to post-treatment in the amlodipine group (shown in Figure 6).

3.7. Ratio of Ang-(1–7) to Ang II in Plasma

Compared to the amlodipine group, the cilnidipine group had a significantly higher ratio of Ang-(1–7) to Ang II in plasma at the end of treatment (; shown in Figure 7).

4. Discussion

In this study, we evaluated whether cilnidipine might exert a renoprotective effect by suppressing the RAS. The results suggested that cilnidipine, unlike amlodipine, had a greater suppressive effect on the RAS when used in combination with a RAS inhibitor to treat hypertensive patients. In addition, the finding that cilnidipine had greater antiproteinuric effects than amlodipine was consistent with our previous study.

In this study, amlodipine increased both plasma Ang I and Ang II levels (), whereas cilnidipine did not. Furthermore, cilnidipine raised the ratio of Ang-(1–7) to Ang II in plasma more than amlodipine did. These results suggest that cilnidipine might shift the balance of the 2 arms of the RAS from the ACE-Ang II-AT1R receptor to the ACE2-Ang-(1–7)-Mas receptor. According to previous studies, the predominant effects of the RAS might be related to the balance between these 2 arms [1315]. This effect of cilnidipine may be partly caused by N-type calcium channel blockade via the close conjunction between the ACE2-Ang-(1–7) pathway and sympathetic nerve activity [16]. It is still unknown if Ang-(1–7) is predominantly formed from Ang II via ACE2 or from Ang-(1–9) via ACE. However, despite the similar hypotensive effects of cilnidipine and amlodipine when combined with RAS inhibitor therapy, the greater increase in the ratio of Ang-(1–7) to Ang II by cilnidipine might contribute to its superior renal and cardiovascular protective effects. This hypothesis is supported by previous reports showing that Ang-(1–7) administration to streptozotocin (STZ)-induced diabetic rats reduced proteinuria and restored vascular reactivity in isolated renal artery segments [17] and that treatment with Ang-(1–7) attenuated NAPDH oxidase activation and reduced proteinuria in spontaneously hypertensive, STZ-induced diabetic rats [18].

We previously showed that in hypertensive patients, cilnidipine decreased urinary levels of both 8-hydroxy-20-deoxyguanosine (OHdG), a biomarker of oxidative stress, and liver-type fatty-acid–binding protein (L-FABP), a useful biomarker for renal tubulointerstitial injury [7]. Cilnidipine may suppress oxidative stress by modulating the renal RAS system. In practice, the increased ratio of Ang-(1–7) to Ang II might have attenuated the significant oxidative stress that contributed to renal injury in this study, because previous reports have shown that Ang-(1–7) has an antioxidative effect in vascular tissues whereas Ang II has an oxidative effect [19, 20]. In agreement with these data, other studies have shown that Ang-(1–7) mediates the effects of ACE2 in suppressing Ang II–induced oxidative stress and ERK1/2 signaling in cultured cardiomyocytes and fibroblasts [21] and that ACE2 attenuates cardiac, kidney, and vascular oxidative stress in SHR [22].

We previously reported that cilnidipine, but not amlodipine, reduced urinary albumin excretion in hypertensive patients receiving RAS inhibitor treatment [7]. In addition, the Cilnidipine vs. Amlodipine Randomized Trial for Evaluation in Renal Disease (CARTER) study showed that cilnidipine was more beneficial than amlodipine in hypertensive patients [23]. Supporting these previous reports, this study showed that only cilnidipine reduced urinary albumin excretion in hypertensive patients receiving ARB treatment. A recent study reported that L/N-type CCBs exert the antialbuminuric and renoprotective effects at least in part by reducing glomerular hypertension through both efferent and afferent arteriolar vasodilation [24]. Furthermore, another study reported that in patients with diabetes, the combination of cilnidipine with a RAS inhibitor had an additive effect in suppressing urinary albumin excretion [25].

Although the present study revealed the association between the renoprotective effects of cilnidipine and the systemic RAS, it remains unknown whether cilnidipine also have an effect on the renal ACE2-Ang-(1–7)-Mas receptors which might contribute to the renoprotection. Fan et al. reported the presence of N-type Ca channels in cultured rat glomerular epithelial cells [26]. In addition, they showed that treatment with cilnidipine, but not amlodipine, significantly suppressed the renal Ang II levels and podocyte injury in spontaneously hypertensive rat/ND mcr-cp, suggesting that the renoprotective mechanism of cilnidipine may involve the suppression of RAS. Furthermore, Toba et al. showed that cilnidipine inhibited the renal renin-angiotensin-aldosterone system, including measurements of renal ACE activity and aldosterone content in the DOCA-salt hypertensive rats [27]. Further studies are needed to clarify the association between the renoprotective effects of cilnidipine and the local RAS including the renal ACE2-Ang-(1–7)-Mas receptors in the kidney.

4.1. Limitations

Our study had several limitations. First, serial measurements of urinary and RAS parameters could only be performed in a limited number of patients at 2 time points. Second, measurements related to the RAS might have fluctuated over the time and position of the patient during the blood sampling. Third, the failure to consider the severity of chronic kidney disease may have influenced the results of the study. Fourth, we did not clarify the precise mechanism whereby cilnidipine suppresses the RAS and oxidative stress. Finally, since the sample size was small in this study, we need to increase the number of samples in future evaluations.

5. Conclusion

In conclusion, cilnidipine and ARB combination therapy reduced urinary albumin excretion and increased the ratio of Ang-(1–7) to Ang II in plasma in hypertensive patients. Better renoprotective effects may be achieved by combining a RAS inhibitor with an L-/N-type CCB rather than an L-type CCB.

Data Availability

The data used to support the findings of this study are available from the corresponding author upon request.

Ethical Approval

The study was approved by the Institutional Review Board of The University of Tokushima Clinical Research Center and the review boards of the four hospitals. The study protocol was in accordance with the Declaration of Helsinki.

Written informed consent was obtained from all patients included in the study.

Conflicts of Interest

The authors have no conflicts of interest declare.

Acknowledgments

The authors thank Etsuko Uematsu for her assistance and contributions to the study. This work was partially supported by JSPS KAKENHI Grants (no. 18K15891 to Y.K., no. 17K09506 to K.K., no. 18K08077 to T.S., no. 18K08040 to S.Y., no. 19K08584 to D.F., and no. 19H03654 to M.S.), a grant from the Japanese Society of Echocardiography (to H.Y.), the Takeda Science Foundation (to K.K. and M.S.), and the Vehicle Racing Commemorative Foundation (to M.S.). This study was funded by EA Pharma Co., Ltd.

References

  1. K. Kundhal and C. E. Lok, “Clinical epidemiology of cardiovascular disease in chronic kidney disease,” Nephron Clinical Practice, vol. 101, no. 2, pp. c47–c52, 2005. View at: Publisher Site | Google Scholar
  2. H. Uneyama, A. Takahara, H. Dohmoto, R. Yoshimoto, K. Inoue, and N. Akaike, “Blockade of N-type Ca2+ current by cilnidipine (FRC-8653) in acutely dissociated rat sympathetic neurones,” British Journal of Pharmacology, vol. 122, no. 1, pp. 37–42, 1997. View at: Publisher Site | Google Scholar
  3. J. Minami, T. Ishimitsu, T. Higashi, A. Numabe, and H. Matsuoka, “Comparison between cilnidipine and nisoldipine with respect to effects on blood pressure and heart rate in hypertensive patients,” Hypertension Research, vol. 21, no. 3, pp. 215–219, 1998. View at: Publisher Site | Google Scholar
  4. A. Takahara, H. Koganei, T. Takeda, and S. Iwata, “Antisympathetic and hemodynamic property of a dual L/N-type Ca2+ channel blocker cilnidipine in rats,” European Journal of Pharmacology, vol. 434, no. 1-2, pp. 43–47, 2002. View at: Publisher Site | Google Scholar
  5. T. Shiga, Y. Yamada, N. Matsuda et al., “Influence of cilnidipine or nisoldipine on sympathetic activity in healthy male subjects,” Heart and Vessels, vol. 22, no. 6, pp. 404–409, 2007. View at: Publisher Site | Google Scholar
  6. S. Nagahama, T. Norimatsu, T. Maki, M. Yasuda, and S. Tanaka, “The effect of combination therapy with an L/N-Type Ca(2+) channel blocker, cilnidipine, and an angiotensin II receptor blocker on the blood pressure and heart rate in Japanese hypertensive patients: an observational study conducted in Japan,” Hypertension Research, vol. 30, no. 9, pp. 815–822, 2007. View at: Publisher Site | Google Scholar
  7. T. Soeki, M. Kitani, K. Kusunose et al., “Renoprotective and antioxidant effects of cilnidipine in hypertensive patients,” Hypertension Research, vol. 35, no. 11, pp. 1058–1062, 2012. View at: Publisher Site | Google Scholar
  8. T. Konda, A. Enomoto, S. Aritomi et al., “Different effects of L/N-type and L-type calcium channel blockers on the renin-angiotensin-aldosterone system in SHR/Izm,” American Journal of Nephrology, vol. 30, no. 2, pp. 155–161, 2009. View at: Publisher Site | Google Scholar
  9. A. Takahara, Y. Nakamura, H. Wagatsuma et al., “Long-term blockade of L/N-type Ca2+ channels by cilnidipine ameliorates repolarization abnormality of the canine hypertrophied heart,” British Journal of Pharmacology, vol. 158, no. 5, pp. 1366–1374, 2009. View at: Publisher Site | Google Scholar
  10. S. Aritomi, K. Niinuma, T. Ogawa, T. Konda, and K. Nitta, “Effects of an N-type calcium antagonist on angiotensin II-renin feedback,” American Journal of Nephrology, vol. 33, no. 2, pp. 168–175, 2011. View at: Publisher Site | Google Scholar
  11. C. M. Ferrario and J. Varagic, “The ANG-(1–7)/ACE2/mas axis in the regulation of nephron function,” American Journal of Physiology-Renal Physiology, vol. 298, no. 6, pp. F1297–F1305, 2010. View at: Publisher Site | Google Scholar
  12. J. Varagic, A. J. Trask, J. A. Jessup, M. C. Chappell, and C. M. Ferrario, “New angiotensins,” Journal of Molecular Medicine, vol. 86, no. 6, pp. 663–671, 2008. View at: Publisher Site | Google Scholar
  13. P. Xu, A. C. Costa-Goncalves, M. Todiras et al., “Endothelial dysfunction and elevated blood pressure in MAS gene-deleted mice,” Hypertension, vol. 51, no. 2, pp. 574–580, 2008. View at: Publisher Site | Google Scholar
  14. M. Donoghue, F. Hsieh, E. Baronas et al., “A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9,” Circulation Research, vol. 87, no. 5, pp. E1–E9, 2000. View at: Publisher Site | Google Scholar
  15. A. Simões e Silva, S. V. B. Pinheiro, R. M. Pereira, A. J. Ferreira, and R. A. S. Santos, “The therapeutic potential of angiotensin-(1–7) as a novel renin- angiotensin system mediator,” Mini-Reviews in Medicinal Chemistry, vol. 6, no. 5, pp. 603–609, 2006. View at: Publisher Site | Google Scholar
  16. T. Matsui, K. Tamaya, K. Matsumoto, Y. Osajima, K. Uezono, and T. Kawasaki, “Plasma concentrations of angiotensin metabolites in young male normotensive and mild hypertensive subjects,” Hypertension Research, vol. 22, no. 4, pp. 273–277, 1999. View at: Publisher Site | Google Scholar
  17. I. F. Benter, M. H. M. Yousif, C. Cojocel, M. Al-Maghrebi, and D. I. Diz, “Angiotensin-(1–7) prevents diabetes-induced cardiovascular dysfunction,” American Journal of Physiology-Heart and Circulatory Physiology, vol. 292, no. 1, pp. H666–H672, 2007. View at: Publisher Site | Google Scholar
  18. I. F. Benter, M. H. M. Yousif, G. S. Dhaunsi, J. Kaur, M. C. Chappell, and D. I. Diz, “Angiotensin-(1–7) prevents activation of NADPH oxidase and renal vascular dysfunction in diabetic hypertensive rats,” American Journal of Nephrology, vol. 28, no. 1, pp. 25–33, 2008. View at: Publisher Site | Google Scholar
  19. J. Varagic, S. Ahmad, S. Nagata, and C. M. Ferrario, “ACE2: angiotensin II/angiotensin-(1–7) balance in cardiac and renal injury,” Current Hypertension Reports, vol. 16, p. 420, 2014. View at: Publisher Site | Google Scholar
  20. M. E. Pueyo, W. Gonzalez, A. Nicoletti, F. Savoie, J.-F. Arnal, and J.-B. Michel, “Angiotensin II stimulates endothelial vascular cell adhesion molecule-1 via nuclear factor-κb activation induced by intracellular oxidative stress,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 20, no. 3, pp. 645–651, 2000. View at: Publisher Site | Google Scholar
  21. J. Zhong, R. Basu, D. Guo et al., “Angiotensin-converting enzyme 2 suppresses pathological hypertrophy, myocardial fibrosis, and cardiac dysfunction,” Circulation, vol. 122, no. 7, pp. 717–728, 2010. View at: Publisher Site | Google Scholar
  22. J. Lo, V. B. Patel, Z. Wang et al., “Angiotensin-converting enzyme 2 antagonizes angiotensin II-induced pressor response and NADPH oxidase activation in Wistar-Kyoto rats and spontaneously hypertensive rats,” Experimental Physiology, vol. 98, no. 1, pp. 109–122, 2013. View at: Publisher Site | Google Scholar
  23. T. Fujita, K. Ando, H. Nishimura et al., “Antiproteinuric effect of the calcium channel blocker cilnidipine added to renin-angiotensin inhibition in hypertensive patients with chronic renal disease,” Kidney International, vol. 72, no. 12, pp. 1543–1549, 2007. View at: Publisher Site | Google Scholar
  24. K. Kuwahara and T. Kimura, “The organ-protective effect of N-type Ca2+ channel blockade,” Pharmacology & Therapeutics, vol. 151, pp. 1–7, 2015. View at: Publisher Site | Google Scholar
  25. V. K. Singh, A. Mishra, K. K. Gupta, R. Misra, M. L. Patel, and Shilpa, “Reduction of microalbuminuria in type-2 diabetes mellitus with angiotensin-converting enzyme inhibitor alone and with cilnidipine,” Indian Journal of Nephrology, vol. 25, no. 6, pp. 334–339, 2015. View at: Publisher Site | Google Scholar
  26. Y.-Y. Fan, M. Kohno, D. Nakano et al., “Cilnidipine suppresses podocyte injury and proteinuria in metabolic syndrome rats: possible involvement of N-type calcium channel in podocyte,” Journal of Hypertension, vol. 28, no. 5, pp. 1034–1043, 2010. View at: Publisher Site | Google Scholar
  27. H. Toba, M. Yoshida, C. Tojo et al., “L/N-type calcium channel blocker cilnidipine ameliorates proteinuria and inhibits the renal renin-angiotensin-aldosterone system in deoxycorticosterone acetate-salt hypertensive rats,” Hypertension Research, vol. 34, no. 4, pp. 521–529, 2011. View at: Publisher Site | Google Scholar

Copyright © 2020 Yutaka Kawabata et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


More related articles

 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder
Views708
Downloads571
Citations

Related articles

Article of the Year Award: Outstanding research contributions of 2020, as selected by our Chief Editors. Read the winning articles.