Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Advertisement

Hypertension Research
  • View all journals
  • Search
  • Log in
  • Content Explore content
  • About the journal
  • Publish with us
  • Sign up for alerts
  • RSS feed
  1. nature
  2. hypertension research
  3. original article
  4. article
Cilnidipine, an N+L-Type Dihydropyridine Ca Channel Blocker, Suppresses the Occurrence of Ischemia/Reperfusion Arrhythmia in a Rabbit Model of Myocardial Infarction
Download PDF
Download PDF
  • Original Article
  • Published: 01 April 2005

Cilnidipine, an N+L-Type Dihydropyridine Ca Channel Blocker, Suppresses the Occurrence of Ischemia/Reperfusion Arrhythmia in a Rabbit Model of Myocardial Infarction

  • Hiroshi Nagai1,
  • Shinya Minatoguchi1,
  • Xue-Hai Chen1,
  • Ningyuan Wang1,
  • Masazumi Arai1,
  • Yoshihiro Uno1,
  • Chuanjiang Lu1,
  • Yu Misao1,
  • Hirohito Onogi1,
  • Hiroyuki Kobayashi1,
  • Genzou Takemura1,
  • Rumi Maruyama1,
  • Takako Fujiwara2 &
  • …
  • Hisayoshi Fujiwara1 

Hypertension Research volume 28, pages 361–368 (2005)Cite this article

  • 2046 Accesses

  • Metrics details

Abstract

Dihydropyridine Ca channel blockers are widely prescribed for the treatment of hypertension and coronary artery diseases, but it remains unknown whether these agents protect against arrhythmias. We investigated whether cilnidipine, an N+L-type Ca channel blocker, reduces the incidences of ventricular premature beats (VPBs) and, if so, via what mechanisms. Japanese white rabbits underwent 30 min of ischemia and 48 h of reperfusion. Cilnidipine (0.5 or 1.0 μg/kg/min, i.v.) or saline (i.v.) was administered from 30 min before ischemia to 30 min after reperfusion. Electrocardiogram and blood pressure were monitored and the incidences of VPBs were measured. At 48 h after reperfusion, myocardial infarct was measured. Myocardial interstitial noradrenaline levels were determined before, during and after 30 min of ischemia with cilnidipine (0.5 and 1.0 μg/kg/min) or saline. The incidences of VPBs during ischemia and reperfusion were significantly attenuated in the cilnidipine 0.5 group (15.6±3.1 and 6.8±1.9 beats/30 min) and in the cilnidipine 1.0 group (10.4±4.9 and 3.5±1.0 beats/30 min) compared to the control group (27.2±4.5 and 24.2±3.1 beats/30 min), respectively. Myocardial interstitial noradrenaline levels were significantly reduced in the cilnidipine 0.5 and 1.0 groups compared to the control group during ischemia and reperfusion. The antiarrhythmic effect of cilnidipine may be related to the attenuation of cardiac sympathetic nerve activity. This finding may provide new insight into therapeutic strategies for hypertensive patients with ventricular arrhythmias.

Similar content being viewed by others

Association between dihydropyridine calcium channel blockers and ischemic strokes in patients with nonvalvular atrial fibrillation

Article 17 February 2022

Kir2.1 dysfunction at the sarcolemma and the sarcoplasmic reticulum causes arrhythmias in a mouse model of Andersen–Tawil syndrome type 1

Article Open access 17 October 2022

Effects of resveratrol supplementation on cardiac remodeling in hypertensive patients: a randomized controlled clinical trial

Article 28 February 2023

Article PDF

References

  1. Maseri A, Chierchia S : Coronary spasm: demonstration, definition, diagnosis, and consequences. Prog Cardiovasc Dis 1982; 25: 169–192.

    Article  CAS  Google Scholar 

  2. Opie LH : Should calcium antagonist be used after myocardial infarction? Ischemia selectivity versus vascular selectivity. Cardiovasc Drugs Ther 1993; 6: 19–24.

    Article  Google Scholar 

  3. Ueyama H, Takahara A, Dohmoto H, Yoshimoto R, Inoue K, Akaike N : Blockade of N-type Ca2+ current by cilnidipine (FRC-8653) in acutely dissociated rat sympathetic neurons. Br J Pharmacol 1997; 122: 37–42.

    Article  Google Scholar 

  4. Hosono M, Fujii S, Hiruma T, et al: Inhibitory effect of cilnidipine on vascular sympathetic neurotransmission and subsequent vasoconstriction in spontaneously hypertensive rats. Jpn J Pharmacol 1995; 69: 127–134.

    Article  CAS  Google Scholar 

  5. Daitoku K, Seya K, Motomura S : Cilnidipine suppresses DMPP-induced cardiac sympathetic nerve activation in canine blood-perfused papillary muscle. J Cardiovasc Pharmacol 1999; 34 ( Suppl 4): S81–S84.

    Google Scholar 

  6. Minami J, Ishimitsu T, Higashi T, Numabe A, Matsuoka H : Comparison between cilnidipine and nisoldipine with respect to effects on blood pressure and heart rate in hypertension. Hypertens Res 1998; 21: 215–219.

    Article  CAS  Google Scholar 

  7. Yagi S, Goto S, Yamamoto T, Kurihara S, Katayama S : Effect of cilnidipine on insulin sensitivity in patients with essential hypertension. Hypertens Res 2003; 26: 383–387.

    Article  CAS  Google Scholar 

  8. Takami T, Shigemasa M : Efficacy of various antihypertensive agents as evaluated by indices of vascular stiffness in elderly hypertensive patients. Hypertens Res 2003; 26: 609–614.

    Article  CAS  Google Scholar 

  9. Akiyama T, Yamazaki T, Ninomiya I : Differential regional responses of myocardial interstitial noradrenaline levels to coronary occlusion. Cardiovasc Res 1993; 27: 817–822.

    Article  CAS  Google Scholar 

  10. Minatoguchi S, Uno Y, Kariya T, et al: Crosstalk among noradrenaline, adenosine and protein kinase C in the mechanisms of ischemic preconditioning. J Cradiovasc Pharmacol 2003; 41 ( Suppl 1): S39–S47.

    CAS  Google Scholar 

  11. Penny WJ : The deleterious effects of myocardial catecholamines on cellular electrophysiology and arrythmias during ischaemia and reperfusion. Eur Heart J 1984; 5: 960–973.

    Article  CAS  Google Scholar 

  12. Zhan CY, Tang F, Lee AY, Wong TM : Effects of reserpine treatment on arrythmogenesis during ischaemia and reperfusion in the isolated rat heart. Clin Exp Pharmacol Physiol 1989; 16: 591–596.

    Article  CAS  Google Scholar 

  13. van Gilst WH, de Graeff PA, Kingma JH, de Langen CD, Wesseling H : Effects of diltiazem on reperfusion-induced arrythmias in vitro and in vivo. J Mol Cell Cardiol 1986; 18: 1255–1266.

    Article  CAS  Google Scholar 

  14. Horwitz LD, Fennessey PV, Shikes RH, Kong Y : Marked reduction in myocardial infarct size due to prolonged infusion of an antioxidant during reperfusion. Circulation 1994; 89: 1792–1801.

    Article  CAS  Google Scholar 

  15. Reimer KA, Vander Heide RS, Richard VJ : Reperfusion in acute myocardial infarction: effect of timing and modulating factors in experimental models. Am J Cardiol 1993; 72: 13G–21G.

    Article  CAS  Google Scholar 

  16. Norris RM : Beta blockers and infarct size. J Mol Cell Cardiol 1986; 19 ( Suppl 4): 99–103.

    Article  Google Scholar 

  17. Toyooka T, Kamishiro T, Fumino H, Masaki T, Hosoda S : Rabbit hearts for the critical evaluation of drugs to reduce the size of experimentally produced acute myocardial infarction. Jpn Heart J 1984; 25: 623–632.

    Article  CAS  Google Scholar 

  18. Tomiyama H, Kimura Y, Kuwabara Y, et al: Cilnidipine more highly attenuates cold pressor stress-induced platelet activation in hypertension than does amlodipine. Hypertens Res 2001; 24: 679–684.

    Article  CAS  Google Scholar 

  19. Konda T, Takahara A, Maeda K, Dohmoto H, Yoshimoto R : Effects of a dual L/N- type Ca2+ channel blocker cilnidipine on neuronally mediated chronotropic response in anesthetized dogs. Eur J Pharmacol 2001; 413: 117–120.

    Article  CAS  Google Scholar 

  20. Sakata K, Shirotani M, Yoshida H, et al: Effects of amlodipine and cilnidipine on cardiac sympathetic nervous system and neurohormonal status in essential hypertension. Hypertension 1999; 33: 1447–1452.

    Article  CAS  Google Scholar 

  21. Lombardi F, Verrier RL, Low B : Relationship between sympathetic neural activity, coronary dynamics, and vulnerability to ventricular fibrillation during myocardial ischemia and reperfusion. Am Heart J 1983; 105: 958–965.

    Article  CAS  Google Scholar 

  22. Naito H, Furukawa Y, Chino D, Yamada C, Hashimoto K : Effects of zatebradine and propranolol on canine ischemia and reperfusion-induced arrythmias. Eur J Pharmacol 2000; 388: 171–176.

    Article  CAS  Google Scholar 

  23. Cinca J, Worner F, Carreno A, Bardaji A, Salas-Caudevilla A, Soler-Soler J : Reperfusion arrythmias after chronic regional denervation of the ischaemic myocardium in pigs. Cardiovasc Res 1992; 26: 962–967.

    Article  CAS  Google Scholar 

  24. Kirchengast M, Hergenroder S : Reperfusion arrythmias in closed-chest rats: the effect of myocardial noradrenaline depletion and Ca2+-antagonism. Clin Exp Pharmacol Physiol 1991; 18: 217–221.

    Article  CAS  Google Scholar 

  25. Yamaguchi N, Kimura T, Lamontagne D, de Champlai J, Nadeau R : Occlusion time dependency of regional noradrenaline release and cardiac arrythmias during reperfusion of acutely ischaemic heart in the dog in vivo. Cardiovasc Res 1990; 24: 688–696.

    Article  CAS  Google Scholar 

  26. Thandroyen FT, McCarthy J, Burton KP, Opie LH : Ryanodine and caffeine prevent ventricular arrythmias during acute myocardial ischemia and reperfusion in rat heart. Circ Res 1988; 62: 306–314.

    Article  CAS  Google Scholar 

  27. Kihara Y, Morgan JP : Intracellular calcium and ventricular fibrillation: studies in the aequorin-loaded isovolumic ferrer heart. Circ Res 1991; 68: 1378–1389.

    Article  CAS  Google Scholar 

  28. Brooks WW, Conrad CH, Morgan JP : Reperfusion induced arrythmias following ischaemia in intact rat heart: role of intracellular calcium. Cardiovasc Res 1995; 29: 536–542.

    Article  CAS  Google Scholar 

  29. Hirayama Y, Saitoh H, Atarashi H, Hayakawa H : Electrical and mechanical alternans in canine myocardium in vivo: dependence on intracellular calcium cycling. Circulation 1993; 88: 2894–2902.

    Article  CAS  Google Scholar 

  30. Woodward B, Zakaria MNM : Effect of some free radical scavengers on reperfusion induced arrhythmia in the isolated rat heart. J Mol Cell Cardiol 1985; 17: 485–493.

    Article  CAS  Google Scholar 

  31. Bernier M, Hearse DJ, Manning AS : Repefusion-induced arrhythmia and oxygen-derived free radicals: studies with “anti-free radical” interventions and a free radical-generating system in the isolated perfused rat heart. Circ Res 1986; 58: 331–340.

    Article  CAS  Google Scholar 

  32. Long W, Zhao Y, Zhang L, Longo LD : Role of Ca2+ channels in NE-induced increase in [Ca2+] i and tension in fetal and adult cerebral arteries. Am J Physiol 1999; 277: R286–R294.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Second Department of Internal Medicine, Gifu University School of Medicine, Gifu, Japan

    Hiroshi Nagai, Shinya Minatoguchi, Xue-Hai Chen, Ningyuan Wang, Masazumi Arai, Yoshihiro Uno, Chuanjiang Lu, Yu Misao, Hirohito Onogi, Hiroyuki Kobayashi, Genzou Takemura, Rumi Maruyama & Hisayoshi Fujiwara

  2. Kyoto Women's University, Kyoto, Japan

    Takako Fujiwara

Authors
  1. Hiroshi Nagai
    View author publications

    Search author on:PubMed Google Scholar

  2. Shinya Minatoguchi
    View author publications

    Search author on:PubMed Google Scholar

  3. Xue-Hai Chen
    View author publications

    Search author on:PubMed Google Scholar

  4. Ningyuan Wang
    View author publications

    Search author on:PubMed Google Scholar

  5. Masazumi Arai
    View author publications

    Search author on:PubMed Google Scholar

  6. Yoshihiro Uno
    View author publications

    Search author on:PubMed Google Scholar

  7. Chuanjiang Lu
    View author publications

    Search author on:PubMed Google Scholar

  8. Yu Misao
    View author publications

    Search author on:PubMed Google Scholar

  9. Hirohito Onogi
    View author publications

    Search author on:PubMed Google Scholar

  10. Hiroyuki Kobayashi
    View author publications

    Search author on:PubMed Google Scholar

  11. Genzou Takemura
    View author publications

    Search author on:PubMed Google Scholar

  12. Rumi Maruyama
    View author publications

    Search author on:PubMed Google Scholar

  13. Takako Fujiwara
    View author publications

    Search author on:PubMed Google Scholar

  14. Hisayoshi Fujiwara
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Hisayoshi Fujiwara.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nagai, H., Minatoguchi, S., Chen, XH. et al. Cilnidipine, an N+L-Type Dihydropyridine Ca Channel Blocker, Suppresses the Occurrence of Ischemia/Reperfusion Arrhythmia in a Rabbit Model of Myocardial Infarction. Hypertens Res 28, 361–368 (2005). https://doi.org/10.1291/hypres.28.361

Download citation

  • Received: 18 August 2004

  • Accepted: 24 January 2005

  • Issue date: 01 April 2005

  • DOI: https://doi.org/10.1291/hypres.28.361

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

Keywords

  • cilnidipine
  • reperfusion arrhythmia
  • infarct size
  • noradrenaline

This article is cited by

  • Comparative effects of valsartan in combination with cilnidipine or amlodipine on cardiac remodeling and diastolic dysfunction in Dahl salt-sensitive rats

    • Kai Nagasawa
    • Keiji Takahashi
    • Kohzo Nagata

    Hypertension Research (2015)

  • Cilnidipine, but not amlodipine, ameliorates osteoporosis in ovariectomized hypertensive rats through inhibition of the N-type calcium channel

    • Hideo Shimizu
    • Hironori Nakagami
    • Ryuichi Morishita

    Hypertension Research (2012)

  • The N-type and L-type calcium channel blocker cilnidipine suppresses renal injury in Dahl rats fed a high-salt diet

    • Shizuka Aritomi
    • Hajime Koganei
    • Tomoyuki Konda

    Heart and Vessels (2010)

Download PDF

Advertisement

Explore content

  • Research articles
  • Reviews & Analysis
  • News & Comment
  • Current issue
  • Collections
  • Sign up for alerts
  • RSS feed

About the journal

  • Journal Information
  • Open Access Fees and Funding
  • Guide to Authors
  • About the Editors
  • Message from Editors
  • Call for Paper
  • Contact
  • About the Partner
  • For Advertisers
  • Subscribe
  • Showcase of Graphical Abstracts on Hypertension Research

Publish with us

  • For Authors & Referees
  • Language editing services
  • Open access funding
  • Submit manuscript

Search

Advanced search

Quick links

  • Explore articles by subject
  • Find a job
  • Guide to authors
  • Editorial policies

Hypertension Research (Hypertens Res)

ISSN 1348-4214 (online)

ISSN 0916-9636 (print)

nature.com footer links

About Nature Portfolio

  • About us
  • Press releases
  • Press office
  • Contact us

Discover content

  • Journals A-Z
  • Articles by subject
  • protocols.io
  • Nature Index

Publishing policies

  • Nature portfolio policies
  • Open access

Author & Researcher services

  • Reprints & permissions
  • Research data
  • Language editing
  • Scientific editing
  • Nature Masterclasses
  • Research Solutions

Libraries & institutions

  • Librarian service & tools
  • Librarian portal
  • Open research
  • Recommend to library

Advertising & partnerships

  • Advertising
  • Partnerships & Services
  • Media kits
  • Branded content

Professional development

  • Nature Awards
  • Nature Careers
  • Nature Conferences

Regional websites

  • Nature Africa
  • Nature China
  • Nature India
  • Nature Japan
  • Nature Middle East
  • Privacy Policy
  • Use of cookies
  • Legal notice
  • Accessibility statement
  • Terms & Conditions
  • Your US state privacy rights
Springer Nature

© 2026 Springer Nature Limited