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Nicorandil Suppresses Ischemia-Induced Norepinephrine Release and Ventricular Arrhythmias in Hypertrophic Hearts

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Abstract

Purpose

Ventricular arrhythmias (VAs) are a common cause of sudden death in acute myocardial infarction (MI), for which hypertension is a major risk factor. Nicorandil opens ATP-sensitive potassium (KATP) channels, which are expressed by nerve terminals and cardiomyocytes and regulate the release of norepinephrine (NE). However, the effects of nicorandil on ischemic NE release in cardiac tissue remain unclear. Therefore, we herein investigated whether nicorandil suppressed interstitial NE concentrations and VAs during acute MI in pressure overload–induced hypertrophic hearts.

Methods

Rats were divided into two groups: an abdominal aortic constriction (AAC) group and sham-operated (Sham) group. Four weeks after constriction, cardiac geometry and functions were examined using echocardiography and hemodynamic analyses. Myocardial ischemia was induced by coronary artery occlusion for 100 min with or without the administration of nicorandil. VAs were assessed by electrocardiography, and NE concentrations in the ischemic region were measured using a micro-dialysis method.

Results

AAC induced left ventricular hypertrophy with diastolic dysfunction. VAs markedly increased in the early phase (0–20 min) of ischemia in both groups and were more frequent in the AAC group. Cardiac interstitial NE concentrations were higher in the AAC group before ischemia and significantly increased during ischemia in both groups. Nicorandil significantly suppressed ischemia-induced VAs and NE increases in the AAC group.

Conclusion

Ischemia-induced VAs were more frequent in hypertrophic hearts and associated with high interstitial concentrations of NE. The attenuation of ischemia-induced increases in NE through neuronal KATP opening by nicorandil may suppress ischemia-induced VAs in hypertrophic hearts.

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Data Availability

The datasets analyzed in the present study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors gratefully thank Dr. T. Akiyama M.D., Ph.D. (Department of Cardiac Physiology, National Cerebral and Cardiovascular Center, Osaka, Japan) for the excellent technical assistance with the microdialysis method.

Funding

The present study was supported in part by the “The Open Research Program” of Kyoto Pharmaceutical University from the Ministry of Education, Science, and Culture of Japan.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Division of Pathological Science, Kyoto Pharmaceutical University, 5 Misasagi Nakauchi-cho, Yamashina-ku, Kyoto, 607-8414, Japan

    Miyuki Kobara, Toshihiro Amano, Hiroe Toba & Tetsuo Nakata

Authors
  1. Miyuki Kobara
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  2. Toshihiro Amano
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  3. Hiroe Toba
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  4. Tetsuo Nakata
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Contributions

All authors contributed to the study conception and design. Miyuki Kobara designed and performed the experiments and wrote the first draft of the manuscript. Toshihiro Amano performed the experiments and data analysis. Hiroe Toba performed the data analysis. Tetsuo Nakata contributed to the concept of the study and drafting the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Miyuki Kobara.

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Ethics Approval

All procedures conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health. The protocol was approved by the Bioethics Committee of Kyoto Pharmaceutical University.

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The authors declare no competing interests.

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Kobara, M., Amano, T., Toba, H. et al. Nicorandil Suppresses Ischemia-Induced Norepinephrine Release and Ventricular Arrhythmias in Hypertrophic Hearts. Cardiovasc Drugs Ther 37, 53–62 (2023). https://doi.org/10.1007/s10557-022-07369-1

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