Tolvaptan Attenuates Left Ventricular Fibrosis After Acute Myocardial Infarction in Rats

Takanori Yamazaki; Yasuhiro Nakamura; Masayuki Shiota; Mayuko Osada-Oka; Hiroyuki Fujiki; Akihisa Hanatani; Kenei Shimada; Katsuyuki Miura; Minoru Yoshiyama; Hiroshi Iwao; Yasukatsu Izumi

doi:10.1254/jphs.13086FP

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Tolvaptan Attenuates Left Ventricular Fibrosis After Acute Myocardial Infarction in Rats

Takanori Yamazaki, Yasuhiro Nakamura, Masayuki Shiota, Mayuko Osada-Oka, Hiroyuki Fujiki, Akihisa Hanatani, Kenei Shimada, Katsuyuki Miura, Minoru Yoshiyama, Hiroshi Iwao, Yasukatsu Izumi

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Takanori Yamazaki
Department of Cardiovascular Medicine, Osaka City University Medical School, Japan
Yasuhiro Nakamura
Department of Cardiovascular Medicine, Osaka City University Medical School, Japan
Masayuki Shiota
Department of Pharmacology, Osaka City University Medical School, Japan
Mayuko Osada-Oka
Department of Pharmacology, Osaka City University Medical School, Japan
Food Hygiene and Environmental Health Division of Applied Life Science, Kyoto Prefectural University, Japan
Hiroyuki Fujiki
First Institute of New Drug Discovery, Otsuka Pharmaceutical Co., Ltd., Japan
Akihisa Hanatani
Department of Cardiovascular Medicine, Osaka City University Medical School, Japan
Kenei Shimada
Department of Cardiovascular Medicine, Osaka City University Medical School, Japan
Katsuyuki Miura
Applied Pharmacology and Therapeutics, Osaka City University Medical School, Japan
Minoru Yoshiyama
Department of Cardiovascular Medicine, Osaka City University Medical School, Japan
Hiroshi Iwao
Department of Pharmacology, Osaka City University Medical School, Japan
Yasukatsu Izumi
Department of Pharmacology, Osaka City University Medical School, Japan

Keywords: arginine vasopressin, acute myocardial infarction, diuretic, tolvaptan, cardiac remodeling

JOURNAL FREE ACCESS

2013 Volume 123 Issue 1 Pages 58-66

DOI https://doi.org/10.1254/jphs.13086FP

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Abstract

Tolvaptan, a non-peptide V₂-receptor antagonist, is a newly developed diuretic agent. Recently, we reported that tolvaptan has diuretic as well as anti-inflammatory and anti-fibrotic actions in chronic heart failure. In this study, we investigated whether tolvaptan has a cardioprotective effect in acute heart failure after myocardial infarction (MI). After MI induction, rats were randomized into 6 groups as follows: vehicle group, group treated with 15 mg∙kg⁻¹∙day⁻¹ furosemide, 2 groups treated with 3 or 10 mg∙kg⁻¹∙day⁻¹ tolvaptan, and 2 groups treated with 15 mg∙kg⁻¹∙day⁻¹ furosemide combined with 3 or 10 mg∙kg⁻¹∙day⁻¹ tolvaptan. Each agent was administered for 2 weeks, and blood pressure levels and infarct sizes were similar in all MI groups. Lower left ventricular end-systolic volumes and greater improvement of left ventricular ejection fraction were observed in the tolvaptan-treated groups compared with the vehicle group. In contrast, furosemide alone did not improve them. Sirius red staining revealed that tolvaptan significantly repressed MI-induced interstitial fibrosis in the left ventricle. MI-induced mRNA expressions related to cardiac load, inflammation, and fibrosis were significantly attenuated in the combination group. The combination treatment also repressed MI-induced mineralocorticoid receptor expression. Tolvaptan, or combination of furosemide and tolvaptan, may improve cardiac function in acute MI.

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