This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shimizu, Y. Articles by Fujiwara, H. Search for Related Content PubMed PubMed Citation Articles by Shimizu, Y. Articles by Fujiwara, H.

CLINICAL STUDY

The role of serotonin in ischemic cellular damage and the infarct size-reducing effect of sarpogrelate, a 5-hydroxytryptamine-2 receptor blocker, in rabbit hearts

Yasuko Shimizu, MD^*, Shinya Minatoguchi, MD^*, Kazuaki Hashimoto, MD^*, Yoshihiro Uno, MD^*, Masazumi Arai, MD^*, Ningyuan Wang, MD^*, Xuehai Chen, MD^*, Chuanjian Lu, MD^*, Genzou Takemura, MD^*, Masaaki Shimomura, MSc, Takako Fujiwara, MD and Hisayoshi Fujiwara, MD^*,*

^* Second Department of Internal Medicine, Gifu University School of Medicine, Gifu, Japan
Kyoto Women’s University, Kyoto, Japan

Manuscript received October 24, 2001; revised manuscript received May 20, 2002, accepted June 27, 2002.

^* Reprint requests and correspondence: Dr. Hisayoshi Fujiwara, Second Department of Internal Medicine, Gifu University School of Medicine, 40 Tsukasa Machi, Gifu 500, Japan.
gifuim-gif{at}umin.ac.jp

OBJECTIVES: We aimed to clarify the relation between sarpogrelate (SG), a 5-hydroxytryptamine (5-HT)-2 receptor blocker, and myocardial interstitial serotonin or infarct size during ischemia and reperfusion.

BACKGROUND: In cardiac tissues serotonin is rich in vascular platelets, mast cells, sympathetic nerve endings, and the receptors are present in platelets and cardiomyocytes.

METHODS: The myocardial interstitial serotonin levels were measured using a microdialysis technique during 30-min ischemia with and without SG in in vivo as well as isolated rabbit hearts. Other rabbits underwent 30 min of ischemia and 48 h of reperfusion, and the effect of SG on the infarct size was investigated in the absence and presence of a selective protein kinase C (PKC) inhibitor, chelerythrine (5 mg/kg, intravenously), or a mitochondrial adenosine triphosphate sensitive potassium (KATP) channel blocker, 5-hydroxydecanoate (5-HD) (5 mg/kg, intravenously). In another series, the effect of SG on PKC isoforms in cytosol and membrane fraction was assessed after a 20-min global ischemia in isolated rabbit hearts.

RESULTS: Interstitial serotonin levels were markedly increased during 30-min ischemia in in vivo and isolated hearts, and the increases were inhibited by SG in each. The infarct size was reduced by SG (27 ± 2% vs. 40 ± 3% of control). This effect was blocked by chelerythrine and 5-HD, respectively. Sarpogrelate further enhanced the ischemia-induced translocation of PKC- to the membrane fraction.

CONCLUSIONS: Sarpogrelate reduces the myocardial infarct size by inhibiting the serotonin release followed by enhancement of PKC- translocation and opening of the mitochondrial KATP channel in ischemic myocytes.

Abbreviations and Acronyms   ANOVA   analysis of variance   EGTA   ethyleneglycoltetraacetic acid   5-HD   5-hydroxydecanoate   5-HT   5-hydroxytryptamine   HPLC   high-performance liquid chromatography   KATP   adenosine triphosphate sensitive potassium   LV   left ventricle   PKC   protein kinase C   PMSF   phenylmethylsulfonyl fluoride   SDS-PAGE   sodium dodecyl sulfate-polyacrylamide gel electrophoresis   SG   sarpogrelate   Tris-HCl   2-amino-2-hydroxymethyl-1,3-propanedial-HCl

This article has been cited by other articles:

				S. Yasuda, H. Kobayashi, M. Iwasa, I. Kawamura, S. Sumi, B. Narentuoya, T. Yamaki, H. Ushikoshi, K. Nishigaki, K. Nagashima, et al. Antidiabetic drug pioglitazone protects the heart via activation of PPAR-{gamma} receptors, PI3-kinase, Akt, and eNOS pathway in a rabbit model of myocardial infarction Am J Physiol Heart Circ Physiol, May 1, 2009; 296(5): H1558 - H1565. [Abstract] [Full Text] [PDF]

				L. R. Wulsin, D. Musselman, C. Otte, E. Bruce, S. Ali, and M. A. Whooley Depression and Whole Blood Serotonin in Patients With Coronary Heart Disease From the Heart and Soul Study Psychosom Med, April 1, 2009; 71(3): 260 - 265. [Abstract] [Full Text] [PDF]

				P. Bianchi, O. Kunduzova, E. Masini, C. Cambon, D. Bani, L. Raimondi, M.-H. Seguelas, S. Nistri, W. Colucci, N. Leducq, et al. Oxidative Stress by Monoamine Oxidase Mediates Receptor-Independent Cardiomyocyte Apoptosis by Serotonin and Postischemic Myocardial Injury Circulation, November 22, 2005; 112(21): 3297 - 3305. [Abstract] [Full Text] [PDF]

				S. Takano, Y. Hoshino, L. Li, I. Matsuoka, T. Ono, and J. Kimura Dual Roles of 5-Hydroxytryptamine in Ischemia-Reperfusion Injury in Isolated Rat Hearts Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2004; 9(1): 43 - 50. [Abstract] [PDF]

				J. Vinten-Johansen Involvement of neutrophils in the pathogenesis of lethal myocardial reperfusion injury Cardiovasc Res, February 15, 2004; 61(3): 481 - 497. [Abstract] [Full Text] [PDF]