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Protective effects of sarpogrelate, a 5-HT2A antagonist, against postischemic myocardial dysfunction in guinea-pig hearts

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Abstract

The protective effects of sarpogrelate (SG), a 5-HT2A antagonist, were investigated in perfused guinea-pig Langendorff hearts subjected to ischemia and reperfusion. Changes in cellular levels of high phosphorous energy, NO and Ca2+ in the heart together with simultaneous recordings of left ventricular developed pressure (LVDP) were monitored using an nitric oxide (NO) electrode, fluorometry and 31P-NMR. The recovery of LVDP from ischemia by reperfusion was 30.1% in the control, while the treatment with SG (5×10-7 M) in pre- and post-ischemia hearts produced a gradual increase to 73.1 and 53.6%, respectively. At the final stage of ischemia, the intracellular concentration of Ca2+ ([Ca2+i) and release of NO increased with no twitching and remained at a high steady level. The addition of SG increased the transient NO signal (TNO) level at the end of ischemia compared with the control, but [Ca2+]i during ischemia decreased. Meanwhile, mitochondrial Ca2+ uptake on acidification or Ca2+ content changes of the perfusate was suppressed by pre-treatment with SG or the KATP channel opener diazoxide, but not the KATP channel blocker 5-HD. The myocardial NO elevated with 5-HT in normal Langendorff hearts was suppressed by the treatment with SG. Therefore, the existence of the 5HT2A receptor in a Langendorff heart was anticipated. By in vitro EPR, SG was found to directly quench the hydroxy radical. Thus, these findings suggested that the 5-HT2A receptor induced in ischemia–reperfusion plays an important role in the mitochondrial KATP channel of hearts in close relation with NO and active oxygen radicals.

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Authors and Affiliations

  1. Department of Pharmacology, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan

    Tatsuya Muto, Yoshihiro Hotta, Kunihiro Miyazeki, Hiroaki Ando & Naohisa Ishikawa

  2. Department of Hospital Pharmacy, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan

    Takaaki Hasegawa

  3. Department of Pharmacology, Kobe Pharmaceutical University, Kobe, 58-8558, Japan

    Yumi Sugimoto & Jun Yamada

  4. Faculty of Pharmaceutical Sciences, Kinki University, Higashi-Osaka, 577-8502, Japan

    Yasuyoshi Miki

  5. Department of Pharmacology, Aichi Medical University School of Medicine, 21 Yazakoaza-Karimata Nagakute, Aichi 480-1195, Japan

    Yoshihiro Hotta

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  1. Tatsuya Muto
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Correspondence to Yoshihiro Hotta.

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Muto, T., Hotta, Y., Miyazeki, K. et al. Protective effects of sarpogrelate, a 5-HT2A antagonist, against postischemic myocardial dysfunction in guinea-pig hearts. Mol Cell Biochem 272, 119–132 (2005). https://doi.org/10.1007/s11010-005-6909-0

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  • DOI: https://doi.org/10.1007/s11010-005-6909-0

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