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

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 x 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.

• Authors: Tatsuya Muto, Yoshihiro Hotta, Kunihiro Miyazeki, Hiroaki Ando, Naohisa Ishikawa, Takaaki Hasegawa, Yumi Sugimoto, Jun Yamada, Yasuyoshi Miki
• Journal: Molecular and cellular biochemistry (Mol Cell Biochem) Vol. 272 Issue 1-2 Pg. 119-32 (Apr 2005) ISSN: 0300-8177 [Print] Netherlands
• PMID: 16010979 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiotonic Agents
• Free Radical Scavengers
• Free Radicals
• Serotonin 5-HT2 Receptor Antagonists
• Serotonin Antagonists
• Succinates
• fura-2-am
• sarpogrelate
• Phosphorus
• Nitric Oxide
• Calcium
• Fura-2

Topics

• Animals
• Calcium (analysis, metabolism)
• Calcium Signaling
• Cardiotonic Agents (pharmacology, therapeutic use)
• Free Radical Scavengers (pharmacology)
• Free Radicals (metabolism)
• Fura-2 (analogs & derivatives, analysis)
• Guinea Pigs
• In Vitro Techniques
• Mitochondria, Heart (chemistry, metabolism)
• Myocardial Contraction (drug effects)
• Myocardial Reperfusion
• Myocardial Reperfusion Injury (metabolism, prevention & control)
• Nitric Oxide (metabolism)
• Phosphorus (metabolism)
• Serotonin 5-HT2 Receptor Antagonists
• Serotonin Antagonists (pharmacology, therapeutic use)
• Succinates (pharmacology, therapeutic use)