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The Pharmaceutical Society of Korea (대한약학회)
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Antiplatelet Activity of [5-(2-Methoxy-5-chlorophenyl)furan-2-ylcarbonyl]guanidine (KR-32570), a Novel Sodium/hydrogen Exchanger-1 and Its Mechanism of Action

  • Lee Kyung-Sup (College of Pharmacy, Chungbuk National University) ;
  • Park Jung-Woo (Department of Applied Biochemistry, Division of Life Science, College of Biomedical and Health Science, Konkuk University) ;
  • Jin Yong-Ri (College of Pharmacy, Chungbuk National University) ;
  • Jung In-Sang (Department of Applied Biochemistry, Division of Life Science, College of Biomedical and Health Science, Konkuk University) ;
  • Cho Mi-Ra (College of Pharmacy, Chungbuk National University) ;
  • Yi Kyu-Yang (Medicinal Science Division, Korea Research Institute of Chemical Technology) ;
  • Yoo Sung-Eun (Medicinal Science Division, Korea Research Institute of Chemical Technology) ;
  • Chung Hun-Jong (Pediatric Department, Chungju Hospital, Konkuk Medical School, Konkuk University) ;
  • Yun Yeo-Pyo (College of Pharmacy, Chungbuk National University) ;
  • Park Tae-Kyu (Department of Biotechnology, Division of Life Science, College of Biomedical and Health Science, Konkuk University) ;
  • Shin Hwa-Sup (Department of Applied Biochemistry, Division of Life Science, College of Biomedical and Health Science, Konkuk University)
  • Published : 2006.05.01
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Abstract

The anti platelet effects of a novel guanidine derivative, KR-32570 ([5-(2-methoxy-5-chlorophenyl) furan-2-ylcarbonyl]guanidine), were investigated with an emphasis on the mechanisms underlying its inhibition of collagen-induced platelet aggregation. KR-32570 significantly inhibited the aggregation of washed rabbit platelets induced by collagen $(10{\mu}g/mL)$, thrombin (0.05 U/mL), arachidonic acid $(100{\mu}M)$, a thromboxane (TX) $A_2$ mimetic agent U46619 (9,11-dideoxy-9,11-methanoepoxy-prostaglandin $F_2,\;1{\mu}M$) and a $Ca^{2+}$ ATPase inhibitor thapsigargin $(0.5{\mu}M)$ ($IC_{50}$ values: $13.8{\pm}1.8,\;26.3{\pm}1.2,\;8.5{\pm}0.9,\;4.3{\pm}1.7\;and\;49.8{\pm}1.4{\mu}M$, respectively). KR-32570 inhibited the collagen-induced liberation of $[^3H]$arachidonic acid from the platelets in a concentration dependent manner with complete inhibition being observed at $50{\mu}M$. The $TXA_2$ synthase assay showed that KR-32570 also inhibited the conversion of the substrate $PGH_2$ to $TXB_2$ at all concentrations. Furthermore, KR-32570 significantly inhibited the $[Ca^{2+}]_i$ mobilization induced by collagen at $50{\mu}M$, which is the concentration that completely inhibits platelet aggregation. KR-32570 also decreased the level of collagen $(10{\mu}g/mL)$induced secretion of serotonin from the dense-granule contents of platelets, and inhibited the NHE-1-mediated rabbit platelet swelling induced by intracellular acidification. These results suggest that the antiplatelet activity of KR-32570 against collagen-induced platelet aggregation is mediated mainly by inhibiting the release of arachidonic acid, $TXA_2$ synthase, the mobilization of cytosolic $Ca^{2+}$ and NHE-1.

Keywords

References

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