Kosakai K, Wakabayashi S, Sato T, Mochizuki S, Tomiyama A, Zhou Q, Satake N, Shibata S
Research Laboratory, Kotobuki Seiyaku Company, Ltd., Nagano, Japan.
J Cardiovasc Pharmacol. 1993 Mar;21(3):441-7. doi: 10.1097/00005344-199303000-00014.
Pharmacologic properties of KT2-962 (6-isopropyl-3-[4-(p-chlorobenzenesulfonylamino)butyl]-azulene+ ++-1-sulfonic acid sodium salt, KT) were studied in isolated rat aorta, rat tail artery, rabbit aorta, rabbit renal artery, and pig coronary artery. KT competitively inhibited the contractions induced by thromboxane A2 (TXA2) mimetic, U46619 (pA2 values 9.95, 8.85, 7.87, 8.49, and 9.12, respectively). KT also inhibited the contraction of rabbit aorta induced by prostaglandin2 alpha (PGF2 alpha, pA2 value 7.85) and the contraction of guinea pig ileum induced by LTD4 (pA2 value 5.48) but did not alter the contractions induced by norepinephrine (NE), Ca2+, serotonin, and histamine. KT did not alter the contractions of guinea pig ileum, which did not contract with U46619, induced by PGE2 and PGF2 alpha. KT inhibited the aggregations of rabbit platelets induced by U46619, arachidonic acid, and collagen (IC50 values 7.9, 140, and 16 microM, respectively) but not those induced by ADP. It also inhibited the specific binding of TXA2/PGH2 receptor antagonist, [3H]SQ29,548, to rabbit gel-filtered platelets with an IC50 value of 1.5 x 10(-8) M. In in vivo experiments with mice, oral administration of KT protected the U46619-induced sudden death with the minimum effective dose of 0.3 mg/kg and provided such protection for > 8 h at 1.0 mg/kg. These results indicate that KT is a new nonprostanoid type TXA2/PGH2 receptor antagonist that is orally effective and long acting.
研究了KT2-962（6-异丙基-3-[4-(对氯苯磺酰氨基)丁基]薁-1-磺酸钠盐，KT）在离体大鼠主动脉、大鼠尾动脉、兔主动脉、兔肾动脉和猪冠状动脉中的药理特性。KT竞争性抑制血栓素A2（TXA2）模拟物U46619诱导的收缩（pA2值分别为9.95、8.85、7.87、8.49和9.12）。KT还抑制前列腺素2α（PGF2α，pA2值7.85）诱导的兔主动脉收缩以及白三烯D4（LTD4，pA2值5.48）诱导的豚鼠回肠收缩，但不改变去甲肾上腺素（NE）、Ca2+、5-羟色胺和组胺诱导的收缩。KT不改变豚鼠回肠由PGE2和PGF2α诱导的收缩，豚鼠回肠对U46619不产生收缩反应。KT抑制U46619、花生四烯酸和胶原诱导的兔血小板聚集（IC50值分别为7.9、140和16μM），但不抑制ADP诱导的聚集。它还抑制TXA2/PGH2受体拮抗剂[3H]SQ29548与兔凝胶过滤血小板的特异性结合，IC50值为1.5×10−8 M。在小鼠体内实验中，口服KT可保护小鼠免受U46619诱导的猝死，最小有效剂量为0.3 mg/kg，1.0 mg/kg时的保护作用可持续>8小时。这些结果表明，KT是一种新型非甾体类TXA2/PGH2受体拮抗剂，口服有效且作用持久。
