1999 Fiscal Year Annual Research Report

陰性変時作用を持つ新しいカルシウムセンシタイザーEGIS-9377の生理学的特性

Research Project

Project/Area Number	10770307
Research Institution	Okayama University
Principal Investigator	毛利聡岡山大学, 医学部, 助手 (00294413)
Keywords	カルシウムセンシタイザー / 心臓メカノエナジェティクス / 陰性変時作用 / 陽性変力作用 / Gregg効果 / 心不全治療薬
Research Abstract	陰性変時作用を持つカルシウムセンシタイザーEGIS-9377の生理学的特性について心臓メカノエナジェティクスの指標を用いて検討した。イヌ交叉灌流摘出心標本にて洞調律下にEGIS-9377を冠動脈内投与したところ1.5mg/minまでは心拍数に影響を及ぼさず、4mg/minでは14%の心拍数減少を認めた。また、冠動脈血流量にも影響を与え、4mg/min投与時に対照群に比較し2.6倍と著明に増加させ、収縮性Emaxを50%増加させた。その成因としてGregg効果が関与していると考え冠動脈血流量を固定したところEmaxの増加は4%であった。血流量の固定により冠動脈圧は低下しており、Gregg効果以外の陽性変力作用があることを確認した。PVAの酸素コストに対してはこれまで報告されてきた陽性変力作用薬と同様に影響を与えなかった。Emaxの酸素コストもドブタミンと同じであった。EGIS-9377急性投与による心臓へのメカノエナジェティクスはこれまでの陽性変力作用薬と同様であり、クロスブリッジでのエネルギー変換効率を改善する効果は認められなかった。βアドレナリン受容体遮断薬は陰性変時作用を持ち、内科的心不全治療の中心的役割を果たしているが、その一つの要因として陰性変時作用が挙げられている。EGIS-9377についても長期予後を改善する可能性があり、慢性効果について検討する予定であったが、動物実験の段階で嘔吐の副作用が強く慢性実験が困難であり、臨床応用には問題があると判断して研究を中断した。

Research Products

(13 results)

All Other

All Publications (13 results)

[Publications] Suzuki S, Araki J, Morita T, Mikane T, Yamaguchi H, Sano S, Ohe T, Hirakawa M, Suga H: "Ventricular contractility in atrial fibrillation is predictable by mechanical restitution and potentiation"Am J Physiol. 275. H1513-H1519 (1998)
[Publications] Shimizu J, Araki J, Mizuno J, Lee S, Syuu Y, Hosogi S, Mohri S, Mikane T, Takaki M, Taylor TW, Suga H: "A new integrative method to quantify total Ca^<2+> handling and futile Ca^<2+> cycling in failing hearts"Am J Physiol. 275. H2325-H2333 (1998)
[Publications] Syuu Y, Araki J, Lee S, Suzuki S, Mizuno J, Mohri S, Mikane T, Shimizu J, Takaki M, Suga H: "Effects of Ca_<2+> and epinephrine on Ca_<2+> recirculation fraction and total Ca_<2+> handling in canine left ventricles"Jpn J physiol. 48・2. 123-132 (1998)
[Publications] Lee S, Ohga Y, Tachibana H, Syuu Y, Ito H, Harada M, Suga H, Takaki M: "Effects of myosin isozyme shift on curvilinearity of the left ventricular end systolic pressure volume relation of in situ rat hearts"Jpn J physiol. 48・6. 445-455 (1998)
[Publications] Mizuno J, Mikane T, Araki J, Hatashima M, Moritan T, Ishikawa T, Komukai K, Kurihara S, Hirakawa M, Suga H: "Hybrid logistic characterization of isometric twitch force curve of isolated ferret right ventricular papillary muscle"Jpn J Physical. 49・2. 145-158 (1999)
[Publications] Mizuno J. Araki J, Iribe G, Maesako M, Morita T, Miyaji K, Imaoka T, Mohri S, Sano S, Ohe T, Hirakawa M, Suga H: "Total Ca handling in canine mild Ca overload failing heart"Heart Vessels. 14・1. 38-51 (1999)
[Publications] Mohri S, Araki J, Imaoka T, Iribe G, Maesako M, Shimizu J, Matsubara H, Ohe T, Hirakawa M, Suga H: "Myocardial mechanical restitution and potentiation partly underlie alternans decay of postextrasystolic potentiation : simulation"Heart Vessels. 14・2. 82-89 (1999)
[Publications] Mikane T, Araki J, Suzuki S, Mizuno J, Shimizu J, Mohri S, Matsubara H, Hirakawa M, Ohe T, Suga H: "O_2 cost of contractility but not of mechanical energy increases with temperature in canine left ventricle"Am J Physiol. 277. H65-H73 (1999)
[Publications] Araki J, Matsubara H, Shimizu J, Mikane T, Mohri S, Mizuno J, Takaki M, Ohe T, Hirakawa M, Suga H: "Weibull distribution function for cardiac contraction: Integrative analysis"Am J Physiol. 277. H1940-H1945 (1999)
[Publications] Lee S, Araki J, Imaoka T, Maesako M, Iribe G, Miyaji K, Mohri S, Shimizu J, Harada M, Ohe T, Hirakawa M, Suga H: "Energy-wasteful total calcium handling underlies increased O_2 cost of contractility in canine stunned heart"Am J Physiol. (In press).
[Publications] Shimizu J, Araki J, Iribe G, Imaoka T, Mohri S, Hohno K, Matsubara H, Ohe T, Takaki M, Suga H: "Postextrasystolic contractile decay independent of extrasystolic interval and compensatory pause in canine heart"Am J Physiol. (In press).
[Publications] Mitani H, Yamaguchi H, Morita T, Oshima Y, Shimizu J, Ito H, Araki J, Takaki M, Sano S, Suga H: "Effective arterial elastance (Ea) of irregular beats during atrial fibrillation in canine left ventricle"Jpn J Physiol. (In press).
[Publications] Takasago T, Goto Y, Hata K, Saeki A, Nishioka T, Taylor TW, Iribe G, Mohri S, Shimizu J, Araki J, Suga H: "Mechanoenergetics characterizing oxygen wasting effect of caffeine in canine left ventricle"Jpn J Physiol. (In press).

1999 Fiscal Year Annual Research Report

陰性変時作用を持つ新しいカルシウムセンシタイザーEGIS-9377の生理学的特性

Principal Investigator

毛利 聡 岡山大学, 医学部, 助手 (00294413)

Research Products

[Publications] Suzuki S, Araki J, Morita T, Mikane T, Yamaguchi H, Sano S, Ohe T, Hirakawa M, Suga H: "Ventricular contractility in atrial fibrillation is predictable by mechanical restitution and potentiation"Am J Physiol. 275. H1513-H1519 (1998)

[Publications] Shimizu J, Araki J, Mizuno J, Lee S, Syuu Y, Hosogi S, Mohri S, Mikane T, Takaki M, Taylor TW, Suga H: "A new integrative method to quantify total Ca^<2+> handling and futile Ca^<2+> cycling in failing hearts"Am J Physiol. 275. H2325-H2333 (1998)

[Publications] Syuu Y, Araki J, Lee S, Suzuki S, Mizuno J, Mohri S, Mikane T, Shimizu J, Takaki M, Suga H: "Effects of Ca_<2+> and epinephrine on Ca_<2+> recirculation fraction and total Ca_<2+> handling in canine left ventricles"Jpn J physiol. 48・2. 123-132 (1998)

[Publications] Lee S, Ohga Y, Tachibana H, Syuu Y, Ito H, Harada M, Suga H, Takaki M: "Effects of myosin isozyme shift on curvilinearity of the left ventricular end systolic pressure volume relation of in situ rat hearts"Jpn J physiol. 48・6. 445-455 (1998)

[Publications] Mizuno J, Mikane T, Araki J, Hatashima M, Moritan T, Ishikawa T, Komukai K, Kurihara S, Hirakawa M, Suga H: "Hybrid logistic characterization of isometric twitch force curve of isolated ferret right ventricular papillary muscle"Jpn J Physical. 49・2. 145-158 (1999)

[Publications] Mizuno J. Araki J, Iribe G, Maesako M, Morita T, Miyaji K, Imaoka T, Mohri S, Sano S, Ohe T, Hirakawa M, Suga H: "Total Ca handling in canine mild Ca overload failing heart"Heart Vessels. 14・1. 38-51 (1999)

[Publications] Mohri S, Araki J, Imaoka T, Iribe G, Maesako M, Shimizu J, Matsubara H, Ohe T, Hirakawa M, Suga H: "Myocardial mechanical restitution and potentiation partly underlie alternans decay of postextrasystolic potentiation : simulation"Heart Vessels. 14・2. 82-89 (1999)

[Publications] Mikane T, Araki J, Suzuki S, Mizuno J, Shimizu J, Mohri S, Matsubara H, Hirakawa M, Ohe T, Suga H: "O_2 cost of contractility but not of mechanical energy increases with temperature in canine left ventricle"Am J Physiol. 277. H65-H73 (1999)

[Publications] Araki J, Matsubara H, Shimizu J, Mikane T, Mohri S, Mizuno J, Takaki M, Ohe T, Hirakawa M, Suga H: "Weibull distribution function for cardiac contraction: Integrative analysis"Am J Physiol. 277. H1940-H1945 (1999)

[Publications] Lee S, Araki J, Imaoka T, Maesako M, Iribe G, Miyaji K, Mohri S, Shimizu J, Harada M, Ohe T, Hirakawa M, Suga H: "Energy-wasteful total calcium handling underlies increased O_2 cost of contractility in canine stunned heart"Am J Physiol. (In press).

[Publications] Shimizu J, Araki J, Iribe G, Imaoka T, Mohri S, Hohno K, Matsubara H, Ohe T, Takaki M, Suga H: "Postextrasystolic contractile decay independent of extrasystolic interval and compensatory pause in canine heart"Am J Physiol. (In press).

[Publications] Mitani H, Yamaguchi H, Morita T, Oshima Y, Shimizu J, Ito H, Araki J, Takaki M, Sano S, Suga H: "Effective arterial elastance (Ea) of irregular beats during atrial fibrillation in canine left ventricle"Jpn J Physiol. (In press).

[Publications] Takasago T, Goto Y, Hata K, Saeki A, Nishioka T, Taylor TW, Iribe G, Mohri S, Shimizu J, Araki J, Suga H: "Mechanoenergetics characterizing oxygen wasting effect of caffeine in canine left ventricle"Jpn J Physiol. (In press).

毛利聡岡山大学, 医学部, 助手 (00294413)