Salzmann R, Scholtysik G, Markstein R, Bormann G
Cardiovascular Unit of Preclinical Research, Sandoz Ltd., Basle, Switzerland.
J Cardiovasc Pharmacol. 1988 Oct;12(4):451-60. doi: 10.1097/00005344-198810000-00011.
DPN 205-734 [5-(4-cyanophenyl)-1,2-dihydro-6-methyl-2-oxopyridin-3-carbo nitrile] was investigated in vitro in Langendorff rabbit hearts, guinea pig and rabbit papillary muscles, and rat myocardium and in vivo in anesthetized and unanesthetized dogs, pithed open-chest cats, anesthetized rats, and cardiomyopathic hamsters. In vitro, this substance caused a concentration-dependent positive inotropic effect. Left ventricular dP/dtmax was increased in anesthetized dogs after intravenous injection of 0.02 and 0.2 mg/kg (35 +/- 10 and 130 +/- 13%, respectively) and in unanesthetized dogs after oral doses of 0.05-0.5 mg/kg (15 +/- 2 to 71 +/- 14%). DPN 205-734 lowered blood pressure and total peripheral resistance in several experimental models, indicating an afterload-reducing effect. It induced moderate tachycardia. The positive inotropic effect is not explainable by beta-stimulation as shown in pithed open-chest cats pretreated with propranolol. A phosphodiesterase-inhibiting activity (IC50 = 35.5 microM), measured in rat myocardium, may be primarily responsible for the positive inotropic action. In guinea pig papillary muscles partially depolarized with 22 mM K+, DPN 205-734 in a concentration of 1 microM restored slow action potentials, which were then blocked by carbachol. These actions can be explained by the increase in cardiac cyclic AMP level due to a phosphodiesterase-inhibiting effect. In rabbit papillary muscles the positive inotropic effect of DPN 205-734 (100 microM) was only moderately inhibited by carbachol (3 microM), suggesting an additional mechanism.
DPN 205 - 734 [5 - (4 - 氰基苯基)-1,2 - 二氢 - 6 - 甲基 - 2 - 氧代吡啶 - 3 - 甲腈] 在离体的Langendorff兔心脏、豚鼠和兔乳头肌以及大鼠心肌中进行了研究，并且在活体的麻醉和未麻醉犬、脊髓横断开胸猫、麻醉大鼠和心肌病仓鼠中进行了研究。在体外，该物质引起浓度依赖性正性肌力作用。静脉注射0.02和0.2mg/kg后，麻醉犬的左心室dP/dtmax增加（分别为35±10%和130±13%），口服0.05 - 0.5mg/kg后，未麻醉犬的左心室dP/dtmax增加（15±2%至71±14%）。DPN 205 - 734在多个实验模型中降低血压和总外周阻力，表明有减轻后负荷的作用。它引起中度心动过速。如用普萘洛尔预处理的脊髓横断开胸猫所示，正性肌力作用不能用β - 刺激来解释。在大鼠心肌中测得的磷酸二酯酶抑制活性（IC50 = 35.5μM）可能是正性肌力作用的主要原因。在22mM K⁺使部分去极化的豚鼠乳头肌中，1μM浓度的DPN 205 - 734恢复了慢动作电位，随后被卡巴胆碱阻断。这些作用可以用磷酸二酯酶抑制作用导致的心脏环磷酸腺苷水平升高来解释。在兔乳头肌中，3μM卡巴胆碱仅适度抑制了100μM DPN 205 - 734的正性肌力作用，提示存在其他机制。
