Haleen S J, Steffen R P, Sircar I, Major T C, Taylor M D, Pugsley T A, Weishaar R E
Department of Pharmacology, Chemistry, and Biochemistry, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan.
J Pharmacol Exp Ther. 1989 Jul;250(1):22-30.
The cardiac and vascular activities of ethyl 5-cyano-1,4-dihydro-6-methyl-2-[(4-pyridinyl-sulfonyl)methyl]-4-[2- (trifluoromethyl)phenyl]-3-pyridine carboxylase (PD 122860), a novel dihydropyridine, were investigated in vitro using rat heart and rabbit aorta, and compared with reference inotropic and vasodilator agents. In the rat heart, PD 122860 increased left ventricular contractility, decreased coronary resistance and altered the shape of the electrocardiogram T-wave. All three effects were observed at comparable concentrations of PD 122860. The inotropic response to PD 122860 was reversed by the Na+ channel blocker tetrodotoxin and blunted by the Na+-Ca++ exchange inhibitor dichlorobenzamil. The effects of tetrodotoxin and dichlorobenzamil on the inotropic response to the reference Na+ channel stimulant veratridine were comparable to PD 122860, whereas tetrodotoxin and dichlorobenzamil had no inhibitory effect on the inotropic responses to the adenylate cyclase stimulator forskolin or the Ca++ channel stimulant BAY K 8644. PD 122860 selectively relaxed potassium-contracted aortic rings and inhibited [3H]nitrendipine binding to rat brain membranes, suggesting that the vasodilator activity of PD 122860 is due to Ca++ channel blockade. In contrast to BAY K 8644, PD 122860 did not contract partially depolarized aortic rings, suggesting an absence of Ca++ channel stimulant activity. PD 122860 is a racemic mixture and both the vasorelaxant and [3H]nitrendipine binding inhibitory activities selectively reside in the (+)-enantiomer [(+)-PD 122860]. In contrast, the inotropic response resides with both enantiomers of PD 122860. It is therefore concluded that PD 122860 represents a unique dihydropyridine derivative which possesses both Na+ channel stimulating and Ca++ channel blocking activities.
使用大鼠心脏和兔主动脉在体外研究了新型二氢吡啶5-氰基-1,4-二氢-6-甲基-2-[(4-吡啶基磺酰基)甲基]-4-[2-(三氟甲基)苯基]-3-吡啶羧酸乙酯(PD 122860)的心脏和血管活性，并与参考性肌力和血管舒张剂进行了比较。在大鼠心脏中，PD 122860增加左心室收缩力，降低冠状动脉阻力并改变心电图T波形状。在相当的PD 122860浓度下观察到所有这三种作用。对PD 122860的肌力反应被Na+通道阻滞剂河豚毒素逆转，并被Na+-Ca++交换抑制剂二氯苯甲酰胺减弱。河豚毒素和二氯苯甲酰胺对参考性Na+通道刺激剂藜芦定的肌力反应的作用与PD 122860相当，而河豚毒素和二氯苯甲酰胺对腺苷酸环化酶刺激剂福斯高林或Ca++通道刺激剂BAY K 8644的肌力反应没有抑制作用。PD 122860选择性地舒张钾收缩的主动脉环，并抑制[3H]尼群地平与大鼠脑膜的结合，表明PD 122860的血管舒张活性是由于Ca++通道阻滞。与BAY K 864相比，PD 122860不会使部分去极化的主动脉环收缩，表明其缺乏Ca++通道刺激活性。PD 122860是一种外消旋混合物，血管舒张和[3H]尼群地平结合抑制活性都选择性地存在于(+)-对映体[(+)-PD 122860]中相反，肌力反应存在于PD 122860的两种对映体中。因此得出结论，PD 12286代表一种独特的二氢吡啶衍生物，它同时具有Na+通道刺激和Ca++通道阻滞活性。
