Clozel J P, Véniant M, Osterrieder W
Pharmaceutical Research Department, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Cardiovasc Drugs Ther. 1990 Jun;4(3):731-6. doi: 10.1007/BF01856562.
Ro 40-5967 is a structurally novel Ca2+ channel blocker that binds to the verapamil-type receptor of cardiac membranes but that has been shown in isolated guinea-pig hearts to be about ten times less potent a negative inotropic agent than verapamil. The goals of the present study were to confirm these findings in vitro in isolated perfused rat hearts as well as in vivo in conscious rats and to compare Ro 40-5967 to verapamil. The effects of Ro 40-5967 and verapamil were tested not only in normal rats, but also in rats with heart failure induced by chronic myocardial infarction. In isolated Langendorff hearts (without heart failure), no decrease of contractility was observed with Ro 40-5967 up to complete AV block. In contrast, verapamil decreased contractility with an IC50 of 100 nM. In isolated, electrically stimulated rat papillary muscles, the IC50 values for the decrease of contractile force were 15,000 and 440 nM for Ro 40-5967 and verapamil, respectively. In vivo, Ro 40-5967 did not decrease left ventricular contractility (as assessed by changes of dP/dt max +) in rats without and with heart failure. In contrast, verapamil was markedly negative inotropic in both conditions.
Ro 40 - 5967是一种结构新颖的钙通道阻滞剂，它与心肌细胞膜上的维拉帕米型受体结合，但在离体豚鼠心脏实验中已表明，其作为负性肌力药物的效力比维拉帕米低约十倍。本研究的目的是在离体灌注大鼠心脏的体外实验以及清醒大鼠的体内实验中证实这些发现，并将Ro 40 - 5967与维拉帕米进行比较。不仅在正常大鼠中，而且在由慢性心肌梗死诱导心力衰竭的大鼠中测试了Ro 40 - 5967和维拉帕米的作用。在离体Langendorff心脏（无心力衰竭）中，直至完全房室传导阻滞，Ro 40 - 5967均未观察到收缩力下降。相比之下，维拉帕米使收缩力下降，IC50为100 nM。在离体电刺激的大鼠乳头肌中，Ro 40 - 5967和维拉帕米使收缩力下降的IC50值分别为15,000和440 nM。在体内，Ro 40 - 5967在无心力衰竭和有心力衰竭的大鼠中均未降低左心室收缩力（通过dP/dt max +的变化评估）。相比之下，维拉帕米在两种情况下均具有明显的负性肌力作用。
