Effects of iptakalim hydrochloride on the functions of endothelin system / 中国药理学通报

ABSTRACT

Aim: To investigate the effects of iptakalim hydrochloride (Ipt), a new antihypertensive drug, on the functions of endothelin system. Methods: Radioimmunoassay was used to test the plasma endothelin (ET) concentration of rats and endothelin released from cultured vasocular endothelial cells. The expressions of ET and endothelin converting enzyme (ECE) were determined by RT-PCR. The effects of endothelin on vascular tone were studied in isolated rat aorta. The pulmonary artery pressure was measured in anaesthetized rats. Results: Circled digit one In stroke-prone spontaneously hypertensive rats (SHRsp), the plasma levels of endothelin were increased, which could be reversed by the treatment with Ipt at the doses of 0.25, 1.0 and 4.0 mg·kg -1 po, once a day, for 3 months. Circled digit two In cultured neonatal bovine aortic endothelial cells (BAEC), Ipt at the concentrations of 1-1000 μmol ·L-1, inhibited the secretion of ET in a concentration-dependent manner. Circled digit three Under the same experimental conditions, Ipt also inhibited the expressions of ET and ECE in BAEC. Circled digit four In isolated preparations derived from rat aorta, the vascular contraction evoked by ET-1 was antagonized by Ipt at the concentrations of 0.5-100 μmol·L-1 in a concentration-dependent manner. The vasorelaxative effects of Ipt were attenuated significantly in buffer without Ca2+. Circled digit five In anaesthetized SD rats, intrapulmonary artery administration of ET-1 induced vascular contraction in vivo, resulting in intrapulmonary artery hypertension, which was prevented by iptakalim hydrochloride at the doses of 0.5-1.0 mg·kg-1. But it had no effects on normal pulmonary artery pressure. Conclusion: Ipt could antagonize the functions of endothelin system. Its characteristics include inhibiting the expression of ET-1 and ECE, inhibiting the releasing of ET-1, reversing the increased plasma levels of ET-1 under pathological condition, and preventing intrapulmonary artery hypertension induced by ET-1.