吡啶甲脒衍生物Ki1769、Ki3315和KRN2391在猪离体冠状动脉中的血管舒张机制比较分析

Comparative analysis of vasodilating mechanisms of Ki1769, Ki3315 and KRN2391, pyridinecarboximidamide derivatives, in porcine isolated coronary artery.

Yokoyama T, Okada Y, Jinno Y, Izumi H, Izawa T, Ogawa N

Pharmaceutical Research Laboratory, Kirin Brewery Co. Ltd., Gunma, Japan.

Gen Pharmacol. 1994 Sep;25(5):941-5. doi: 10.1016/0306-3623(94)90100-7.

Abstract

The vasodilating mechanisms of pyridinecarboximidamide derivatives which have a nitroxyl group (KRN2391), a phenyl group (Ki1769) or a hydroxyl group (Ki3315) were studied in porcine isolated coronary artery. 2. KRN2391 (10(-6) M) increased cyclic GMP formation but did not affect intracellular cyclic AMP level. Ki1769 (10(-5) M) and Ki3315 (10(-3) M) had no effect on intracellular cyclic GMP and cyclic AMP levels. 3. Despite producing submaximal relaxation at KRN2391 (10(-6) M) and nitroglycerin (10(-6) M), the increase in cyclic GMP caused by KRN2391 was lower than that caused by nitroglycerin. 4. Methylene blue (10(-5) M) inhibited KRN2391- and nitroglycerin-induced relaxations but did not affect Ki1769- and Ki3315-induced relaxation. 5. Glibenclamide (10(-6) M) inhibited KRN2391-, Ki1769- and Ki3315-induced relaxation but did not affect nitroglycerin-induced relaxation. 6. These results suggest that the nitroxyl group of KRN239 contributes to its nitrate action and the pyridinecarboximidamide moiety plays an important role of developing a K channel opening action.

摘要

在猪离体冠状动脉中研究了具有硝酰基（KRN2391）、苯基（Ki1769）或羟基（Ki3315）的吡啶甲脒衍生物的血管舒张机制。2. KRN2391（10^(-6) M）增加了环鸟苷酸的形成，但不影响细胞内环磷酸腺苷水平。Ki1769（10^(-5) M）和Ki3315（10^(-3) M）对细胞内环鸟苷酸和环磷酸腺苷水平无影响。3. 尽管KRN2391（10^(-6) M）和硝酸甘油（10^(-6) M）产生了亚最大舒张，但KRN2391引起的环鸟苷酸增加低于硝酸甘油引起的增加。4. 亚甲蓝（10^(-5) M）抑制KRN2391和硝酸甘油诱导的舒张，但不影响Ki1769和Ki3315诱导的舒张。5. 格列本脲（10^(-6) M）抑制KRN2391、Ki1769和Ki3315诱导的舒张，但不影响硝酸甘油诱导的舒张。6. 这些结果表明，KRN239的硝酰基有助于其硝酸盐作用，吡啶甲脒部分在发挥钾通道开放作用中起重要作用。