Kaneta S, Yokoyama T, Izumi H, Izawa T, Ogawa N
Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd., Gunma, Japan.
Arch Int Pharmacodyn Ther. 1994 Mar-Apr;327(2):184-93.
The cardiovascular effects of KRN2391, N-cyano-N'-(2-nitroxyethyl)-3-pyridine carboximidamide monomethanesulfonate, were compared with those of cromakalim and nitroglycerin in anesthetized dogs. KRN2391 (3-30 micrograms/kg, i.v.), cromakalim (3-30 micrograms/kg, i.v.) and nitroglycerin (1-10 micrograms/kg, i.v.) produced a dose-related decrease of the mean blood pressure with concomitant increase in heart rate. The increase in heart rate caused by cromakalim was lower than that caused by KRN2391 and nitroglycerin. Left ventricular end-diastolic pressure was decreased by all doses of KRN2391 and nitroglycerin. Cromakalim at 3 and 10 micrograms/kg decreased this end-diastolic pressure but increased it at 30 micrograms/kg. Left ventricular dP/dt was increased by KRN2391 and nitroglycerin but was decreased by cromakalim. KRN2391 and cromakalim produced a dose-dependent increase in aortic and coronary blood flow. Nitroglycerin showed biphasic changes in aortic and coronary blood flow, i.e., an initial increase followed by a decrease. At equipotent hypotensive doses, the increase in coronary blood flow induced by KRN2391 was greater than that by cromakalim and nitroglycerin, and total peripheral and coronary vascular resistances were decreased by KRN2391 and cromakalim. Nitroglycerin showed biphasic changes in total peripheral and coronary vascular resistances, i.e., these resistance showed an initial decrease followed by an increase. The relative decrease of coronary vascular resistance compared to the total peripheral vascular resistance was greater for KRN2391 than for cromakalim and nitroglycerin. The changes in hemodynamic parameters caused by KRN2391 were inhibited by pretreatment with glibenclamide (5 mg/kg, i.v.). These results suggest that the hemodynamic profile of KRN2391 is closer to that of cromakalim than to that of nitroglycerin, but that the selectivity for the coronary vascular bed is higher for KRN2391 than for cromakalim. In addition, it is considered that, compared with KRN2391 and nitroglycerin, cromakalim has a low selectivity for the vasculature vs the myocardium.
在麻醉犬中，比较了KRN2391（N-氰基-N'-（2-硝氧乙基）-3-吡啶甲脒单甲磺酸盐）与克罗卡林和硝酸甘油对心血管系统的影响。静脉注射KRN2391（3 - 30微克/千克）、克罗卡林（3 - 30微克/千克）和硝酸甘油（1 - 10微克/千克）均可使平均血压呈剂量依赖性下降，同时心率增加。克罗卡林引起的心率增加低于KRN2391和硝酸甘油。所有剂量的KRN2391和硝酸甘油均可降低左心室舒张末期压力。3微克/千克和10微克/千克的克罗卡林可降低此舒张末期压力，但30微克/千克时则使其升高。KRN2391和硝酸甘油可增加左心室dP/dt，而克罗卡林则使其降低。KRN2391和克罗卡林可使主动脉和冠状动脉血流量呈剂量依赖性增加。硝酸甘油使主动脉和冠状动脉血流量呈双相变化，即先增加后减少。在等效降压剂量下，KRN2391诱导的冠状动脉血流量增加大于克罗卡林和硝酸甘油，KRN2391和克罗卡林可降低总外周血管阻力和冠状动脉血管阻力。硝酸甘油使总外周血管阻力和冠状动脉血管阻力呈双相变化，即这些阻力先降低后增加。与克罗卡林和硝酸甘油相比，KRN2391使冠状动脉血管阻力相对于总外周血管阻力的相对降低更大。用格列本脲（5毫克/千克，静脉注射）预处理可抑制KRN2391引起的血流动力学参数变化。这些结果表明，KRN2391的血流动力学特征与克罗卡林比与硝酸甘油更接近，但KRN2391对冠状动脉血管床的选择性高于克罗卡林。此外，与KRN2391和硝酸甘油相比，克罗卡林对血管系统与心肌的选择性较低。
