Kawahara J, Izumi H, Okada Y, Izawa T
Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd., Gunma, Japan.
Naunyn Schmiedebergs Arch Pharmacol. 1996 Oct;354(4):460-5. doi: 10.1007/BF00168437.
We examined the different vasodilatory effects of the K+ channel openers levcromakalim and 5-amino-N- [2-(2-chlorophenyl)ethyl]-N'-cyano-3-pyridinecarboxamidine (KRN4884), and the Ca2+ channel blocker nifedipine in the rat aorta. KRN 4884 (10(-10)-10(-5) M) and nifedipine (10(-10)-10(-5) M) produced concentration-dependent relaxation in the rat aorta precontracted by 25 mM KCl. The K+ channel blocker glibenclamide (1 microM) inhibited the relaxation induced by KRN4884 but did not influence nifedipine-induced relaxation. KRN4884 had almost no effect on contraction induced by 80 mM KCl, whereas nifedipine completely relaxed the muscle precontracted by 80 mM KCl, whereas nifedipine completely relaxed the muscle precontracted by 80 mM KCl. These results indicate that KRN4884 is a K+ channel opener. We investigated the relaxant effects of KRN4884 (10(-10)-10(-5) M), levcromakalim (10(-9)-10(-5) M) and nifedipine (10(-9)-10(-5) M) on A23187 (1 microM)-induced contraction. KRN4884 and levcromakalim had a potent relaxant effect but nifedipine only a weak effect on the smooth muscle contracted by A23187. Glibenclamide (1 microM) inhibited the relaxation induced by KRN4884 and levcromakalim, but did not influence the nifedipine-induced relaxation. KRN4884 (1 microM) produced a larger relaxation of A23187-induced contraction but had little effect on the increase in intracellular [Ca2+] induced by A23187. These results suggest that KRN4884 is a specific K+ channel opener and its vasodilating mechanisms involve not only deactivation of Ca2+ channels but also a decrease in the Ca2+ sensitivity of contractile elements.
我们研究了钾通道开放剂左旋克罗卡林和5-氨基-N-[2-(2-氯苯基)乙基]-N'-氰基-3-吡啶甲脒（KRN4884）以及钙通道阻滞剂硝苯地平在大鼠主动脉中的不同血管舒张作用。KRN 4884（10⁻¹⁰ - 10⁻⁵ M）和硝苯地平（10⁻¹⁰ - 10⁻⁵ M）在由25 mM氯化钾预收缩的大鼠主动脉中产生浓度依赖性舒张。钾通道阻滞剂格列本脲（1 μM）抑制KRN4884诱导的舒张，但不影响硝苯地平诱导的舒张。KRN4884对80 mM氯化钾诱导的收缩几乎没有影响，而硝苯地平能使由80 mM氯化钾预收缩的肌肉完全舒张。这些结果表明KRN4884是一种钾通道开放剂。我们研究了KRN4884（10⁻¹⁰ - 10⁻⁵ M）、左旋克罗卡林（10⁻⁹ - 10⁻⁵ M）和硝苯地平（10⁻⁹ - 10⁻⁵ M）对A23187（1 μM）诱导的收缩的舒张作用。KRN4884和左旋克罗卡林有强效舒张作用，而硝苯地平对由A23187收缩的平滑肌只有微弱作用。格列本脲（1 μM）抑制KRN4884和左旋克罗卡林诱导的舒张，但不影响硝苯地平诱导的舒张。KRN4884（1 μM）对A23187诱导的收缩产生更大的舒张作用，但对A23187诱导的细胞内[Ca²⁺]升高几乎没有影响。这些结果表明KRN4884是一种特异性钾通道开放剂，其血管舒张机制不仅涉及钙通道失活，还涉及收缩成分对钙的敏感性降低。
