Trongvanichnam K, Mitsui-Saito M, Ozaki H, Karaki H
Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, University of Tokyo, Japan.
Eur J Pharmacol. 1996 May 6;303(1-2):39-45. doi: 10.1016/0014-2999(96)00031-3.
It has been shown that oral administration of 0.038-0.15 mg/kg levcromakalim elicits a dose-related antihypertensive response in spontaneously hypertensive rats (Clapham et al., Arzneim. Forsch. 41 (1991) 385). In the present study, we examined the effects of long term administration of a high dose of levcromakalim on in vitro vascular contractility. Levcromakalim (2.25 mg/kg/day) was administered to the rats for 2 weeks and the thoracic aorta was then isolated. The levcromakalim treatment markedly reduced the relaxant effect of levcromakalim itself on norepinephrine-induced contraction. Relaxant effects of sodium nitroprusside and 8-bromo-cGMP were also attenuated by the levcromakalim treatment, although the relaxant effects of verapamil and forskolin were unchanged. The levcromakalim treatment decreased the threshold concentration for KCl and norepinephrine to induce contraction. The chronic levcromakalim treatment did not affect the cGMP production due to 3-isobutyl-1-methylxanthine and/or sodium nitroprusside. The aorta isolated from spontaneous hypertensive rats did not exhibit spontaneous activity in normal solution. After treatment with levcromakalim, however, the aorta showed spontaneous rhythmic contractions. Verapamil (10 microM) completely suppressed the spontaneous activity and decreased the basal tension below the original level. Similar to the effects of chronic treatment with levcromakalim, high-K+ solution (15.4 mM) augmented the contractile response to norepinephrine in the aorta of normotensive rats and induced rhythmic contractions in the aorta of spontaneously hypertensive rats. These results suggest that chronic treatment with a high dose of levcromakalim attenuates not only the effects of levcromakalim itself but also the cGMP-mediated relaxation, possibly by desensitizing the K+ channel.
研究表明，对自发性高血压大鼠口服0.038 - 0.15 mg/kg的左卡尼汀可引发剂量相关的降压反应（克拉彭等人，《药物研究》41 (1991) 385）。在本研究中，我们检测了长期给予高剂量左卡尼汀对体外血管收缩性的影响。将左卡尼汀（2.25 mg/kg/天）给予大鼠2周，然后分离胸主动脉。左卡尼汀治疗显著降低了左卡尼汀自身对去甲肾上腺素诱导收缩的舒张作用。硝普钠和8 - 溴 - cGMP的舒张作用也因左卡尼汀治疗而减弱，尽管维拉帕米和福斯可林的舒张作用未改变。左卡尼汀治疗降低了氯化钾和去甲肾上腺素诱导收缩的阈浓度。长期左卡尼汀治疗不影响由3 - 异丁基 - 1 - 甲基黄嘌呤和/或硝普钠引起的cGMP生成。从自发性高血压大鼠分离的主动脉在正常溶液中未表现出自发活动。然而，经左卡尼汀治疗后，主动脉出现自发节律性收缩。维拉帕米（10 μM）完全抑制了自发活动，并使基础张力降至原始水平以下。与长期左卡尼汀治疗的效果相似，高钾溶液（15.4 mM）增强了正常血压大鼠主动脉对去甲肾上腺素的收缩反应，并在自发性高血压大鼠主动脉中诱导节律性收缩。这些结果表明，高剂量左卡尼汀的长期治疗不仅减弱了左卡尼汀自身的作用，还减弱了cGMP介导的舒张作用，可能是通过使钾通道脱敏实现的。
