Takizawa S, Hori M, Ozaki H, Karaki H
Department of Veterinary Pharmacology, Faculty of Agriculture, University of Tokyo, Japan.
Eur J Pharmacol. 1993 Dec 21;250(3):431-7. doi: 10.1016/0014-2999(93)90030-l.
The effects of isoquinoline derivatives, HA1077 (1-[5-isoquinolinesulfonyl]-homopiperazine) and H-7 (1-[5-isoquinolinesulfonyl]-2-methylpiperazine), on cytosolic Ca2+ levels ([Ca2+]i) and muscle tension were examined in vascular smooth muscle of rat aorta. High K+ (72.7 mM) and norepinephrine (1 microM) induced a sustained contraction with a sustained increase in [Ca2+]i. HA1077 and H-7 (3-10 microM) inhibited the increase in muscle tension more strongly than the increase in [Ca2+]i. Verapamil (10 microM) completely inhibited the increase in [Ca2+]i and the contraction induced by high K+ whereas it inhibited the increase in [Ca2+]i more strongly than the contraction due to norepinephrine. The verapamil-insensitive portion of the norepinephrine-induced contraction was inhibited by HA1077 or H-7. In Ca(2+)-free solution, 0.1 microM norepinephrine induced a transient increase in [Ca2+]i and muscle tension. The transient contraction was inhibited by 10 microM HA1077 or 10 microM H-7 without inhibiting the increase in [Ca2+]i. 12-Deoxyphorbol 13-isobutyrate (DPB) (1 microM) caused a sustained contraction, and this contraction was inhibited by HA1077 and H-7 at similar concentrations needed to inhibit the contractions induced by high K+ or norepinephrine. In rabbit mesenteric artery permeabilized with Staphylococcus aureus alpha-toxin, 100 microM HA1077 and 100 microM H-7 inhibited the contraction induced by 0.3 microM Ca2+. These results suggest that the inhibitory effects of isoquinoline derivatives, HA1077 and H-7, are due to a decrease in [Ca2+]i and in the Ca2+ sensitivity of contractile elements in vascular smooth muscle.
研究了异喹啉衍生物HA1077（1-[5-异喹啉磺酰基]-高哌嗪）和H-7（1-[5-异喹啉磺酰基]-2-甲基哌嗪）对大鼠主动脉血管平滑肌胞浆钙水平（[Ca2+]i）和肌肉张力的影响。高钾（72.7 mM）和去甲肾上腺素（1 microM）诱导持续收缩，并伴有[Ca2+]i持续升高。HA1077和H-7（3 - 10 microM）对肌肉张力升高的抑制作用比对[Ca2+]i升高的抑制作用更强。维拉帕米（10 microM）完全抑制高钾诱导的[Ca2+]i升高和收缩，而它对[Ca2+]i升高的抑制作用比对去甲肾上腺素引起的收缩的抑制作用更强。去甲肾上腺素诱导的收缩中维拉帕米不敏感部分被HA1077或H-7抑制。在无钙溶液中，0.1 microM去甲肾上腺素诱导[Ca2+]i和肌肉张力短暂升高。短暂收缩被10 microM HA1077或10 microM H-7抑制，而不抑制[Ca2+]i升高。12-脱氧佛波醇13-异丁酸酯（DPB）（1 microM）引起持续收缩，该收缩被HA1077和H-7以抑制高钾或去甲肾上腺素诱导的收缩所需的相似浓度抑制。在经金黄色葡萄球菌α-毒素通透的兔肠系膜动脉中，100 microM HA1077和100 microM H-7抑制0.3 microM Ca2+诱导的收缩。这些结果表明，异喹啉衍生物HA1077和H-7的抑制作用是由于血管平滑肌中[Ca2+]i降低以及收缩元件对Ca2+的敏感性降低。
