FR144420, A NOVEL, SLOW, NITRIC OXIDE-RELEASING AGENT

被引：24

作者：

KITA, Y ^{[1
]}

OHKUBO, K ^{[1
]}

HIRASAWA, Y ^{[1
]}

KATAYAMA, Y ^{[1
]}

OHNO, M ^{[1
]}

NISHINO, S ^{[1
]}

KATO, M ^{[1
]}

YOSHIDA, K ^{[1
]}

机构：

[1] DOJINDO LABS,MASHIKI,KUMAMOTO 86122,JAPAN

来源：

EUROPEAN JOURNAL OF PHARMACOLOGY | 1995年 / 275卷 / 02期

关键词：

FR144420; FK409; NITRIC OXIDE (NO);

D O I：

10.1016/0014-2999(94)00750-2

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

We report that (+/-)-(E)-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexeneamide (FK409) decomposes and releases nitric oxide (NO) spontaneously in solution. (+/-)N-[(E)-4-Ethyl-3-[(Z)-hydroxyimino]-5-nitro-3-hexen-1-yl]-3-pyridinecarboxamide (FR144420) was synthesized with the aim of discovering a compound with longer duration of effects in vivo, compared with FK409. FR144420, like FK409, released NO spontaneously in solution, but the amount of NO released from FR144420 during a 5-min incubation was half the amount from FK409. In addition, FR144420 spontaneously decomposed and generated nitrite, which is an oxidative metabolite of NO, at half the rate of FK409. In a vasorelaxant study with isolated rat aorta, FR144420 had a weaker potency than FK409 (EC(50) = 54 and 8.1 nM, respectively). In in vivo studies, FR144420 decreased mean blood pressure immediately after intravenous and oral administration to conscious rats. The maximum hypotensive effects of FR144420 were less than those of FK409. However, the durations of FR144420-induced (i.v. and p.o.) hypotensive effects were longer than those of FK409-induced effects. In conclusion, FR144420 is more stable and releases NO more slowly in solution than does FK409. In in vivo experiments, FR144420 showed a longer duration of effects than FK409. FR144420 may be very useful for investigating the in vivo actions of NO.

引用

页码：125 / 130

页数：6

共 12 条

[1]

Akaike, Yoshida, Miyamoto, Sato, Kohno, Sasamoto, Miyazaki, Ueda, Maeda, Antagonistic action of imidazolineoxyl N-oxides against endothelium-derived relaxing factor/·NO through a radical reaction, Biochemistry, 32, (1993)

[2]

Bell, O'Neill, Burgison, Determination of the oil/water distribution coefficients of glyceryl trinitrate and two similar nitrate esters, J. Pharmacol. Sci., 52, (1963)

[3]

Hino, Iwami, Okamoto, Yoshida, Haruta, Okuhara, Hosoda, Kofsak, Aoki, Imanaka, FK409, a novel vasodilator isolated from the acid-treated fermentation broth of Streptomyces griseosporeus. I. Taxonomy, fermentation, isolation, and physio-chemical and biological characteristics, J. Antibiot., 42, (1989)

[4]

Ignarro, Lippon, Edwards, Baricos, Gruetter, Hyman, Kadowitz, Mechanism of vascular smooth muscle relaxation by organic nitrates, nitrites, nitroprusside and nitric oxide: evidence for the involvement of s-nitrosothiols as active intermediates, J. Pharmcol. Exp. Ther., 218, (1981)

[5]

Isono, Sato, Koibuchi, Sakai, Yamamoto, Ozaki, Mori, Kohsaka, Ohtsuka, Effects of FK409, a novel nitric oxide donor, on acute experimental myocardial ischenia, Jpn. J. Pharmacol., 62, (1993)

[6]

Isono, Sato, Yamamoto, Sawada, Yamazaki, Miura, Furuichi, Ozaki, Koibuchi, Ohtsuka, Tolerance to the vascular effect of a novel nitric oxide-donating vasodilator, FK409, Eur. J. Pharmacol., 260, (1994)

[7]

Kita, Hirasawa, Maeda, Nishio, Yoshida, Spontaneous nitric oxide release accounts for the potent pharmacological actions of FK409, Eur. J. Pharmacol., 257, (1994)

[8]

Kita, Ozaki, Sakai, Sugimoto, Hirasawa, Ohtsuka, Senoh, Yoshida, Maeda, Antianginal effects of FK409, a new spontaneous NO releaser, Br. J. Pharmacol., 113, (1994)

[9]

Kita, Sugimoto, Hirasawa, Yoshida, Maeda, Close correlation of the cardioprotective effect of FK409, a spontaneous NO releaser, with an increase in plasma cyclic GMP level, Br. J. Pharmacol., 113, (1994)

[10]

Kita, Hirasawa, Yoshida, Maeda, Antiplatelet activities of FK409, a new spontaneous NO releaser, Br. J. Pharmacol., 113, (1994)

← 1 2 →