Antianginal effects of FR144420, a novel slow nitric oxide-releasing agent.
The aim of this study was to compare the antianginal effects of two compounds that release nitric oxide (NO) spontaneously, i.e. (+/-)-N-[(E)-4-ethyl-3-[(Z-hydroxyimino]-5-nitro-3-hexenyl] -3-pyridinecarboxamide (FR144420) and (+/-)-(E)-ethyl-2-[(E)-hydroxyimino] -5-nitro-3-hexenamide (FK409), in two different rat models of coronary vasospasm. In the rat methacholine-induced coronary vasospasm model, FR144420 suppressed the elevation of the ST segment dose dependently and significantly at 1.0 mg/kg, i.d. 185 min after its administration. FK409 suppressed the ST elevation only 5 min after its administration at 1.0 mg/kg, i.d. FR144420 and FK409 significantly decreased mean blood pressure at all doses tested only 5 min after their intraduodenal administration, but did not change heart rate at any time. Although the suppression of the ST elevation by FK409 had the same duration as its hypotensive effect, the FR144420-induced suppression of the ST elevation lasted longer than its hypotensive effect. In the rat vasopressin-induced coronary vasospasm model, FR144420 (32 mg/kg) significantly inhibited the depression of the ST segment both 60 min and 120 min after oral administration, whereas FK409 (32 mg/kg) significantly inhibited this ST depression only 60 min after oral administration. These data suggest that FR144420 inhibits coronary vasospasm for longer than FK409 does and particularly shows more prolonged antianginal effects than hypotensive effects in the methacholine-induced coronary vasospasm model. Thus FR144420 is expected to be a useful NO releaser for investigating the in vivo actions of NO.
Hirasawa
Y
Y
New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Sugimoto
T
T
Fukuyama
S
S
Kato
Y
Y
Takamatu
H
H
Ohno
M
M
Nishino
S
S
Kato
M
M
Maeda
K
K
Seki
J
J
Kita
Y
Y
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003329:Coronary Vasospasm / Q000139:chemically induced / Q000188:drug therapy*; D004562:Electrocardiography / Q000187:drug effects; D008297:Male; D016210:Methacholine Chloride / Q000633:toxicity; D009539:Nicotinic Acids / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000737:chemistry; D009574:Nitro Compounds / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000627:therapeutic use*; D014667:Vasopressins / Q000633:toxicity
C094368:FR 144420; D009539:Nicotinic Acids; D009574:Nitro Compounds; D014665:Vasodilator Agents; D016210:Methacholine Chloride; D014667:Vasopressins; D009569:Nitric Oxide; C061872:FK 409