Antianginal effects of FK409, a new spontaneous NO releaser.
1. The aim of this study was to compare antianginal effects of (+/-)-(E)-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexeneamide (FK409), a new spontaneous nitric oxide releaser, with those of isosorbide dinitrate (ISDN). We used two types of rat angina model; methacholine- and arginine vasopressin (AVP)-induced coronary vasospasm models. 2. In the in vitro study, FK409 showed 80 times more potent vasorelaxant effect in dog isolated coronary artery than ISDN (EC50 = 16.7 +/- 4.8 and 1340 +/- 320 nM, respectively). 3. In the rat methacholine-induced coronary vasospasm model, FK409 suppressed the elevation of ST segment dose-dependently and significantly at 0.1 mg kg-1, i.d. On the other hand, ISDN suppressed it significantly at 3.2 mg kg-1, i.d. In addition, the efficacy of 3.2 mg kg-1 ISDN in the model was almost the same as that of 0.1 mg kg-1 FK409. 4. In the above experiments, FK409 and ISDN decreased mean blood pressure significantly at the maximum dose tested (1.0 mg kg-1, i.d. and 3.2 mg kg-1, i.d., respectively) but did not change heart rate at these doses. Therefore, the hypotensive effect of FK409 was 10 times weaker than the antianginal effect of the compound, while those of ISDN were almost the same. 5. In the rat AVP-induced coronary vasospasm model, 32 mg kg-1 FK409 significantly inhibited the depression of ST segment 60 min after oral administration. On the other hand, 32 mg kg-1 ISDN did not inhibit it at 60 and 120 min after oral administration. 6. In conclusion, FK409 inhibits coronary vasospasm more potently in two types of rat angina models than ISDN. In addition, FK409 shows an antianginal effect more selectively that a hypotensive effect,compared with ISDN.
Kita
Y
Y
Department of Pharmacology, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Ozaki
R
R
Sakai
S
S
Sugimoto
T
T
Hirasawa
Y
Y
Ohtsuka
M
M
Senoh
H
H
Yoshida
K
K
Maeda
K
K
D000788:Angina Pectoris, Variant / Q000139:chemically induced / Q000188:drug therapy*; D000818:Animals; D001127:Arginine Vasopressin; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects; D066298:In Vitro Techniques; D007548:Isosorbide Dinitrate / Q000494:pharmacology; D008688:Methacholine Compounds; D009569:Nitric Oxide / Q000378:metabolism*; D009574:Nitro Compounds / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000627:therapeutic use*
D008688:Methacholine Compounds; D009574:Nitro Compounds; D014665:Vasodilator Agents; D001127:Arginine Vasopressin; D009569:Nitric Oxide; C061872:FK 409; D007548:Isosorbide Dinitrate