Effect of FK409, a novel nitric oxide donor, on acute experimental myocardial ischemia.
The anti-ischemic heart effect of (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]- 5-nitro-3-hexenamide (FK409), a novel nitric oxide donor, was studied in dog and rat preparations in vivo and in vitro. In anesthetized dogs with partially occluded coronary artery that were subjected to atrial pacing at a constant blood pressure, FK409 (1-100 micrograms/kg, i.v.) suppressed the ST-segment elevation on epicardial electrocardiograms. Glyceryl trinitrate (GTN; 10, 32 micrograms/kg) or dipyridamole (1000 micrograms/kg) failed to suppress the ST-segment elevation, although continuous i.v. infusion of GTN (32, 100 micrograms/kg/min) was effective. FK409 also suppressed the ST-segment elevation induced by methacholine in anesthetized rats by both i.v. (10, 100 micrograms/kg) and intraduodenal (i.d., 100, 1000 micrograms/kg) injections, while GTN (100 micrograms/kg, i.v.; 1000 micrograms/kg, i.d.) was effective only by the i.v. route. FK409 (0.32 microgram/kg/min, i.v.) and GTN (10 micrograms/kg/min) increased the blood flows of the endomyocardium (ENDO) and the epicardium (EPI) and the flow ratio of ENDO/EPI in the ischemic zone in anesthetized dogs with occluded coronary artery. Furthermore, in isolated dog vascular preparations, FK409 (4.6 x 10(-10)-4.6 x 10(-7) M) had a greater vasorelaxing effect on the large coronary artery [2.0-2.5-mm outer diameter (od)] than on the small coronary artery (0.3-0.5-mm od) or the saphenous artery. The results suggest that FK409 protects against acute experimental myocardial ischemia through relaxation of the large conductive coronary artery, and may be a useful oral drug for the treatment of angina pectoris.
Isono
T
T
Pharmacological Division, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Sato
N
N
Koibuchi
Y
Y
Sakai
S
S
Yamamoto
T
T
Ozaki
R
R
Mori
J
J
Kohsaka
M
M
Ohtsuka
M
M
D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects; D004176:Dipyridamole / Q000494:pharmacology; D004195:Disease Models, Animal; D004285:Dogs; D004558:Electric Stimulation; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D016210:Methacholine Chloride / Q000633:toxicity; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism*; D009574:Nitro Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D005996:Nitroglycerin / Q000494:pharmacology; D051381:Rats; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use*
D009574:Nitro Compounds; D014665:Vasodilator Agents; D016210:Methacholine Chloride; D009569:Nitric Oxide; D004176:Dipyridamole; C061872:FK 409; D005996:Nitroglycerin