EFFECT OF FK409, A NOVEL NITRIC-OXIDE DONOR, ON ACUTE EXPERIMENTAL MYOCARDIAL-ISCHEMIA

The anti-ischemic heart effect of -4-ethyl-2-[(E)-hydroxyimino]-5-nitr o-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 pacin g at a constant blood pressure, FK409 (1 - 100 mug/kg, i.v.) suppresse d the ST-segment elevation on epicardial electrocardiograms. Glyceryl trinitrate (GTN; 10, 32 mug/kg) or dipyridamole (1000 mug/kg) failed t o suppress the ST-segment elevation, although continuous i.v. infusion of GTN (32, 100 mug/kg/min) was effective. FK409 also suppressed the ST-segment elevation induced by methacholine in anesthetized rats by b oth i.v. (10, 100 mug/kg) and intraduodenal (i.d., 100, 1000 mug/kg) i njections, while GTN (100 mug/kg, i.v.; 1000 mug/kg, i.d.) was effecti ve only by the i.v. route. FK409 (0.32 mug/kg/min, i.v.) and GTN (10 m ug/kg/min) increased the blood flows of the endomyocardium (ENDO) and the epicardium (EPI) and the flow ratio of ENDO/EPI in the ischemic zo ne 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 prot ects against acute experimental myocardial ischemia through relaxation of the large conductive coronary artery, and may be a useful oral dru g for the treatment of angina pectoris.