Pharmacological Properties of Blood Pressure and Heart Rate Control in Suncus

Abstract

ABSTRACT-Theanti-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 pg/kg, i.v.) suppressed the ST-segment elevation on epicardial electrocar diograms. Glyceryl trinitrate (GTN; 10, 32 pig/kg) or dipyridamole (1000 ,ug/kg) failed to suppress the ST segment elevation, although continuous i.v. infusion of GTN (32, 100 pg/kg/min) was effective. FK409 also suppressed the ST-segment elevation induced by methacholine in anesthetized rats by both i.v. (10, 100,ug/kg) and intraduodenal (i.d., 100, 1000 pg/kg) injections, while GTN (100 pg/kg, i.v.; 1000 pg/kg, i.d.) was effective only by the i.v. route. FK409 (0.32 pg/kg/min, i.v.) and GTN (10 pg/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.

Differing rates of loss ofDPC4 expression and ofp53 overexpression among carcinomas of the proximal and distal bile ducts

“…It is relatively unstable, with a half‐life of approximately 45 min at 37°C in phosphate buffer. FK409 has been reported to attenuate experimental liver, cardiac, lung, and renal I/R injury14–17. We have recently shown that FK409 can improve survival and reduce microcirculatory disturbances after intestinal I/R injury18.…”

Hydroxyimine NO-Donors; FK409 and Derivatives

“…Isono et al [15] extended this work by evaluating FK409 on coronary ischemia using the canine open chest, occluded coronary artery model. When the heart rate was increased by pacing for 5 minutes the electrocardiogram (ECG) showed an ST elevation which was more potently inhibited by FK409 (10 ug/kg, i.v.)…”

FK409: A New Vasodilator with Nitric Oxide‐donating Ability

“…M . OHTSUKA ET AL.. 5 (16). It has been reported that GTN acts preferentially on the large canine coronary arteries in in vitro, this effect may contribute to the antianginal effect of the drug (36).…”

“…From the in vitro findings that FK409 acts preferentially on the large coronary artery (16,29,35), the compound may be expected to facilitate redistribution of the blood to the ischemic region of the myocardium due to dilation of the large conductive coronary or collateral vessels.…”

“…Isono et al (16) studied the effect of FK409 on regional myocardial blood flow in anesthetized dogs with coronary artery occlusion. The regional myocardial blood flow was determined by the colored microsphere method (12).…”