Cardiovascular activity of FK409, a new drug for ischemic heart diseases, on dog in vitro and in vivo preparations

Ohtsuka, Minora; Koibuchi, Yasushi; Sakai, Shigeru; Sato, Natsuki; Isono, Toyokazu; Sudo, Yuji; Ono, Takaharu; Mori, Jo; Shibayama, Fumio

doi:10.1016/0014-2999(90)94401-i

Cited by 9 publications

(8 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Reprinted with permission from ref. 16. Ohtsuka et al (29) and Isono et al (16) further demonstrated that the coronary vasodilator activity of FK409 was greater on the large vessels [2.0-2.5-mm outer diameter (od)] than on the small ones (0.3-4.5-mm od); as shown in Fig. 2, FK409 was more potent on the large vessels than on the small coronary arteries contracted by KCl(35 mM).…”

mentioning

confidence: 75%

FK409: A New Vasodilator with Nitric Oxide‐donating Ability

Ohtsuka

Honbo

Esumi

1994

Cardiovascular Drug Reviews

View full text Add to dashboard Cite

Endothelium-derived relaxing factor (EDRF), which plays important regulatory roles in the cardiovascular system (10,26,30), has recently been identified as nitric oxide (26,27). Generation of nitric oxide requires the presence of functionally normal endothelium, and any alteration of its function could contribute to the genesis of a wide variety of diseases. Recent studies have demonstrated decreased endothelium-dependent relaxation in response to pharmacological stimulation of human atherosclerotic coronary arteries ( 1,2, 7,8), of vessels from atherosclerotic rabbits (13,41,44) or other hypertensive animals (21,22,39,43). Therefore, compounds which have an ability to donate nitric oxide seem to represent likely candidates for use in the treatment of such cardiovascular diseases as coronary vasospasm, myocardial ischemia, or hypertension.FK409 is a novel semisynthetic fermentation product of Streptomyces griseosporeus with vasodilator and antiplatelet activities (14). FK409 has a nitric oxide-donating ability, and exerts a potent dilating effect on dog and rabbit isolated arteries, especially coronary arteries, through elevation of 3' ,5'-cyclic guanosine monophosphate (cyclic GMP) levels in vascular smooth muscle.FK409 has no nitro ester in its chemical structure, and, compared with glyceryl trinitrate (GTN), elicits less selftolerance to its vasodilator effect and relatively little crosstolerance to organic nitrates. Thus, FK409 appears to be a unique vasodilator with the ability to accumulate cyclic GMP. This article reviews the chemistry, pharmacology, pharmacokinetics, and toxicology of FK409 in animals and clinical findings in humans. CHEMISTRY The chemical structure of FK409, (*)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide, is shown in Fig. 1. The compound was discovered in the search for agents with vasodilator and antiplatelet activities in fermentation products of Streptomyces

show abstract

mentioning

confidence: 75%

FK409: A New Vasodilator with Nitric Oxide‐donating Ability

Ohtsuka

Honbo

Esumi

1994

Cardiovascular Drug Reviews

View full text Add to dashboard Cite

show abstract

“…FK409 was found to be an effective pulmonary vasorelaxant in both main and intralobar pulmonary arteries from rats. The potency values for FK409 in these pulmonary artery preparations were greater than was found in rabbit aorta (Shibata et al , 1991), lower than in dog coronary arteries (Yamada et al , 1991; Kita et al , 1994) but comparable to values in a range of other systemic artery preparations from dogs (Ohtsuka et al , 1990). The observations that the effects of FK409 on rat main pulmonary artery were inhibited by methylene blue, but not by endothelial removal, are consistent with its classification as an NO donor drug.…”

Section: Discussionmentioning

confidence: 98%

“…It is interesting to note that in another vascular bed, i.e. the coronary vasculature, FK409 is likewise less potent on small vessels than on large vessels (Ohtsuka et al , 1990). It will be interesting to know whether the mechanism underlying this potency difference between vessels of different sizes is the same in the pulmonary and coronary circulations.…”

Section: Discussionmentioning

confidence: 99%

“…It releases NO from its structure spontaneously without requiring enzymic activation (Kita et al , 1994). The vasodilator properties of this drug have been described in vitro in a number of systemic arteries (Ohtsuka et al , 1990; Shibata et al , 1991; Yamada et al , 1991; Isono et al , 1993). Its potency has been found to vary in different systemic artery types and it is particularly potent in coronary vessels (Ohtsuka et al , 1990).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The in vitro pulmonary vascular effects of FK409 (nitric oxide donor): a study in normotensive and pulmonary hypertensive rats

Wanstall

Kaye

Gambino

1997

British J Pharmacology

View full text Add to dashboard Cite

1 Vasorelaxant responses to the nitric oxide (NO) donor, FK409 ((+)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide), were evaluated on precontracted isolated ring preparations of main pulmonary artery and intralobar pulmonary artery from rats. 2 On main pulmonary artery FK409 fully reversed the precontractions. Responses were inhibited by methylene blue but were independent of the endothelium. The potency (7log EC 50 ) of FK409 was the same on preparations contracted with noradrenaline (7.62) or the thromboxane-mimetic, U44619 (7.63). 3 On intralobar pulmonary artery FK409 caused only 80% reversal of the precontraction and was 2 fold less potent than on main pulmonary artery. These di erences in maximum response and potency between main and intralobar arteries are in keeping with previous ®ndings with other NO donors. 4 Pulmonary hypertension was induced in rats by chronic exposure to hypoxia (10% O 2 ) for 1 or 4 weeks. Main pulmonary arteries from 1 week hypoxic rats had inherent tone and showed spontaneous contractile activity. In these arteries FK409 reversed not only the precontraction induced by noradrenaline but also the inherent tone. However, FK409 was 17 fold less potent than in control arteries, re¯ecting previous ®ndings with other NO donors. Main pulmonary arteries from 4 week hypoxic rats had minimal inherent tone and were quiescent and FK409 was 4.5 fold less potent than in control arteries. In intralobar pulmonary arteries from 4 week hypoxic rats FK409 was 12 fold less potent than in controls. 5 Treatment of arteries with either (a) in vitro hypoxic conditions (PO 2 of solution in organ bath 510 mmHg) or (b) superoxide dismutase (SOD; 150 u ml 71 ) together with catalase (1200 u ml 71 ) signi®cantly increased the potency of FK409 in preparations from hypoxic rats but had no e ect on the potency in control preparations. Neither SOD nor catalase, alone, nor the nitric oxide synthase inhibitor, N G -nitro-L-arginine methyl ester, had any e ect on the potency of FK409 in preparations from control or hypoxic rats. 6 It is concluded that the reduction in potency of FK409 seen in pulmonary arteries from rats with chronic hypoxic pulmonary hypertension may be due in part to the presence of one or more reactive oxygen species (either hydroxyl or superoxide plus hydrogen peroxide).

show abstract

“…The differ ence in their suppressing effects on methacholine-induced ECG changes after i.d.-administration is probably due to a difference in their absorption from the intestinal tract or in their first-pass extraction in animals, as the doses of FK409 and GTN we used were based on their in vitro vasorelaxing activities (2)(3)(4)(5). GTN is well known to be degraded during its first pass through the liver.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Properties of Blood Pressure and Heart Rate Control in Suncus

Isono¹,

Sato²,

Koibuchi³

et al. 1993

Japanese Journal of Pharmacology

View full text Add to dashboard Cite

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.

show abstract

Cardiovascular activity of FK409, a new drug for ischemic heart diseases, on dog in vitro and in vivo preparations

Cited by 9 publications

References 0 publications

FK409: A New Vasodilator with Nitric Oxide‐donating Ability

FK409: A New Vasodilator with Nitric Oxide‐donating Ability

The in vitro pulmonary vascular effects of FK409 (nitric oxide donor): a study in normotensive and pulmonary hypertensive rats

Pharmacological Properties of Blood Pressure and Heart Rate Control in Suncus

Contact Info

Product

Resources

About