Toshiko Sugimoto

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, 32mg 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.

Close correlation of the cardioprotective effect of FK409, a spontaneous NO releaser, with an increase in plasma cyclic GMP level

FK409 ((±)‐(E)‐ethyl‐2‐[(E)‐hydroxyimino]‐5‐nitro‐3‐hexeneamide), which has been reported by us to be a new spontaneous nitric oxide (NO) releaser, prevented myocardial infarction following occlusion and reperfusion in rat coronary artery and increased plasma cyclic GMP level in rats, dose‐dependently and significantly at 32 mg kg−1. Isosorbide dinitrate (ISDN), which is the most popular orally active NO donor used in the treatment of ischaemic cardiovascular diseases, did not show significant effects at 32 mg kg−1 in either experiment. Therefore, it is suggested that FK409 can attenuate myocardial injury during ischaemia and reperfusion in contrast to ISDN and a change in plasma cyclic GMP level may serve as an indicator of the cardioprotective effect of NO‐releasing drugs.

Preischemic and postischemic treatment with a new Na+/H+-exchange inhibitor, FR183998, shows cardioprotective effects in rats with cardiac ischemia and reperfusion

This study describes the pharmacologic profile of a new Na+/H(+)-exchange inhibitor, FR183998, in anesthetized rats. FR183998 had a potent inhibitory effect on Na+/H+ exchange of rat lymphocytes with median inhibitory (IC50) value of 0.3 nM. Treatment with FR183998 (0.01-0.32 mg/kg, i.v.) reduced or completely abolished ventricular fibrillation and mortality induced by 5-min ischemia followed by reperfusion, when it was administered not only 5 min before ischemia but also 1 min before reperfusion. Myocardial infarct size induced by 30-min ischemia and 60-min reperfusion was reduced significantly in a dose-dependent manner by FR183998 (0.1-1.0 mg/kg, i.v.) when the drug was administered preischemically or at an early phase of ischemia. The ventricular tachycardia and the ventricular fibrillation observed during the ischemic period also were suppressed significantly. These results indicate that FR183998 has a strong inhibitory effect on Na+/H+ exchange and suggest that treatment with FR183998 either before or immediately after the onset of ischemia can prevent the occurrence of arrhythmias and myocardial cell necrosis in situations of ischemia and reperfusion.

Antianginal effects of FR144420, a novel slow nitric oxide-releasing agent

The aim of this study was to compare the antianginal effects of two compounds that release nitric oxide (NO) spontaneously, i.e. (+/-)-N-[(E)-4-ethyl-3-[(Z-hydroxyimino]-5-nitro-3-hexenyl] -3-pyridinecarboxamide (FR144420) and (+/-)-(E)-ethyl-2-[(E)-hydroxyimino] -5-nitro-3-hexenamide (FK409), in two different rat models of coronary vasospasm. In the rat methacholine-induced coronary vasospasm model, FR144420 suppressed the elevation of the ST segment dose dependently and significantly at 1.0 mg/kg, i.d. 185 min after its administration. FK409 suppressed the ST elevation only 5 min after its administration at 1.0 mg/kg, i.d. FR144420 and FK409 significantly decreased mean blood pressure at all doses tested only 5 min after their intraduodenal administration, but did not change heart rate at any time. Although the suppression of the ST elevation by FK409 had the same duration as its hypotensive effect, the FR144420-induced suppression of the ST elevation lasted longer than its hypotensive effect. In the rat vasopressin-induced coronary vasospasm model, FR144420 (32 mg/kg) significantly inhibited the depression of the ST segment both 60 min and 120 min after oral administration, whereas FK409 (32 mg/kg) significantly inhibited this ST depression only 60 min after oral administration. These data suggest that FR144420 inhibits coronary vasospasm for longer than FK409 does and particularly shows more prolonged antianginal effects than hypotensive effects in the methacholine-induced coronary vasospasm model. Thus FR144420 is expected to be a useful NO releaser for investigating the in vivo actions of NO.