ANTIANGINAL EFFECTS OF FK409, A NEW SPONTANEOUS NO RELEASER

1 The aim of this study was to compare antianginal effects )-ethyl-2-[ (E)-hydroxyimino]-5-nitro-3-hexeneamide (FK409), a new spontaneous nit ric 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, FK4 09 showed 80 times more potent vasorelaxant effect in dog isolated cor onary artery than ISDN (EC(50) = 16.7 +/- 4.8 and 1340 +/- 320 nM, res pectively). 3 In the rat methacholine-induced coronary vasospasm model , FK409 suppressed the elevation of ST segment dose-dependently and si gnificantly 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 k g(-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 hear t rate at these doses. Therefore, the hypotensive effect of FK409 was 10 times weaker than the antianginal effect of the compound, while tho se of ISDN were almost the same. 5 In the rat AVP-induced coronary vas ospasm model, 32 mg kg(-1) FK409 significantly inbibited the depressio n of ST segment 60 min after oral administration. On the other hand, 3 2 mg kg(-1);ISDN did not inhibit it at 60 and 120 min after oral admin istration. 6 In conclusion, FK409 inbibits coronary vasospasm more pot ently 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.