THE IN-VITRO PULMONARY VASCULAR EFFECTS OF FK409 (NITRIC-OXIDE DONOR)- A STUDY IN NORMOTENSIVE AND PULMONARY HYPERTENSIVE RATS

1 Vasorelaxant responses to the nitric oxide (NO) donor, FK(409 -ethyl -2-[(E)-hydroxqimino]-5-nitro-3-hcxenamide), were evaluated on precont racted isolated ring preparations of main pulmonary artery and intralo bar pulmonary artery from rats. 2 On main pulmonary artery FK409 fully reversed the precontractions. Responses by ere inhibited by methylene blue but were independent of the endothelium. The potency (-log EC50) of FK409 was the same on preparations contracted with noradrenaline ( 7.62) or the thromboxane-mimetic, U44619 (7.63). 3 On intralobar pulmo nary artery FK409 caused only 80% reversal of the precontraction and w as 2 fold less potent than on main pulmonary artery. These differences in maximum response and potency between main and intralobar arteries are in keeping with previous findings with other NO donors. 4 Pulmonar y hypertension was induced in rats by chronic exposure to hypoxia (10% O-2) for 1 or 4 weeks. Main pulmonary arteries from I week hypoxic ra ts had inherent tone and showed spontaneous contractile activity. In t hese arteries PK409 reversed not only the precontraction induced by no radrenaline but also the inherent lone. However, FK409 was 17 fold les s potent than in control arteries, reflecting previous findings with o ther NO donors. Main pulmonary arteries from 4 week hypoxic rats had m inimal inherent tone and wen quiescent and FI(409 was 4.5 fold less po tent than In control arteries. In intralobar pulmonary arteries from i i week hypoxic rats FI(409 tv;ls 12 fold less potent than in controls. 5 Treatment of arteries with either (a) in vitro hypoxic conditions ( PO2) of solution in organ bath <10 mmHg) or (b) superoxide dismutase ( SOD; 150 u ml(-1)) together with catalase (1200 u ml(-1)) significantl y increased the potency of FK409 in preparations from hypoxic rats but had no effect 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 effect on the potency of FK409 in prep arations from control or hypoxic rats. 6 It is concluded that the redu ction in potency of FK409 seen in pulmonary arteries from rats with ch ronic hypoxic pulmonary hypertension may be due in part to the presenc e of one or more reactive oxygen species (either hydroxyl or superoxid e plus hydrogen peroxide).