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

Abstract

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 (-log EC50) 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 differences in maximum response and potency between main and intralobar arteries are in keeping with previous findings with other NO donors. 4. Pulmonary hypertension was induced in rats by chronic exposure to hypoxia (10% O2) 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, reflecting previous findings 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 (PO2 of solution in organ bath < 10 mmHg) or (b) superoxide dismutase (SOD; 150 u ml-1) together with catalase (1200 u ml-1) significantly 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, NG-nitro-L-arginine methyl ester, had any effect 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).