Exposure of animals to chronic hypoxia induces pulmonary vascular remodeling leading to pulmonary hypertension. Melatonin, the principal hormone of the pineal gland, is known to have an inhibitory effect on rat vascular reactivity. This study examined the effect of chronic hypoxia on the influence of melatonin on the vasoreactivity of the pulmonary artery. The inhibitory effect of melatonin on the phenylephrine-induced constriction in normoxia-adapted rings (101.5+/-4% versus 82.2+/-4%) in the presence or absence of melatonin, respectively) was lost following chronic hypoxic treatment (100.2+/-4% versus 102.2+/-2%) and this effect was independent of the endothelium. Melatonin also significantly enhanced the relaxant response to acetylcholine of the pulmonary arterial rings from normoxic rats (34.76+/-5.67% versus 53.82+/-4.736%) in the absence or presence of melatonin, respectively). In contrast, melatonin had no significant effect (21.71+/-1.37% versus 23.51+/-6.891%) on the relaxant response to acetylcholine of the pulmonary arterial rings from chronic hypoxia-adapted rats. Pre-treatment with melatonin (10(-4) M) showed no significant effect on the vasorelaxation by the nitric oxide donor; sodium nitroprusside (10(-7)-10(-5) M). The melatonin-induced changes were blocked by the melatonergic-receptor antagonist luzindole (2x10(-6) M). The results from our study confirm the presence of melatonergic receptors on the pulmonary trunk of rats and also suggest that the modulatory role of melatonin on the vasoreactivity of pulmonary trunk does not involve the nitric oxide pathway. Most importantly, our results show that development of pulmonary hypertension in rats is associated with the loss of the vasorelaxant influence of melatonin.