ABSTRACT
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.
Subject(s)
Hypertension, Pulmonary/drug therapy , Hypoxia/complications , Melatonin/pharmacology , Pulmonary Artery/drug effects , Vasoconstriction/drug effects , Animals , Chronic Disease , Disease Models, Animal , Hypertension, Pulmonary/physiopathology , Male , Muscle, Smooth, Vascular/drug effects , Phenylephrine/pharmacology , Pulmonary Artery/physiology , Random Allocation , Rats , Reference Values , Risk Factors , Sensitivity and Specificity , Vasoconstriction/physiology , Vasodilation/drug effectsABSTRACT
The present study determined Ca2+ handling in the hearts of rats subjected to chronic hypoxia (CH). Spectrofluorometry was used to measure intracellular Ca2+ concentration ([Ca2+]i) and its responses to electrical stimulation, caffeine, and isoproterenol in myocytes from the right ventricle of rats breathing 10% oxygen for 1, 3, 7, 14, 21, 28, and 56 days and age-matched controls. The protein expression of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) and its ryanodine receptor (RyR) were measured. The uptake of 45Ca2+ by SERCA, release by RyR, and extrusion by Na+/Ca2+ exchange (NCX) were determined. It was found that Ca2+ homeostasis and Ca2+ responses to beta-adrenoceptor stimulation reached a new equilibrium after 4 wk of CH. Ca2+ content in the sarcoplasmic reticulum (SR) was reduced, but cytosolic Ca2+ remained unchanged after CH. Expression of SERCA and its Ca2+ uptake, Ca2+ release via RyR, and NCX activity were suppressed by CH. The results indicate impaired Ca2+ handling, which may be responsible for the attenuated Ca2+ responses to beta-adrenoceptor stimulation in CH.
