Chronic hypoxia augments endothelin-B receptor-mediated vasodilation in isolated perfused rat lungs

To investigate whether chronic hypoxia affects endothelin-B (ETB) receptor- mediated pulmonary vasodilation, we compared the vasodilator responses to I RL-1620, a selective ETB-receptor agonist, in isolated perfused lungs from normoxic and chronically hypoxic adult male rats. IRL-1620 caused a dose-de pendent vasodilation that was greater in the hypertensive lungs than in the normotensive lungs. In normotensive lungs, a nitric oxide (NO) synthase in hibitor, N-omega-nitro-L-arginine (L-NNA; 300 mu M), and an ATP-sensitive p otassium (K-ATP)-channel inhibitor, glibenclamide (Glib; 10 mu M), each red uced the vasodilator response to IRL-1620 (1 nM), but the combination of L- NNA and Glib inhibited it more effectively than either drug alone. In contr ast, L-NNA alone, but not Glib alone, completely blocked IRL-1620-induced v asodilation in hypertensive lungs. The vasodilator response to a K-ATP- cha nnel opener, NIP-121 (1 mu M), but not the response to sodium nitroprusside (1 mu M), was enhanced in hypertensive lungs. We also found increased expr ession of mRNA for the ETB receptor in lung tissue after hypoxic exposure. In addition, semiquantitative immunohistochemistry demonstrated higher expr ession levels of ETB receptors in the endothelium of distal segments of the pulmonary artery in hypoxic than in normoxic rats. These results suggest t hat ETB receptor-mediated pulmonary vasodilation is augmented after chronic hypoxic exposure and that release of NO may be the sole mechanism of this vasodilation in hypertensive lungs, whereas both release of NO and activati on of K-ATP channels are involved in normotensive lungs. We speculate that the underlying mechanism responsible for this augmentation may partly be re lated to upregulation of ETB receptors in the endothelium of pulmonary resi stance arteries in hypertensive lungs.