To investigate whether chronic hypoxia affects endothelin-B (ET_B) receptor-mediated pulmonary vasodilation, we compared the vasodilator responses to IRL-1620, a selective ET_B-receptor agonist, in isolated perfused lungs from normoxic and chronically hypoxic adult male rats. IRL-1620 caused a dose-dependent vasodilation that was greater in the hypertensive lungs than in the normotensive lungs. In normotensive lungs, a nitric oxide (NO) synthase inhibitor, N-nitro-L-arginine (L-NNA; 300 µM), and an ATP-sensitive potassium (K_ATP)-channel inhibitor, glibenclamide (Glib; 10 µM), each reduced 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 contrast, L-NNA alone, but not Glib alone, completely blocked IRL-1620-induced vasodilation in hypertensive lungs. The vasodilator response to a K_ATP-channel opener, NIP-121 (1 µM), but not the response to sodium nitroprusside (1 µM), was enhanced in hypertensive lungs. We also found increased expression of mRNA for the ET_B receptor in lung tissue after hypoxic exposure. In addition, semiquantitative immunohistochemistry demonstrated higher expression levels of ET_B receptors in the endothelium of distal segments of the pulmonary artery in hypoxic than in normoxic rats. These results suggest that ET_B 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 activation of K_ATP channels are involved in normotensive lungs. We speculate that the underlying mechanism responsible for this augmentation may partly be related to upregulation of ET_B receptors in the endothelium of pulmonary resistance arteries in hypertensive lungs.

pulmonary hypertension; endothelium-derived hyperpolarizing factor; nitric oxide; potassium channels

This article has been cited by other articles:

				N. L. Jernigan, B. R. Walker, and T. C. Resta Reactive oxygen species mediate RhoA/Rho kinase-induced Ca2+ sensitization in pulmonary vascular smooth muscle following chronic hypoxia Am J Physiol Lung Cell Mol Physiol, September 1, 2008; 295(3): L515 - L529. [Abstract] [Full Text] [PDF]

				T. Nishida, S. Tsuji, A. Kimura, M. Tsujii, S. Ishii, T. Yoshio, S. Shinzaki, S. Egawa, T. Irie, M. Yasumaru, et al. Endothelin-1, an ulcer inducer, promotes gastric ulcer healing via mobilizing gastric myofibroblasts and stimulates production of stroma-derived factors Am J Physiol Gastrointest Liver Physiol, May 1, 2006; 290(5): G1041 - G1050. [Abstract] [Full Text] [PDF]

				X. Wang, M. Tong, S. Chinta, J. U. Raj, and Y. Gao Hypoxia-induced reactive oxygen species downregulate ETB receptor-mediated contraction of rat pulmonary arteries Am J Physiol Lung Cell Mol Physiol, March 1, 2006; 290(3): L570 - L578. [Abstract] [Full Text] [PDF]

				C. Cao, W. Lee-Kwon, E. P. Silldorff, and T. L. Pallone KATP channel conductance of descending vasa recta pericytes Am J Physiol Renal Physiol, December 1, 2005; 289(6): F1235 - F1245. [Abstract] [Full Text] [PDF]

				S. Granchi, G.B. Vannelli, L. Vignozzi, C. Crescioli, P. Ferruzzi, R. Mancina, M.C. Vinci, G. Forti, S. Filippi, M. Luconi, et al. Expression and regulation of endothelin-1 and its receptors in human penile smooth muscle cells Mol. Hum. Reprod., December 1, 2002; 8(12): 1053 - 1064. [Abstract] [Full Text] [PDF]

				T. F. Luscher and M. Barton Endothelins and Endothelin Receptor Antagonists : Therapeutic Considerations for a Novel Class of Cardiovascular Drugs Circulation, November 7, 2000; 102(19): 2434 - 2440. [Abstract] [Full Text] [PDF]

				Y. Abe, K. Nakayama, A. Yamanaka, T. Sakurai, and K. Goto Subtype-specific Trafficking of Endothelin Receptors J. Biol. Chem., March 17, 2000; 275(12): 8664 - 8671. [Abstract] [Full Text] [PDF]

				C. A. Nankervis and P. T. Nowicki Role of endothelin-1 in regulation of the postnatal intestinal circulation Am J Physiol Gastrointest Liver Physiol, March 1, 2000; 278(3): G367 - G375. [Abstract] [Full Text] [PDF]

				K. Sato, Y. Morio, K. G. Morris, D. M. Rodman, and I. F. McMurtry Mechanism of hypoxic pulmonary vasoconstriction involves ETA receptor-mediated inhibition of KATP channel Am J Physiol Lung Cell Mol Physiol, March 1, 2000; 278(3): L434 - L442. [Abstract] [Full Text] [PDF]

				L. A. Shimoda, J. T. Sylvester, and J. S. K. Sham Chronic hypoxia alters effects of endothelin and angiotensin on K+ currents in pulmonary arterial myocytes Am J Physiol Lung Cell Mol Physiol, September 1, 1999; 277(3): L431 - L439. [Abstract] [Full Text] [PDF]

				D. D. Ivy, M. Yanagisawa, C. E. Gariepy, S. A. Gebb, K. L. Colvin, and I. F. McMurtry Exaggerated hypoxic pulmonary hypertension in endothelin B receptor-deficient rats Am J Physiol Lung Cell Mol Physiol, April 1, 2002; 282(4): L703 - L712. [Abstract] [Full Text] [PDF]