PW Shaul, AJ North, TS Brannon, K Ujiie, LB Wells, PA Nisen, CJ Lowenstein, SH Snyder and RA Star
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas 75235, USA.

Prolonged hypoxia in the adult rat causes a decline in endothelium- derived nitric oxide (NO) production in the pulmonary circulation. To evaluate whether this is related to a decrease in endothelial NO synthase (NOS-III) expression, we determined the effects of hypobaric hypoxia (7 or 21 days) on NOS-III gene expression in adult rat lung. Neuronal NOS (NOS-I) expression was also examined; NOS-I has been immunohistochemically localized to rat bronchiolar epithelium. NOS-III and NOS-I mRNA abundance were assessed in reverse transcription- polymerase chain reaction assays and the proteins were evaluated by immunoblot analysis. After 7 and 21 days of hypoxia, there were increases in the steady-state levels of both NOS-III and NOS-I mRNA, rising 2.7- to 3.0-fold and 2.5- to 2.8-fold, respectively. These findings were confirmed by Northern analyses. In parallel, NOS-III and NOS-I protein abundance were also increased with hypoxia by 3.0- to 3.5- fold and 2.4- to 3.0-fold, respectively. NOS activity detected by [3H]arginine to [3H]citrulline conversion rose 109%. Thus, prolonged in vivo hypoxia causes enhancement of NOS-III and NOS-I gene expression in adult rat lung, indicating that the pulmonary expression of these genes is modulated in vivo. The increase in NOS-III expression does not explain the declines in pulmonary endothelial NO production previously observed following prolonged hypoxia in this model. Alternatively, the fall in NO production may be related to diminished NOS co-factor availability.

This article has been cited by other articles:

				A.-C. Peyter, V. Muehlethaler, L. Liaudet, M. Marino, S. Di Bernardo, G. Diaceri, and J.-F. Tolsa Muscarinic receptor M1 and phosphodiesterase 1 are key determinants in pulmonary vascular dysfunction following perinatal hypoxia in mice Am J Physiol Lung Cell Mol Physiol, July 1, 2008; 295(1): L201 - L213. [Abstract] [Full Text] [PDF]

				K. Takemori, K. Kobayashi, and A. Sakamoto Expression of pulmonary vasoactive factors after sevoflurane anaesthesia in rats: a quantitative real-time polymerase chain reaction study Br. J. Anaesth., February 1, 2008; 100(2): 190 - 194. [Abstract] [Full Text] [PDF]

				J. B. Snow, V. Kitzis, C. E. Norton, S. N. Torres, K. D. Johnson, N. L. Kanagy, B. R. Walker, and T. C. Resta Differential effects of chronic hypoxia and intermittent hypocapnic and eucapnic hypoxia on pulmonary vasoreactivity J Appl Physiol, January 1, 2008; 104(1): 110 - 118. [Abstract] [Full Text] [PDF]

				M. Kirsch, B. Kemp-Harper, N. Weissmann, F. Grimminger, and H. H. H. W. Schmidt Sildenafil in hypoxic pulmonary hypertension potentiates a compensatory up-regulation of NO-cGMP signaling FASEB J, January 1, 2008; 22(1): 30 - 40. [Abstract] [Full Text] [PDF]

				M. P. Coggins and K. D. Bloch Nitric Oxide in the Pulmonary Vasculature Arterioscler. Thromb. Vasc. Biol., September 1, 2007; 27(9): 1877 - 1885. [Abstract] [Full Text] [PDF]

				L. J. Frederiksen, R. Sullivan, L. R. Maxwell, S. K. Macdonald-Goodfellow, M. A. Adams, B. M. Bennett, D. R. Siemens, and C. H. Graham Chemosensitization of Cancer In vitro and In vivo by Nitric Oxide Signaling Clin. Cancer Res., April 1, 2007; 13(7): 2199 - 2206. [Abstract] [Full Text] [PDF]

				C. D. Searles Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression Am J Physiol Cell Physiol, November 1, 2006; 291(5): C803 - C816. [Abstract] [Full Text] [PDF]

				Z.-K. Dai, M.-S. Tan, C.-Y. Chai, S.-H. Chou, P.-C. Lin, J.-L. Yeh, A. Y. Jeng, C.-I Chang, I.-J. Chen, and J.-R. Wu Effects of Sildenafil on Pulmonary Hypertension and Levels of ET-1, eNOS, and cGMP in Aorta-Banded Rats. Experimental Biology and Medicine, June 1, 2006; 231(6): 942 - 947. [Abstract] [Full Text] [PDF]

				S.-H. Chou, C.-Y. Chai, J.-R. Wu, M.-S. Tan, C.-C. Chiu, I.-J. Chen, A. Y. Jeng, C.-I Chang, A.-L. Kwan, and Z.-K. Dai The Effects of Debanding on the Lung Expression of ET-1, eNOS, and cGMP in Rats with Left Ventricular Pressure Overload. Experimental Biology and Medicine, June 1, 2006; 231(6): 954 - 959. [Abstract] [Full Text] [PDF]

				J. Min, Y.-M. Jin, J.-S. Moon, M.-S. Sung, S. Ahn Jo, and I. Jo Hypoxia-Induced Endothelial NO Synthase Gene Transcriptional Activation Is Mediated Through the Tax-Responsive Element in Endothelial Cells Hypertension, June 1, 2006; 47(6): 1189 - 1196. [Abstract] [Full Text] [PDF]

				T. S. Maxey, L. G. Fernandez, T. B. Reece, W. B. Keeling, I. L. Kron, and V. E. Laubach Endothelial Nitric Oxide Synthase is Essential for Postpneumonectomy Compensatory Vasodilation Ann. Thorac. Surg., April 1, 2006; 81(4): 1234 - 1238. [Abstract] [Full Text] [PDF]

				E. B. Manukhina, H. F. Downey, and R. T. Mallet Role of nitric oxide in cardiovascular adaptation to intermittent hypoxia. Experimental Biology and Medicine, April 1, 2006; 231(4): 343 - 365. [Abstract] [Full Text] [PDF]

				N. L. Jernigan, B. R. S. Broughton, B. R. Walker, and T. C. Resta Impaired NO-dependent inhibition of store- and receptor-operated calcium entry in pulmonary vascular smooth muscle after chronic hypoxia Am J Physiol Lung Cell Mol Physiol, March 1, 2006; 290(3): L517 - L525. [Abstract] [Full Text] [PDF]

				T. Murata, K. Kinoshita, M. Hori, M. Kuwahara, H. Tsubone, H. Karaki, and H. Ozaki Statin Protects Endothelial Nitric Oxide Synthase Activity in Hypoxia-Induced Pulmonary Hypertension Arterioscler. Thromb. Vasc. Biol., November 1, 2005; 25(11): 2335 - 2342. [Abstract] [Full Text] [PDF]

				R. Liu, O. V. Evgenov, and F. Ichinose NOS3 deficiency augments hypoxic pulmonary vasoconstriction and enhances systemic oxygenation during one-lung ventilation in mice J Appl Physiol, February 1, 2005; 98(2): 748 - 752. [Abstract] [Full Text] [PDF]

				N. L. Jernigan, B. R. Walker, and T. C. Resta Chronic hypoxia augments protein kinase G-mediated Ca2+ desensitization in pulmonary vascular smooth muscle through inhibition of RhoA/Rho kinase signaling Am J Physiol Lung Cell Mol Physiol, December 1, 2004; 287(6): L1220 - L1229. [Abstract] [Full Text] [PDF]

				N. L. Jernigan, B. R. Walker, and T. C. Resta Endothelium-derived reactive oxygen species and endothelin-1 attenuate NO-dependent pulmonary vasodilation following chronic hypoxia Am J Physiol Lung Cell Mol Physiol, October 1, 2004; 287(4): L801 - L808. [Abstract] [Full Text] [PDF]

				T. Murata, M. Hori, K. Sakamoto, H. Karaki, and H. Ozaki Dexamethasone Blocks Hypoxia-induced Endothelial Dysfunction in Organ-cultured Pulmonary Arteries Am. J. Respir. Crit. Care Med., September 15, 2004; 170(6): 647 - 655. [Abstract] [Full Text] [PDF]

				P. M. Hassoun, G. Filippov, M. Fogel, C. Donaldson, U. S. Kayyali, L. A. Shimoda, and K. D. Bloch Hypoxia Decreases Expression of Soluble Guanylate Cyclase in Cultured Rat Pulmonary Artery Smooth Muscle Cells Am. J. Respir. Cell Mol. Biol., June 1, 2004; 30(6): 908 - 913. [Abstract] [Full Text] [PDF]

				C. D. Fike, J. L. Aschner, Y. Zhang, and M. R. Kaplowitz Impaired NO signaling in small pulmonary arteries of chronically hypoxic newborn piglets Am J Physiol Lung Cell Mol Physiol, June 1, 2004; 286(6): L1244 - L1254. [Abstract] [Full Text] [PDF]

				N. L. Jernigan, T. C. Resta, and B. R. Walker Contribution of oxygen radicals to altered NO-dependent pulmonary vasodilation in acute and chronic hypoxia Am J Physiol Lung Cell Mol Physiol, May 1, 2004; 286(5): L947 - L955. [Abstract] [Full Text] [PDF]

				F. Coulet, S. Nadaud, M. Agrapart, and F. Soubrier Identification of Hypoxia-response Element in the Human Endothelial Nitric-oxide Synthase Gene Promoter J. Biol. Chem., November 21, 2003; 278(47): 46230 - 46240. [Abstract] [Full Text] [PDF]

				L. J. Millatt, G. StJ. Whitley, D. Li, J. M. Leiper, H. M. Siragy, R. M. Carey, and R. A. Johns Evidence for Dysregulation of Dimethylarginine Dimethylaminohydrolase I in Chronic Hypoxia-Induced Pulmonary Hypertension Circulation, September 23, 2003; 108(12): 1493 - 1498. [Abstract] [Full Text] [PDF]

				N. L. Jernigan, B. R. Walker, and T. C. Resta Pulmonary PKG-1 is upregulated following chronic hypoxia Am J Physiol Lung Cell Mol Physiol, September 1, 2003; 285(3): L634 - L642. [Abstract] [Full Text] [PDF]

				F. C. Blumberg, K. Wolf, M. Arzt, C. Lorenz, G. A. J. Riegger, and M. Pfeifer Effects of ET-A receptor blockade on eNOS gene expression in chronic hypoxic rat lungs J Appl Physiol, February 1, 2003; 94(2): 446 - 452. [Abstract] [Full Text] [PDF]

				F. C Blumberg, C. Lorenz, K. Wolf, P. Sandner, G. A.J Riegger, and M. Pfeifer Increased pulmonary prostacyclin synthesis in rats with chronic hypoxic pulmonary hypertension Cardiovasc Res, July 1, 2002; 55(1): 171 - 177. [Abstract] [Full Text] [PDF]

				S. Earley, L. D. Nelin, L. G. Chicoine, and B. R. Walker Hypoxia-induced pulmonary endothelin-1 expression is unaltered by nitric oxide J Appl Physiol, March 1, 2002; 92(3): 1152 - 1158. [Abstract] [Full Text] [PDF]

				B. C Kone Molecular biology of natriuretic peptides and nitric oxide synthases Cardiovasc Res, August 15, 2001; 51(3): 429 - 441. [Abstract] [Full Text] [PDF]

				J-C. Schneider, I. Blazy, M. Dechaux, D. Rabier, N.P. Mason, and J-P. Richalet Response of nitric oxide pathway to l-arginine infusion at the altitude of 4,350 m Eur. Respir. J., August 1, 2001; 18(2): 286 - 292. [Abstract] [Full Text] [PDF]

				D. Li, V. E. Laubach, and R. A. Johns Upregulation of lung soluble guanylate cyclase during chronic hypoxia is prevented by deletion of eNOS Am J Physiol Lung Cell Mol Physiol, August 1, 2001; 281(2): L369 - L376. [Abstract] [Full Text] [PDF]

				R. M. Mohan, S. Golding, and D. J. Paterson Intermittent hypoxia modulates nNOS expression and heart rate response to sympathetic nerve stimulation Am J Physiol Heart Circ Physiol, July 1, 2001; 281(1): H132 - H138. [Abstract] [Full Text] [PDF]

				T. D. Le Cras and I. F. McMurtry Nitric oxide production in the hypoxic lung Am J Physiol Lung Cell Mol Physiol, April 1, 2001; 280(4): L575 - L582. [Abstract] [Full Text] [PDF]

				D. Xiao, I. M. Bird, R. R. Magness, L. D. Longo, and L. Zhang Upregulation of eNOS in pregnant ovine uterine arteries by chronic hypoxia Am J Physiol Heart Circ Physiol, February 1, 2001; 280(2): H812 - H820. [Abstract] [Full Text] [PDF]

				T. C. Resta, N. L. Kanagy, and B. R. Walker Estradiol-induced attenuation of pulmonary hypertension is not associated with altered eNOS expression Am J Physiol Lung Cell Mol Physiol, January 1, 2001; 280(1): L88 - L97. [Abstract] [Full Text] [PDF]

				W. Budts, P. Pokreisz, Z. Nong, N. Van Pelt, H. Gillijns, R. Gerard, R. Lyons, D. Collen, K. D. Bloch, and S. Janssens Aerosol Gene Transfer With Inducible Nitric Oxide Synthase Reduces Hypoxic Pulmonary Hypertension and Pulmonary Vascular Remodeling in Rats Circulation, December 5, 2000; 102(23): 2880 - 2885. [Abstract] [Full Text] [PDF]

				L. P. Thompson, K. Aguan, G. Pinkas, and C. P. Weiner Chronic hypoxia increases the NO contribution of acetylcholine vasodilation of the fetal guinea pig heart Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2000; 279(5): R1813 - R1820. [Abstract] [Full Text] [PDF]

				B. R. Walker, T. C. Resta, and L. D. Nelin Nitric oxide-dependent pulmonary vasodilation in polycythemic rats Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2382 - H2389. [Abstract] [Full Text] [PDF]

				V. Hampl and J. Herget Role of Nitric Oxide in the Pathogenesis of Chronic Pulmonary Hypertension Physiol Rev, October 1, 2000; 80(4): 1337 - 1372. [Abstract] [Full Text] [PDF]

				T. D. Le Cras, D.-H. Kim, N. E. Markham, and A. S. H. Abman Early abnormalities of pulmonary vascular development in the Fawn-Hooded rat raised at Denver's altitude Am J Physiol Lung Cell Mol Physiol, August 1, 2000; 279(2): L283 - L291. [Abstract] [Full Text] [PDF]

				M. M. White, R. E. McCullough, R. Dyckes, A. D. Robertson, and L. G. Moore Chronic hypoxia, pregnancy, and endothelium-mediated relaxation in guinea pig uterine and thoracic arteries Am J Physiol Heart Circ Physiol, June 1, 2000; 278(6): H2069 - H2075. [Abstract] [Full Text] [PDF]

				M. Toporsian, K. Govindaraju, M. Nagi, D. Eidelman, G. Thibault, and M. E. Ward Downregulation of Endothelial Nitric Oxide Synthase in Rat Aorta After Prolonged Hypoxia In Vivo Circ. Res., March 31, 2000; 86(6): 671 - 675. [Abstract] [Full Text] [PDF]

				C. Chassagne, S. Eddahibi, C. Adamy, D. Rideau, F. Marotte, J.-L. Dubois-Randé, S. Adnot, J.-L. Samuel, and E. Teiger Modulation of Angiotensin II Receptor Expression during Development and Regression of Hypoxic Pulmonary Hypertension Am. J. Respir. Cell Mol. Biol., March 1, 2000; 22(3): 323 - 332. [Abstract] [Full Text]

				M. KAKOKI, Y. HIRATA, H. HAYAKAWA, E. SUZUKI, D. NAGATA, A. TOJO, H. NISHIMATSU, N. NAKANISHI, Y. HATTORI, K. KIKUCHI, et al. Effects of Tetrahydrobiopterin on Endothelial Dysfunction in Rats with Ischemic Acute Renal Failure J. Am. Soc. Nephrol., February 1, 2000; 11(2): 301 - 309. [Abstract] [Full Text] [PDF]

				J. W. Berkenbosch, J. Baribeau, and T. Perreault Decreased synthesis and vasodilation to nitric oxide in piglets with hypoxia-induced pulmonary hypertension Am J Physiol Lung Cell Mol Physiol, February 1, 2000; 278(2): L276 - L283. [Abstract] [Full Text] [PDF]

				F. Schweda, F. C. Blumberg, A. Schweda, M. Kammerl, S. R. Holmer, G. A. J. Riegger, M. Pfeifer, and B. K. Kramer Effects of chronic hypoxia on renal renin gene expression in rats Nephrol. Dial. Transplant., January 1, 2000; 15(1): 11 - 15. [Abstract] [Full Text] [PDF]

				J. A. Whitney, Z. German, T. S. Sherman, I. S. Yuhanna, and P. W. Shaul Cell growth modulates nitric oxide synthase expression in fetal pulmonary artery endothelial cells Am J Physiol Lung Cell Mol Physiol, January 1, 2000; 278(1): L131 - L138. [Abstract] [Full Text] [PDF]

				I. S. Yuhanna, A. N. MacRitchie, R. L. Lantin-Hermoso, L. B. Wells, and P. W. Shaul Nitric Oxide (NO) Upregulates NO Synthase Expression in Fetal Intrapulmonary Artery Endothelial Cells Am. J. Respir. Cell Mol. Biol., November 1, 1999; 21(5): 629 - 636. [Abstract] [Full Text]

				D. Li, N. Zhou, and R. A. Johns Soluble guanylate cyclase gene expression and localization in rat lung after exposure to hypoxia Am J Physiol Lung Cell Mol Physiol, October 1, 1999; 277(4): L841 - L847. [Abstract] [Full Text] [PDF]

				K. A. Fagan, R. C. Tyler, K. Sato, B. W. Fouty, K. G. Morris Jr., P. L. Huang, I. F. McMurtry, and D. M. Rodman Relative contributions of endothelial, inducible, and neuronal NOS to tone in the murine pulmonary circulation Am J Physiol Lung Cell Mol Physiol, September 1, 1999; 277(3): L472 - L478. [Abstract] [Full Text] [PDF]

				K. Sato, D. M. Rodman, and I. F. McMurtry Hypoxia inhibits increased ETB receptor-mediated NO synthesis in hypertensive rat lungs Am J Physiol Lung Cell Mol Physiol, April 1, 1999; 276(4): L571 - L581. [Abstract] [Full Text] [PDF]

				R. C. Tyler, M. Muramatsu, S. H. Abman, T. J. Stelzner, D. M. Rodman, K. D. Bloch, and I. F. McMurtry Variable expression of endothelial NO synthase in three forms of rat pulmonary hypertension Am J Physiol Lung Cell Mol Physiol, February 1, 1999; 276(2): L297 - L303. [Abstract] [Full Text] [PDF]

				H. F. Frasch, C. Marshall, and B. E. Marshall Endothelin-1 is elevated in monocrotaline pulmonary hypertension Am J Physiol Lung Cell Mol Physiol, February 1, 1999; 276(2): L304 - L310. [Abstract] [Full Text] [PDF]

				T. C. Resta, L. G. Chicoine, J. L. Omdahl, and B. R. Walker Maintained upregulation of pulmonary eNOS gene and protein expression during recovery from chronic hypoxia Am J Physiol Heart Circ Physiol, February 1, 1999; 276(2): H699 - H708. [Abstract] [Full Text] [PDF]

				P. W. Shaul, M. C. Pace, Z. Chen, and T. S. Brannon Developmental Changes in Prostacyclin Synthesis Are Conserved in Cultured Pulmonary Endothelium and Vascular Smooth Muscle Am. J. Respir. Cell Mol. Biol., January 1, 1999; 20(1): 113 - 121. [Abstract] [Full Text]

				D. Gozal and E. Gozal Episodic hypoxia enhances late hypoxic ventilation in developing rat: putative role of neuronal NO synthase Am J Physiol Regulatory Integrative Comp Physiol, January 1, 1999; 276(1): R17 - R22. [Abstract] [Full Text] [PDF]

				T. C. Resta, T. L. O'Donaughy, S. Earley, L. G. Chicoine, and B. R. Walker Unaltered vasoconstrictor responsiveness after iNOS inhibition in lungs from chronically hypoxic rats Am J Physiol Lung Cell Mol Physiol, January 1, 1999; 276(1): L122 - L130. [Abstract] [Full Text] [PDF]

				M. M. White, R. E. McCullough, R. Dyckes, A. D. Robertson, and L. G. Moore Effects of pregnancy and chronic hypoxia on contractile responsiveness to alpha 1-adrenergic stimulation J Appl Physiol, December 1, 1998; 85(6): 2322 - 2329. [Abstract] [Full Text] [PDF]

				D. U. Frank, D. J. Horstman, G. N. Morris, R. A. Johns, and G. F. Rich Regulation of the endogenous NO pathway by prolonged inhaled NO in rats J Appl Physiol, September 1, 1998; 85(3): 1070 - 1078. [Abstract] [Full Text] [PDF]

				U. Förstermann, J.-p. Boissel, and H. Kleinert Expressional control of the `constitutive' isoforms of nitric oxide synthase (NOS I and NOS III) FASEB J, July 1, 1998; 12(10): 773 - 790. [Abstract] [Full Text]

				A. D. Everett, T. D. Le Cras, C. Xue, and R. A. Johns eNOS expression is not altered in pulmonary vascular remodeling due to increased pulmonary blood flow Am J Physiol Lung Cell Mol Physiol, June 1, 1998; 274(6): L1058 - L1065. [Abstract] [Full Text] [PDF]

				A. G. Estevez, N. Spear, J. A. Thompson, T. L. Cornwell, R. Radi, L. Barbeito, and J. S. Beckman Nitric Oxide-Dependent Production of cGMP Supports the Survival of Rat Embryonic Motor Neurons Cultured with Brain-Derived Neurotrophic Factor J. Neurosci., May 15, 1998; 18(10): 3708 - 3714. [Abstract] [Full Text] [PDF]

C. D. Fike, M. R. Kaplowitz, C. J. Thomas, and L. D. Nelin Chronic hypoxia decreases nitric oxide production and endothelial nitric oxide synthase in newborn pig lungs Am J Physiol Lung Cell Mol Physiol, April 1, 1998; 274(4): L517 - L526. [Abstract]