Hypoxic pulmonary hypertension (HPH) and iptakalim, a novel ATP-sensitive potassium channel opener targeting smaller arteries in hypertension

Cardiovascular Drug Reviews

Volumn 23, Issue 4, 2005, Pages 293-316

  Wang, Hai ^a,b   Tang, Yuan ^a,c   Zhang, Ying Li ^a,d  

^a BEIJING INSTITUTE OF PHARMACOLOGY AND TOXICOLOGY   (China)

^b Institute of Health and Environment Medicine   (China)

^c Thadweik Academy of Medicine   (China)

^d Enhua Academy of Medicine   (China)

Author keywords

HPH; Iptakalim; KATP channel opener; KATP channels; Pulmonary hypertension

Indexed keywords

2 CYANO 1 (1,1 DIMETHYLPROPYL) 3 (3 PYRIDYL)GUANIDINE; 4 AMINOPYRIDINE; ADENOSINE DIPHOSPHATE; ADENOSINE TRIPHOSPHATE; ADENOSINE TRIPHOSPHATE SENSITIVE POTASSIUM CHANNEL; ANTICOAGULANT AGENT; ARGININE; BONE MORPHOGENETIC PROTEIN; CALCIUM CHANNEL BLOCKING AGENT; CALCIUM ION; DEXAMETHASONE; DIGOXIN; DIURETIC AGENT; ENDOTHELIN 1; GLIBENCLAMIDE; INWARDLY RECTIFYING POTASSIUM CHANNEL; IPTAKALIM; MESSENGER RNA; MITOGEN ACTIVATED PROTEIN KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE 3; NITRIC OXIDE; P1075; PINACIDIL; POTASSIUM CHANNEL STIMULATING AGENT; POTASSIUM CHLORIDE; SEROTONIN; SULFONYLUREA RECEPTOR; SULFONYLUREA RECEPTOR 2; TETRAMETHYLAMMONIUM; UNCLASSIFIED DRUG; UNINDEXED DRUG; URIDINE DIPHOSPHATE;

ANTIHYPERTENSIVE ACTIVITY; CARDIOVASCULAR DISEASE; CARDIOVASCULAR EFFECT; CHRONIC DISEASE; DRUG ANTAGONISM; DRUG SAFETY; DRUG TARGETING; HUMAN; HYPOXIC LUNG VASOCONSTRICTION; HYPOXIC PULMONARY HYPERTENSION; LUNG ARTERY PRESSURE; LUNG CIRCULATION; LUNG VASCULAR RESISTANCE; NONHUMAN; PRIORITY JOURNAL; PULMONARY HYPERTENSION; REVIEW; VASCULAR ENDOTHELIUM;

EID: 33744951269     PISSN: 08975957     EISSN: None     Source Type: Journal    
DOI: 10.1111/j.1527-3466.2005.tb00174.x     Document Type: Review

References (119)

1. ATP channels. Annu Rev Physiol 1998;60:667-687.
2. Barnes PJ, Liu SF. Regulation of pulmonary vascular tone. Pharmacol Rev 1995;47:87-131.
3. Barst RJ, McGoon M, McLaughlin V, et al. Beraprost therapy for pulmonary arterial hypertension. J Am Coll Cardiol 2003;41:2119-2125.
4. Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension: The Primary Pulmonary Hypertension study group. N Engl J Med 1996;334:296-302.
5. Catherine VB, Patrice C. Role of endothelial and smooth muscle cells in the physiopathology and treatment management of pulmonary hypertension. Cardiovasc Res 1999;44:274-282.
6. Celada P, Bel N, Artigas F. The effects of brofaromine, a reversible MAO-A inhibitor, on extracellular serotonin in the raphe nuclei and frontal cortex of freely moving rats. J Neural Transm Suppl 1994;41:357-363.
7. Chen YP, Qiu CR, Wang H. Cardiovascular pharmacological characterization of novel 2,3-dimethyl-2-butylamine derivatives in rats. Life Sci 2004;75:2131-2142.
8. Chen YP, Yin XF, Cui WY, Yang RF, Wang L, Wang H. Effects of 2,3-dimethyl-2-butylamine derivatives on potassium channels in arterial smooth muscle cells from rats. Chin Pharmacol Bull 2003;19:525-529.
9. Cool CD, Kennedy D, Voelkel NF, Tuder RM. Pathogenesis and evolution of plexiform lesions in pulmonary hypertension associated with scleroderma and human immunodeficiency virus infection. Hum Pathol 1997;28:434-442.
10. Cui WY, Wang H. Effects of iptakalim hydrochloride on potassium currents in isolated vascular smooth muscle cells derived from rat intrapulmonary arteries. Med J Chin PLA 2003;19:401-404.
11. Dingemans KP, Wagenvoort CA. Pulmonary arteries and veins in experimental hypoxia. An ultrastructural study. Am J Pathol 1978;93:353-368.
12. Dumas JP, Bardou M, Goirand F, Dumas M. Hypoxic pulmonary vasoconstriction. Gen Pharmacol 1999;33:289-297.
13. Eddahibi S, Humbert M, Fadel E, et al. Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension. J Clin Invest 2001;108:1141-1150.
14. 2+ entry in human pulmonary artery endothelial cells. Am J Physiol Lung Cell Mol Physiol 2003;285:L1233-L1245.
15. +-channel opener. Am J Physiol 1998;274:L186-L195.
16. Fattinger K., Funk C, Pantze M, et al. The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: A potential mechanism for hepatic adverse reactions. Clin Pharmacol Ther 2001;69:223-231
17. Frid MG, Dempsey EC, Durmowicz AG, Stenmark KR. Smooth muscle cell heterogeneity in pulmonary and systemic vessels. Importance in vascular disease. Arterioscler Thromb Vasc Biol 1997;17:1203-1209.
18. + channel openers. Pharmacol Ther 2000;85:39-53.
19. Gaine SP, Rubin LJ. Primary pulmonary hypertension. Lancet 1998;352:719-725.
20. Galie N, Manes A, Branzi A. Emerging medical therapies for pulmonary arterial hypertension. Prog Cardiovasc Dis 2002;45:213-224.
21. Galie N, Manes A, Branzi A. The new clinical trials on pharmacological treatment in pulmonary arterial hypertension. Eur Respir J 2002;20:1037-1049.
22. ATP subunits in spontaneously hypertensive rats. Life Sci 2005:In press.
23. Ghofrani HA, Wiedemann R, Rose F, et al. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: A randomised controlled trial. Lancet 2002;360:895-900.
24. Goldie RG, Henry PJ, Rigby PJ, Knott PG. Influence of respiratory tract viral infection on endothelin-1-induced modulation of cholinergic nerve-mediated contractions in murine airway smooth muscle. J Cardiovasc Pharmacol 1998;31(Suppl 1):S219-S221.
25. Hardingham GE, Chawla S, Johnson CM, Bading H. Distinct functions of nuclear and cytoplasmic calcium in the control of gene expression. Nature 1997;385:260-265.
26. Hartness ME, Brazier SP, Peers C, Bateson AN, Ashford ML, Kemp PJ. Post-transcriptional control of human maxiK potassium channel activity and acute oxygen sensitivity by chronic hypoxia. J Biol Chem 2003;278:51422-51432.
27. 3H]glibenclamide binding with ATP-sensitive potassium channels in artery smooth muscles and its crosstalk with nucleotides. Chin Pharmacol Bull 2004;20:402-408.
28. He HM, Long CL, Wang H. Regulatory effects of nucleotides on ATP-sensitive potassium channel opener pinacidil-induced vascular relaxation. Chin J Appl Physiol 2005;21:46-50.
29. Herve P, Launay JM, Scrobohaci ML, et al. Increased plasma serotonin in primary pulmonary hypertension. Am J Med 1995;99:249-254.
30. Hishikawa K, Nakaki T, Marumo T, et al. Pressure promotes DNA synthesis in rat cultured vascular smooth muscle cells. J Clin Invest 1994;93:1975-1980.
31. Hogan J, Smith P, Heath D, Harris P. The thickness of the alveolar capillary wall in the human lung at high and low altitude. Br J Dis Chest 1986;80:13-18.
32. Hong Z, Weir EK, Nelson DP, Olschewski A. Subacute hypoxia decreases voltage-activated potassium channel expression and function in pulmonary artery myocytes. Am J Respir Cell Mol Biol 2004;31:337-343.
33. Huang W, Yen RT, McLaurine M, Bledsoe G. Morphometry of the human pulmonary vasculature. J Appl Physiol 1996;81:2123-2133.
34. + channels. Neuron 1996;16:1011-1017.
35. Ivy DD, Parker TA, Abman SH. Prolonged endothelin B receptor blockade causes pulmonary hypertension in the ovine fetus. Am J Physiol Lung Cell Mol Physiol 2000;279:L758-L765.
36. Jia GD, Liu GS, Wang H. Vasodilating characteristics of iptakalim hydrochloride. Med J Chin PLA 2004;29:116-119.
37. Jia GD, Cui WY, Long CL, Liu GS, Wang H. Selective vasodilating action in small artery and its pharmacological mechanisms of novel antihypertensive drug iptakalim hydrochloride. Chin J Clin Pharmacol Ther 2004;9:140-145.
38. Jia GD, Liu GS, Wang H. Effects of iptakalim hydrochloride on secretion function of blood vessel endothelial cells. Chin J Clin Pharmacol Ther 2004;9:382-385.
39. Jiang YG, Yin XF, Cui RY, Wang H. Effects of iptakalim hydrochloride on potassium currents in artery smooth muscles. Chin Pharmacol Bull 2003;19:540-547.
40. Jin N, Packer CS, Rhoades RA. Pulmonary arterial hypoxic contraction: signal transduction. Am J Physiol 1992;263:L73-L78.
41. Khurana R, Martin JF, Zachary I. Gene therapy for cardiovascular disease: A case for cautious optimism. Hypertension 2001;38:1210-1216.
42. Kirchengast M, Munter K. Endothelin-1 and endothelin receptor antagonists in cardiovascular remodeling. Proc Soc Exp Biol Med 1999;221:312-325.
43. Lee SD, Shroyer KR, Markham NE, Cool CD, Voelkel NF, Tuder RM. Monoclonal endothelial cell proliferation is present in primary but not secondary pulmonary hypertension. J Clin Invest 1998;101:927-934.
44. Lee TJ, Ueno M, Sunagane N, Sun MH. Serotonin relaxes porcine pial veins. Am J Physiol 1994;266:H1000-H1006.
45. Lesch KP, Balling U, Gross J, et al. Organization of the human serotonin transporter gene. J Neural Transm Gen Sect 1994;95:157-162.
46. Lewczuk J, Piszko P, Jagas J, et al. Prognostic factors in medically treated patients with chronic pulmonary embolism. Chest 2001;119:818-823.
47. Li KX, Fouty B, McMurtry IF, Rodman DM. Enhanced ET(A)-receptor-mediated inhibition of K(v) channels in hypoxic hypertensive rat pulmonary artery myocytes. Am J Physiol 1999;277:H363-H370.
48. Liu W, Xiao WB, Wang H. Glybenclamide attenuates the cardiovascular effects of iptakalim in rats. Chin J Hypertens 2003;11:359-362.
49. Liu Y, Suzuki YJ, Day RM, Fanburg BL. Rho kinase-induced nuclear translocation of ERK1/ERK2 in smooth muscle cell mitogenesis caused by serotonin. Circ Res 2004;95:579-586.
50. 3H]P1075 binding with ATP-sensitive potassium channels in artery smooth muscles. Chin J Clin Pharmacol Ther 2004;9:35-38.
51. Long CL, Zhu QL, Wang AP, Sun HY, Wang H. Study on selective antihypertensive effects of iptakalim hydrochloride. Chin J Clin Pharmacol Ther 2003;8:494-498.
52. Louis WJ. Primary pulmonary hypertension and anorectic drugs. N Engl J Med 1999;340:480-482.
53. MacLean MR. Pulmonary hypertension, anorexigens and 5-HT: pharmacological synergism in action? Trends Pharmacol Sci 1999;20:490-495.
54. Mandegar M, Fung YC, Huang W, Remillard CV, Rubin LJ, Yuan JX. Cellular and molecular mechanisms of pulmonary vascular remodeling: Role in the development of pulmonary hypertension. Microvasc Res 2004;68:75-103.
55. Mandegar M, Remillard CV, Yuan JX. Ion channels in pulmonary arterial hypertension. Prog Cardiovasc Dis 2002;45:81-114.
56. + channels in pulmonary hypertension. Vasc Pharmacol 2002;38:25-33.
57. Massague J, Chen YG. Controlling TGF-beta signaling. Genes Dev 2000;14:627-644.
58. McCulloch KM, Osipenko ON, Gurney AM. Oxygen-sensing potassium currents in pulmonary artery. Gen Pharmacol 1999;32:403-411.
59. McLaughlin VV, Shillington A, Rich. Survival in primary pulmonary hypertension: The impact of epoprostenol therapy. Circulation 2002;106:1477-1482.
60. + channel axis in pulmonary arterial hypertension. Activation by experimental oral therapies. Adv Exp Med Biol 2003;543:293-322.
61. Michelakis ED, McMurtry MS, Wu XC, et al. Dichloroacetate, a metabolic modulator, prevents and reverses chronic hypoxic pulmonary hypertension in rats: Role of increased expression and activity of voltage-gated potassium channels. Circulation 2002;105:244-250.
62. Murray TR, Chen L, Marshall BE, Macarak EJ Hypoxic contraction of cultured pulmonary vascular smooth muscle cells. Am J Respir Cell Mol Biol 1990;3:457-465.
63. Naeije R, Rondelet B. Pathobiology of pulmonary arterial hypertension. Bull Mem Acad R Med Belg 2004;159:219-226.
64. Nagaya N, Uematsu M, Oya H, et al. Short-term oral administration of L-arginine improves hemodynamics and exercise capacity in patients with precapillary pulmonary hypertension. Am J Respir Crit Care Med 2001;163:887-891.
65. Nelson MT, Quayle JM. Physiological roles and properties of potassium channels in arterial smooth muscle. Am J Physiol 1995;268:C799-C822.
66. Olschewski H, Simonneau G, Galie N, et al. Aerosolized Iloprost Randomized Study Group. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002;347:322-329.
67. Ono K, Matsumori A. Endothelin antagonisms with bosentan: Current status and future perspectives. Cardiovasc Drug Rev 2002;20:1-18.
68. Packer M, Halperin JL, Brooks KM, Rothlauf EB, Lee WH. Nitroglycerin therapy in the management of pulmonary hypertensive disorders. Am J Med 1984;76:67-75.
69. Petkov V, Mosgoeller W, Ziesche R, et al. Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension. J Clin Invest 2003;111:1339-1346.
70. v1.5 reduces pulmonary hypertension and restores hypoxic pulmonary vasoconstriction in chronically hypoxic rats. Circulation 2003;107:2037-2044.
71. Rabinovitch M. Investigational approaches to pulmonary hypertension. Toxicol Pathol 1991;19:458-469.
72. Rabinovitch M. Elastase and the pathobiology of unexplained pulmonary hypertension. Chest 1998;114:213S-224S.
73. Rich S, Brundage BH. High-dose calcium channel-blocking therapy for primary pulmonary hypertension: Evidence for long-term reduction in pulmonary arterial pressure and regression of right ventricular hypertrophy. Circulation 1987;76:135-141.
74. Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992;327:76-81.
75. Rothman RB, Ayestas MA, Dersch CM, Baumann MH. Aminorex, fenfluramine, and chlorphentermine are serotonin transporter substrates. Implications for primary pulmonary hypertension. Circulation 1999;100:869-875.
76. Rubin LJ. primary pulmonary hypertension. Chest 1993;104:236-250.
77. Rubin LJ. Primary pulmonary hypertension. N Engl J Med 1997;336:111-117.
78. Russ RD, Walker BR. Maintained endothelium-dependent pulmonary vasodilation following chronic hypoxia in the rat. J Appl Physiol 1993;74:339-344.
79. Saini HK, Takeda N, Goyal RK, Kumamoto H, Arneja AS, Dhalla NS. Therapeutic potentials of sarpogrelate in cardiovascular disease. Cardiovasc Drug Revs 2004;22:27-54.
80. Sakura H, Ammala C, Smith PA, Gribble FM, Ashcroft FM. Cloning and functional expression of the cDNA encoding a novel ATP-sensitive potassium channel subunit expressed in pancreatic beta-cells, brain, heart and skeletal muscle. FEBS Lett 1995;377:338-344.
81. Seino S. ATP-sensitive potassium channels: A model of heteromultimeric potassium channel/receptor assemblies. Annu Rev Physiol 1999;61:337-362.
82. Simonneau G, Barst RJ, Galie N, et al.; Treprostinil Study Group. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: A double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med 2002;165:800-804.
83. Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004;43(12,Suppl S):5S-12S.
84. Sitbon O, Brenot F, Denjean A, et al. Inhaled nitric oxide as a screening vasodilator agent in primary pulmonary hypertension. A dose-response study and comparison with prostacyclin. Am J Respir Crit Care Med 1995;151:384-389.
85. Stenmark KR, Gerasimovskaya E, Nemenoff RA, Das M. Hypoxic activation of adventitial fibroblasts: Role in vascular remodeling. Chest 2002;122:326S-334S.
86. Stewart DJ, Levy RD, Ceraacek P, Langleben D. Increased plasma endothelin-1 in pulmonary hypertension: Marker or mediator of disease? Ann Intern Med 1991;114:464-469.
87. Stotz WH, Li D, Johns RA. Exogenous nitric oxide upregulates p21(waf1/cip1) in pulmonary microvascular smooth muscle cells. J Vasc Res 2004;41:211-219.
88. Takahashi T, Kanda T, Imai S, Suzuki T, Kobayashi I, Murata K Semotiadil inhibits the development of right ventricular hypertrophy and medial thickening of pulmonary arteries in a rat model of pulmonary hypertension. Cardiovasc Drugs Ther 1995;9:809-814.
89. Tozzi CA, Christiansen DL, Poiani GJ, Riley DJ. Excess collagen in hypertensive pulmonary arteries decreases vascular distensibility. Am J Respir Crit Care Med 1994;149:1317-1326.
90. Trina K Jeffery, Janet C. Wanstall. Pulmonary vascular remodeling: A target for therapeutic intervention in pulmonary hypertension. Pharmacol Ther 2001;92:1-20.
91. Tuder RM, Groves B, Badesch DB, Voelkel NF. Exuberant endothelial cell growth and elements of inflammation are present inplexiform lesions of pulmonary hypertension. Am J Pathol 1994;144:275-285.
92. Twarog BM, Takuno H, Petrou S, Wahlqvist I, Marcus R, Campbell GL. Pathogenesis of pulmonary hypertension in the rat model. Chest 1988;93:100S-101S.
93. Wadsworth RM. Vasoconstrictor and vasodilator effects of hypoxia. Trends Pharmacol Sci 1994;15:47-53.
94. Wang H, Long CL, Jia GD, et al. Effects of iptakalim hydrochloride on the functions of endothelin system. Chin Pharmacol Bull 2005;21:33-38.
95. Wang H, Long CL, Zhang YL. A new ATP-sensitive potassium channel opener reduces blood pressure and reverses cardiovascular remodeling in experimental hypertension. J Pharmacol Exp Ther 2005;312:1326-1333.
96. Wang H, Xie WP, Wang H, Hu G Effects of iptakalim on endothelin-1-induced pulmonary hypertension in rats. Chin J Clin Pharmacol Ther 2005;10:9-14.
97. Wang H, Zhang YL, Chen YP. Targeting small arteries of hypertensive status with novel ATP-sensitive potassium channel openers. Curr Vasc Pharmacol 2005;3,119-124.
98. Wang H. Pharmacological characteristics of the novel antihypertensive drug iptakalim hydrochloride and its molecular mechanisms. Drug Dev Res 2002;54:240-241.
99. + channel in 24 hour-hypoxic human pulmonary artery smooth muscle cells. Chin Med J (Engl) 2005;118:12-19.
100. Wanstall JC, Hughes IE, O'Donnell SR. Evidence that nitric oxide from the endothelium attenuates inherent tone in isolated pulmonary arteries from rats with hypoxic pulmonary hypertension. Br J Pharmacol 1995;114:109-114.
101. Wanstall JC. In vitro hypoxia attenuates vasorelaxation by potassium channel opening drugs and nitroprusside in isolated pulmonary arteries from rats. J Pharmacol Exp Ther 1994;271:845-851.
102. Wanstall JC. The pulmonary vasodilator properties of potassium channel opening drugs. Gen Pharmacol 1996;27:599-605.
103. Wohrley JD, Frid MG, Moiseeva EP, Orton EC, Belknap JK, Stenmark KR. Hypoxia selectively induces proliferation in a specific subpopulation of smooth muscle cells in the bovine neonatal pulmonary arterial media. J Clin Invest 1995;96:273-281.
104. Wong J, Vanderford PA, Fineman JR, Chang R, Soifer SJ. Endothelin-1 produces pulmonary vasodilation in the intact newborn lamb. Am J Physiol 1993;265:H1318-H1325.
105. Xiao X, Chen W, Cheng D. Inhibition of potassium channel by chronic hypoxia on pulmonary artery smooth muscle cells in rats. Zhonghua Jie He He Hu Xi Za Zhi 1998;21:681-685.
106. + channel of pulmonary arterial smooth muscle cells in pulmonary hypertensive rats. Zhonghua Jie He He Hu Xi Za Zhi 2003;26:97-100.
107. ATPCO iptakalim on airway hyperresponsiveness and remodeling in guinea pigs with asthma. Chin J Clin Pharmacol Ther 2005;10:128-132.
108. Xie WP, Ding JH, Wang H, Wang H, Hu G. Effects of pinacidil on proliferation of cultured rabbit pulmonary arterial smooth muscle cells induced by endothelin-1. Chin J Clin Pharmacol Ther 2005;10:20-23.
109. ATP channel opener, in cultured rabbit pulmonary arterial smooth muscle cells. Eur J Pharmacol 2005;511:81-87.
110. ATP channel opener, on pulmonary vascular remodeling in hypoxic rats. Life Sci 2004;75:2065-2076.
111. Xie WP, Wang H, Wang H, Li BZ, Hu G. Effects of iptakalim, a novel ATP-sensitive potassium channel opener, on hypoxia-induced pulmonary vascular remodeling in rats. Chin J Appl Physiol 2003;19:4-7.
112. Yi ES, Kim H, Ahn H, et al. Distribution of obstructive intimal lesions and their cellular phenotypes in chronic pulmonary hypertension: A morphometric and immunohistochemical study. Am J Respir Crit Care Med 2000;162:1577-1586.
113. Yuan XJ, Tod ML, Rubin LJ, Blaustein MP. Contrasting effects of hypoxia on tension in rat pulmonary and mesenteric arteries. Am J Physiol 1990;259:H281-H289.
114. Zamora MR, Stelzner TJ, Webb S, Panos RJ, Ruff LJ, Dempsey EC. Overexpression of endothelin-1 and enhanced growth of pulmonary artery smooth muscle cells from fawn-hooded rats. Am J Physiol 1996;270:L101-L109.
115. Zhang HL, Bolton TB. Two types of ATP-sensitive potassium channels in rat portal vein smooth muscle cells. Br J Pharmacol 1996;118:105-114.
116. Zhang S, Fantozzi I, Tigno DD, et al. Bone morphogenetic proteins induce apoptosis in human pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 2003;285:L740-L754.
117. 2+ in cultured human pulmonary artery smooth muscle cells. Am J Physiol Cell Physiol 2005;288:C245-C252.
118. + channel in pulmonary artery smooth muscle cells from rats exposed to chronic hypoxia. Zhonghua Jie He He Hu Xi Za Zhi 2003;26:93-96.
119. Zhao Y, Parker CS, Rhoades RA. Pulmonary veins contract in response to hypoxia. Am J Physiol 1993;265:L87-L92.