Constant daily hypoxia leads to different degrees of pulmonary hypertension in two different rat strains

Chadi E. Bouserhal, Erik van Lunteren, Frank J. Jacono, Kingman P. Strohl

Division of Pulmonary, Critical Care and Sleep Medicine, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, University Hospitals Case Medical Center and Case Western Reserve University, Cleveland, USA.

DOI: 10.4236/ojmip.2012.23012                

Abstract

Pulmonary diseases associated with diurnal hypoxemia are known to be associated with pulmonary hypertension in some patients. In this study we examined the effects of daily hypoxia (10% oxygen; 8h/day for 14 days) on two strains of rats to simulate sleep related hypoxia in pulmonary diseases expecting to find differences in vascular responses, the develop-ment of right ventricular hypertrophy and pulmonary hypertension according to genetic background. In response to daily hypoxia, Sprague Dawley rats developed right ventricular hypertrophy while Brown Norway rats did not. Both strains developed pulmonary hypertension (elevated right ventricular pressure) although the increase was significantly greater in the Sprague Dawley strain. Pulmonary artery (first branch) vasoconstrictive responses to potassium chloride were increased equally in both strains and the subsequent vasodilation with acetylcholine were reduced equally with daily hypoxia in both strains. Taken together, these findings suggest that the genetic makeup of the rats contributed significantly to the development of right ventricular hypertrophy and the degree of pulmonary hypertension. Moreover, this response is not secondary to differences in the intralobar pulmonary vascular reactivity. Genetic background could explain why certain patients do worse with hypoxia inducing pulmonary vascular diseases.

Keywords

Pulmonary Hypertension; Daily Hypoxia; Right Ventricular Hypertrophy; Pulmonary Artery; Contractility

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Bradley, T.D., Rutherford, R., Grossman, R.F., Lue, F., Zamel, N., Moldofsky, H. and Phillipson, E.A. (1985) Role of daytime hypoxemia in the pathogenesis of right heart failure in the obstructive sleep apnea syndrome. American Review of Respiratory Disease, 131, 835-839.
[2]	Hedner, J. (1996) Vascular function in OSA. Sleep, 19, S213-S217.
[3]	Shahar, E., Whitney, C.W., Redline, S., Lee, E.T., Newman, A.B., Javier, Nieto, F., O’Connor, G.T., Boland, L.L., Schwartz, J.E. and Samet, J.M. (2001) Sleep-disordered breathing and cardiovascular disease: Cross-sectional results of the sleep heart health study. American Journal of Respiratory and Critical Care Medicine, 163, 19-25.
[4]	Weitzenblum, E., Krieger, J., Apprill, M., Vallee, E., Herhart, M., Ratomaharo, J., Oswald, M. and Kurtz, D. (1988) Daytime pulmonary hypertension in patients with obstructive sleep apnea syndrome. American Review of Respiratory Disease, 138, 345-349.
[5]	Tobin, M.J. (2001) Chronic obstructive pulmonary disease, pollution, pulmonary vascular disease, transplantation, pleural disease, and lung cancer in AJRCCM 2000. American Journal of Respiratory and Critical Care Medicine, 164, 1789-1804.
[6]	Niermeyer, S., Yang, P., Shanmina, Drolkar, Zhuang, J., and Moore, L.G. (1995) Arterial oxygen saturation in Tibetan and Han infants born in Lhasa, Tibet. New England Journal of Medicine, 333, 1248-1252. doi:10.1056/NEJM199511093331903
[7]	Jin, X.R., Fan, M., Wang, Z.Q., Su, Y.C., Yang, G.T., Hu, H.B., Zhang, Y.P., Feng, C.J., Ding, Y.X. and Wang, D.X. (1990) Strain difference in pulmonary vascular responsiveness to hypoxia in rats. Journal of Tongji Medical University, 10, 134-140. doi:10.1007/BF02986450
[8]	Thomas, B.J. and Wanstall, J.C. (2003) Alterations in pulmonary vascular function in rats exposed to intermittent hypoxia. European Journal of Pharmacology, 477, 153-161. doi:10.1016/j.ejphar.2003.08.015
[9]	Rafanan, A.L., Golish, J.A., Dinner, D.S., Hague, L.K. and Arroliga, A.C. (2001) Nocturnal hypoxemia is common in primary pulmonary hypertension. Chest, 120, 894-899. doi:10.1378/chest.120.3.894
[10]	Simonneau, G., Galie, N., Rubin, L.J., Langleben, D., Seeger, W., Domenighetti, G., Gibbs, S., Lebrec, D., Speich, R., Beghetti, M., Rich, S. and Fishman, A. (2004) Clinical classification of pulmonary hypertension. Journal of the American College of Cardiology, 43, 5S-12S. doi:10.1016/j.jacc.2004.02.037
[11]	Fagan, K.A. and Weil, J.V. (2001) Potential genetic contributions to control of the pulmonary circulation and ventilation at high altitude. High Altitude Medicine & Biology, 2, 165-171. doi:10.1089/152702901750265279
[12]	Mortola, J.P. (2004) Breathing around the clock: An overview of the circadian pattern of respiration. European Journal of Applied Physiology, 91, 119-129. doi:10.1007/s00421-003-0978-0
[13]	Nattie, E.E., Bartlett, D. Jr. and Johnson, K. (1978) Pulmonary hypertension and right ventricular hypertrophy caused by intermittent hypoxia and hypercapnia in the rat. American Review of Respiratory Disease, 118, 653-658.
[14]	Fagan, K.A. (2001) Selected contribution: Pulmonary hypertension in mice following intermittent hypoxia. Journal of Applied Physiology, 90, 2502-2507.
[15]	Rogers, T.K., Stewart, A.G. and Morice, A.H. (1992) Effect of chronic hypoxia on rat pulmonary resistance vessels: Vasodilatation by atrial natriuretic peptide. Clinical Science, 83, 723-729.
[16]	McIntyre, C.A., Buckley, C.H., Jones, G.C., Sandeep, T.C., Andrews, R.C., Elliott, A.I., Gray, G.A., Williams, B.C., McKnight, J.A., Walker, B.R. and Hadoke, P.W. (2001) Endothelium-derived hyperpolarizing factor and potassium use different mechanisms to induce relaxation of human subcutaneous resistance arteries. British Journal of Pharmacology, 133, 902-908. doi:10.1038/sj.bjp.0704143
[17]	Li, J., Grigoryev, D.N., Ye, S.Q., Thorne, L., Schwartz, A.R., Smith, P.L., O’Donnell, C.P. and Polotsky, V.Y. (2005) Chronic intermittent hypoxia upregulates genes of lipid biosynthesis in obese mice. Journal of Applied Physiology, 99, 1643-1648. doi:10.1152/japplphysiol.00522.2005
[18]	Polotsky, V.Y., Li, J., Punjabi, N.M., Rubin, A.E., Smith, P.L., Schwartz, A.R. and O’Donnell, C.P. (2003) Intermittent hypoxia increases insulin resistance in genetically obese mice. Journal of Physiology, 552, 253-264. doi:10.1113/jphysiol.2003.048173
[19]	Brindeiro, T.C.M., da Silva, A.Q., Allahdadi, K.J., Youngblood, V. and Kanagy, N.L. (2007) Reactive oxygen species contribute to sleep apnea-induced hypertension in rats. American Journal of Physiology Heart and Circulatory Physiology, 293, H2971-H2976. doi:10.1152/ajpheart.00219.2007
[20]	Snow, J.B., Kitzis, V., Norton, C.E., Torres, S.N., Johnson, K.D., Kanagy, N.L., Walker, B.R. and Resta, T.C. (2007) Differential effects of chronic hypoxia and intermittent hypocapnic and eucapnic hypoxia on pulmonary vasoreactivity. Journal of Applied Physiology, 101, 110118. doi:10.1152/japplphysiol.00698.2005
[21]	Tagaito, Y., Polotsky, V.Y., Campen, M.J., Wilson, J.A., Balbir, A., Smith, P.L., Schwartz, A.R. and O’Donnell, C.P. (2001) A model of sleep-disordered breathing in the C57BL/6J mouse. Journal of Applied Physiology, 91, 2758-2766.
[22]	Bao, G., Metreveli, N., Li, R., Taylor, A. and Fletcher, E.C. (1997) Blood pressure response to chronic episodic hypoxia: Role of the sympathetic nervous system. Journal of Applied Physiology, 83, 95-101.
[23]	Subramanian, S., Dostal, J., Erokwu, B., Han, F., Dick, T.E. and Strohl, K.P. (2007) Domperidone and ventilatory behavior: Sprague-Dawley versus Brown Norway rats. Respiratory Physiology & Neurobiology, 155, 22-28. doi:10.1016/j.resp.2006.04.002
[24]	Subramanian, S., Erokwu, B., Han, F., Dick, T.E. and Strohl, K.P. (2002) L-NAME differentially alters ventilatory behavior in Sprague-Dawley and Brown Norway rats. Journal of Applied Physiology, 93, 984-989.
[25]	Kitada, K., Voigt, B., Kondo, Y. and Serikawa, T. (2000) An integrated rat genome map based on genetic and cytogenetic data. Experimental Animals, 49, 119-126. doi:10.1538/expanim.49.119
[26]	Sajkov, D., Wang, T., Saunders, N.A., Bune, A.J., Neill, A.M. and Mcevoy, D.R. (1999) Daytime pulmonary hemodynamics in patients with obstructive sleep apnea without lung disease. American Journal of Respiratory and Critical Care Medicine, 159, 1518-1526.
[27]	Bao, G., Randhawa, P.M. and Fletcher, E.C. (1997) Acute blood pressure elevation during repetitive hypocapnic and eucapnic hypoxia in rats. Journal of Applied Physiology, 82, 1071-1078.
[28]	Baudouin, S.V. and Evans, T.W. (1993) Action of carbon dioxide on hypoxic pulmonary vasoconstriction in the rat lung: Evidence against specific endothelium-derived relaxing factor-mediated vasodilation. Critical Care Medicine, 21, 740-746. doi:10.1097/00003246-199305000-00018