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Strain Differences of Hypoxia-Induced Pulmonary Hypertension

  • Chapter
Hypoxic Pulmonary Vasoconstriction

Part of the book series: Developments in Cardiovascular Medicine ((DICM,volume 252))

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Conclusion

Differences in the severity of hypoxia-induced pulmonary hypertension between species and strains have long been known, based on the work of high altitude physiologists on species adapted to high altitude. The mechanisms responsible for these differences are of interest not only to physiologists, but also to clinicians, because understanding them could lead to valuable insights into the regulation of vascular tone as well as to potential therapies for pulmonary hypertension. One of the most studied models has been the Madison and Hilltop strains of Sprague Dawley rat that have markedly different cardiopulmonary responses to both acute and chronic hypoxia. These differences are heritable and associated with differences in vascular reactivity. Notably, the strains exhibit a dissociation between the intensities of acute and chronic hypoxic pulmonary hypertension. The Madison rats have a more intense acute vasoconstrictor response than the Hilltops, but then promptly blunt the response so that the severity of chronic hypoxic pulmonary hypertension is considerably less than in the Hilltops that fail to blunt. The biochemical/cellular mechanisms underlying this interesting phenomenon have not been elucidated. Although the strains also have differing polycythemic responses that parallel the cardiopulmonary differences, these hematologic differences do not appear to be contributing to the cardiopulmonary differences. Pulmonary artery rings isolated from the 2 strains retain the differences in reactivity to acute hypoxic exposure, and stripping the endothelium eliminates the difference, suggesting that an endothelium-derived mediator is at least partly responsible for the differences. Endothelin 1 appears to contribute to strain differences in some cases, such as those observed between the Wistar-Kyoto and Fisher 344 rat strains, but not in the Madison and Hilltop rats. There is evidence for EDHF release in pulmonary arteries isolated from normoxic Madisons but not Hilltops. However, the reasons for the enhanced susceptibility to chronic hypoxia remain unclear. Genetic approaches including cross-breeding and gene array experiments may yield additional insights, but as yet, the fundamental mechanisms responsible for enhancement of cardio- pulmonary responses to hypoxia remain largely unknown.

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Authors and Affiliations

  1. Wyeth Pharmaceuticals, Richmond, Virginia

    Mallik R. Karamsetty, James C. Leiter, Lo Chang Ou, Ioana R. Preston & Nicholas S. Hill

  2. Dartmouth Medical School, Lebanon, New Hampshire

    Mallik R. Karamsetty, James C. Leiter, Lo Chang Ou, Ioana R. Preston & Nicholas S. Hill

  3. Tufts University, Boston, Massachusetts, USA

    Mallik R. Karamsetty, James C. Leiter, Lo Chang Ou, Ioana R. Preston & Nicholas S. Hill

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  1. Department of Medicine, University of California, San Diego School of Medicine, San Diego, California

    Jason X. -J. Yuan M.D., Ph.D.

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© 2004 Kluwer Academic Publishers

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Karamsetty, M.R., Leiter, J.C., Ou, L.C., Preston, I.R., Hill, N.S. (2004). Strain Differences of Hypoxia-Induced Pulmonary Hypertension. In: Yuan, J.X.J. (eds) Hypoxic Pulmonary Vasoconstriction. Developments in Cardiovascular Medicine, vol 252. Springer, Boston, MA. https://doi.org/10.1007/1-4020-7858-7_30

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  • DOI: https://doi.org/10.1007/1-4020-7858-7_30

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