The long-term objectives of this project are to gain a better understanding of the pathophysiological effects and the adaptive mechanisms of high altitude (HA) or chronic hypoxic (CH) exposure. Excessive polycythemia (EP) and severe pulmonary hypertension (PH) are the two most deletions effects of HA exposure and are also frequent and important clinical problems in patients suffering from heart, lung and blood diseases. Elucidation of the causes of the EP and PH therefore constitutes the important task in HA physiology, and is also of clinical relevance for hypoxemic patients at both sea level and HA. Upon exposure to CH, the Hilltop (H) strain of Sprague-Dawley rats develops EP and severe PH and suffers a high mortality rate, while the Madison (M) strain exhibits only moderate polycythemia and PH and remains healthy. These animal models provide responsible for the strain differences in coping with CH. Hypoxic pulmonary vasoconstrictive response (HPVR) is an important factor contributing to PH. Attenuation of the HPVR which occurs in the M rats in CH minimizes the severity of the PH and facilities their acclimatization to CH, whereas absence of this attenuation in the response to prolonged hypoxia in H rats aggravates PH and the susceptibility of these animals to the morbid effects of CH. Thus, attenuation of HPVR may represent an important adaptive mechanism in CH. Atrial natriuretic factor (ANF) -- a naturally occurring antagonist of pulmonary vasoconstriction that is released under both acute and chronic hypoxia --- may contribute to this adaptive mechanism. There are two specific aims in this project. The first is to evaluate the roles of the following factors in EP: 1) accentuated renal venous hypoxemia and its cause(s), 2) hypoventilation, 3) increased sensitivity of EPO-production to hypoxia, 4) increased sensitivity of the erythroid progenitor cells to EPO, 5) increased splenic erythropoiesis and 6) impaired feedback control of erythropoiesis. The second specific aim is to evaluate the following roles of ANF: 1) increased release of ANF attenuates HPVR in CH, 2) altered ANF release and/or 3) altered sensitivity of HPVR to inhibition by ANF, account for the strain differences in the attenuation of the HPVR in CH.
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