Chronic hypoxemia is a common manifestation of pulmonary disease as well as of exposure of healthy individuals to the reduced barometric pressure of high altitude. Although the effects of acute hypoxic exposure on cardiovascular control have been described, little is known of the effect of chronic hypoxemia on neurohumoral control of the cardiovascular system. Preliminary data from our laboratory suggest that prolonged hypoxemia may elicit attenuated vasoreactive responses to major pressor stimuli, as well as altered arterial baroreflex function. Both of these responses could greatly alter the efficacy of cardiovascular control under these clinically relevant conditions. The present application is designed to extend our pilot observations and to attempt to define the mechanisms involved in hypoxia-induced alterations in cardiovascular function using both in vivo and in vitro approaches. Specific goals of the project are: 1) To determine whether the observed attenuation in systemic vasoreactivity to alpha-agonist, vasopressin, or angiotensin II administration is present selectively in different vascular beds of the conscious chronically instrumented animal. 2) To test whether a portion of the attenuated pressor response in chronically hypoxemic animals is due to augmented arterial baroreflex function. 3) To examine the in vitro responses of arteries from chronically hypoxic animals to determine if the attenuated responsiveness to pressor agonists may be due to a common effect on vascular smooth muscle. Since our pilot data indicate that diminished responsiveness to pressor agonists is demonstrable in aortic rings from chronically hypoxic rats, the next specific aims will address possible mechanisms for that attenuation, such as: 4) To examine the possibility that vascular smooth muscle contraction is attenuated due to increased release of vasodilatory modulators such as endothelium derived relaxing factor, prostacyclin or adenosine. 5) To test whether there is a reduction in agonist receptor number or affinity in chronically hypoxic rats. 6) To test whether chronic hypoxia affects intracellular signal transduction within vascular smooth muscle cells, thereby reducing agonist- induced contraction. The experiments in the proposal utilize both in vitro preparations and conscious animals, and are designed such that positive findings in the in vitro experiments will be corroborated where possible in the intact animal. This approach allows determination of the significance of putative cellular mechanisms in the integrated response to hypoxemia by the whole animal.
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