The overall aim of this renewal proposal is to uncover the mechanisms that underlie plasma volume expansion. We have developed two models to study these mechanisms. Our human model, involving 32 min of intense exercise, produces a 10% plasma volume and albumin expansion within the following 24 h. Our animal model, involving hypotensive hemorrhage in rats, produces a complete recovery of both volume and albumin within 24 h. Although the human and animal models differ from each other in certain respects, the two are sufficiently analogous to permit us to generate and test hypotheses in humans and then perform more invasive experiments to uncover mechanisms in rats. Using the human model, we will test the following hypotheses: i) the fall in central venous and/or mean arterial pressure following intense exercise are the primary signals that initiate events leading to increased plasma albumin content. ii) an initial (1-2 h) elevation in plasma albumin content after intense exercise is of interstitial origin and the subsequent (24 h) elevation in plasma albumin content is due to increased hepatic albumin synthetic rate. iii) acute albumin expansion is not sufficient to expand the plasma volume after 24 h. iv) the transcapillary escape rate of albumin is decreased after intense exercise. Using the animal model, we will test the following hypotheses: i) increased albumin synthesis is initiated within hours following hemorrhage. ii) increased albumin synthesis following hemorrhage is due to increased hepatic albumin mRNA transcription. iii) increased hepatic albumin mRNA transcription following hemorrhage is initiated by neural signals generated by unloading cardiopulmonary and/or arterial baroreceptors. iv) certain of the salt and water retention hormones cause increased hepatic albumin mRNA transcription in an isolated, perfused liver preparation. v) a portion of the increased albumin content following hemorrhage is due to a reduction in the transcapillary escape rate of albumin. Our studies characterizing the mechanisms underlying plasma albumin synthesis during recovery from exercise in humans and hemorrhage in in vitro and in vivo animal models will provide insight into the mechanisms underlying volume restoration. Such knowledge will lead to the development of methods to volume-expand compromised individuals more effectively without transfusion. Our employment of both human and animal models enables the testing of hypotheses that are both relevant and mechanistic.
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