Hemoglobins will be used as a blood substitute if the cardiovascular actions of these solutions do not cause significant toxicity. The objective of this application is to determine the physiologic actions of bovine polymerized hemoglobins in dogs. Since hemoglobin binds nitric oxide the specific aims of our proposal are to determine how hemoglobin interferes with the physiologic control of the circulation by NO. The most obvious change which occurs in the circulation after administration of hemoglobin containing solutions is an increase in arterial pressure and vascular resistance. An understanding of the mechanisms responsible for this, the site of the increase in resistance and modulation by reflex mechanisms will be the first specific aim of this proposal. The second specific aim will focus on the ability of hemoglobin containing solutions to scavenge NO. This depends primarily on the ability of tetrameric hemoglobin to diffuse between the endothelial cell and the underlying smooth muscle cell. We propose that polymers of hemoglobin will not diffuse due to the large size and will not increase arterial pressure. After all, hemoglobin contained in red cells does not scavenge interstitial EDRF. The third specific aim of our proposal is that hemoglobin containing solutions also alter the way in which oxygen is used by the peripheral tissues. This is based on the observation that inhibition of NO formation using substituted arginine molecules markedly alters oxygen extraction and consumption by the heart and skeletal muscle. The fourth specific aim is to determine if the repeated administration of hemoglobin containing solutions alters the production of NO by blood vessels and the biochemical and molecular mechanism responsible for this. Our studies will be conducted in chronically instrumented dogs and tissues from the same animals. This, we believe will allow extrapolation of our results to cardiovascular control in man and to a understanding of the mechanisms of cardiovascular control which are modified by hemoglobin containing solutions.
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