When oxygen supply is supply is lowered until oxygen uptake becomes limited, the body compensates by directing blood flow to areas of greatest need. This occurs at the organ system level as well as within regional circulations as the result of vigorous vasoconstrictor tone being modulated by local vasodilatory factors produced in proportion to the imbalance between oxygen supply and demand. Decompensation occurs when local dilatoy forces in nonvital areas such as resting skeletal muscle overcome vasoconstriction and are able to divert blood flow away from more vital organ systems. At that point mean arterial pressure begins a precipitous fall that marks the end of survival time for the whole organism in hypoxia. Although this basic regulatory scheme is well established, we do not know what role is played within that framework by adrenergic receptor subtypes and nonadrenergic vasoconstictors, particularly if hypotensive ischemic hypoxia is compared with hypoxic hypoxia. Furthermore, the separate vasodilator actions of low vascular PO2 and locally produced hypoxic metabolites have not been evaluated. The overall goal is to put all of these elements into perspective in terms of bringing about the onset of decompensation to the two types of hypoxia.
specific Aim #1 will measure the respective contributions of alpha 1 and alpha 2-adrenergic receptors to vasoconstrictor tone in resting, normoxic skeletal muscle.
Specific Aim #2 will determine whether that balance is altered by the two forms of hypoxia and how much is neurally mediated.
Specific Aim #3 will establish the importance of nonadrenergic vasoconstrictor, arginine vasopressin and angiotensin II, and any difference in their contributions during the two types of hypoxia.
Specific Aim #4 will study how each vasoconstrictor element affects time to decompensate in hypoxia and the specific vasodilator contributions of locally produced metabolites and of low vascular PO2 to that time. New information will be forthcoming from the use of specific antagonists, a nerve cooling probe for reversible block, and a pump-membrane oxygenator system to dissociate muscle oxygenation from that of the whole body. In addition to furnishing basic physiological information about control of peripheral oxygenation in hypoxia that is not presently available, the results may also suggest more efficacious therapeutic approaches to preserving vital functions in respiratory and circulatory failure.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Experimental Cardiovascular Sciences Study Section (ECS)
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University of Alabama Birmingham
Schools of Dentistry
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Curtis, S E; Vallet, B; Winn, M J et al. (1995) Role of the vascular endothelium in O2 extraction during progressive ischemia in canine skeletal muscle. J Appl Physiol 79:1351-60
King-Vanvlack, C E; Curtis, S E; Mewburn, J D et al. (1995) Role of endothelial factors in active hyperemic responses in contracting canine muscle. J Appl Physiol 79:107-12
Vallet, B; Lund, N; Curtis, S E et al. (1994) Gut and muscle tissue PO2 in endotoxemic dogs during shock and resuscitation. J Appl Physiol 76:793-800
Cain, S M (1994) Oxygen delivery and intentional hemodilution. Adv Exp Med Biol 361:271-8
Cain, S M; Curtis, S E; Vallet, B et al. (1994) Resuscitation of dogs from endotoxic shock by continuous dextran infusion with and without perflubron added. Adv Exp Med Biol 345:235-42
Winn, M J; Vallet, B; Curtis, S E et al. (1994) Critical oxygen extraction in dog hindlimb after inhibition of nitric oxide synthase and cyclooxygenase systems. Adv Exp Med Biol 361:295-301
King, C E; Melinyshyn, M J; Mewburn, J D et al. (1994) Canine hindlimb blood flow and O2 uptake after inhibition of EDRF/NO synthesis. J Appl Physiol 76:1166-71
Vallet, B; Winn, M J; Asante, N K et al. (1994) Influence of oxygen on endothelium-derived relaxing factor/nitric oxide and K(+)-dependent regulation of vascular tone. J Cardiovasc Pharmacol 24:595-602
Vallet, B; Curtis, S E; Winn, M J et al. (1994) Hypoxic vasodilation does not require nitric oxide (EDRF/NO) synthesis. J Appl Physiol 76:1256-61
King, C E; Curtis, S E; Winn, M J et al. (1994) The role of endothelium-derived relaxing factor (EDRF) in the whole body and hindlimb vascular responses during hypoxic hypoxia. Adv Exp Med Biol 361:285-93

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