application): Colloidal or crystalloid solutions are used to restore blood volume up to the transfusion trigger of 7g Hb/dL. Their use beyond this threshold reduces oxygen carrying capacity, which limits tissue oxygen delivery and survival. This proposal examines the hypothesis that the lack of clinical benefit for plasma expanders (PEs) beyond the transfusion trigger is due to a microvascular malfunction, not due to a reduced oxygen carrying capacity. In particular, alteration of blood properties, including viscosity and oncotic pressure, beyond the transfusion trigger causes: 1) arteriolar vasoconstriction and decreased blood flow; 2) reduced functional capillary density (FCD); and, 3) lowered tissue oxygenation. A proposed mechanism underlying these changes is that below the transfusion trigger blood and plasma viscosity are reduced beyond the compensatory capacity of the cardiovascular system, which causes capillary pressure to decrease, capillaries to become obstructed, and a lowering of FCD. Furthermore, the viscosity of blood with conventional PEs is too low to generate endothelial NO through arteriolar wall shear stress, resulting in reduced vascular tone and increased mitochondrial O2 consumption. The proposed studies will use dextran and starch solutions with different viscosities as PEs in hamster studies using the skin fold microcirculatory model.
The aim will be to partially restore the viscosity of the circulating blood to near normal values in extreme hemodilution (hemodilution beyond the transfusion trigger.) and examine the stated hypothesis by direct in vivo measurement of micro-p02 and micro-NO in blood and tissue, capillary pressure, blood flow velocity, functional capillary density and arteriolar reactivity. In particular the correlation between FCD, a key determinant of tissue survival, and NO regulation will be explored.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL062354-03
Application #
6527545
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Mondoro, Traci
Project Start
2000-09-01
Project End
2004-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
3
Fiscal Year
2002
Total Cost
$366,945
Indirect Cost
Name
University of California San Diego
Department
Engineering (All Types)
Type
Schools of Arts and Sciences
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Roche, Camille J; Talwar, Abhinav; Palmer, Andre F et al. (2015) Evaluating the capacity to generate and preserve nitric oxide bioactivity in highly purified earthworm erythrocruorin: a giant polymeric hemoglobin with potential blood substitute properties. J Biol Chem 290:99-117
Cabrales, Pedro; Ortiz, Daniel; Friedman, Joel M (2015) NO supplementation for transfusion medicine and cardiovascular applications. Future Sci OA 1:
Meng, Fantao; Tsai, Amy G; Intaglietta, Marcos et al. (2015) PEGylation of ??-Hb using succinimidyl propionic acid PEG 5K: Conjugation chemistry and PEG shell structure dictate respectively the oxygen affinity and resuscitation fluid like properties of PEG ??-Hbs. Artif Cells Nanomed Biotechnol 43:270-81
Yalcin, Ozlem; Ortiz, Daniel; Tsai, Amy G et al. (2014) Microhemodynamic aberrations created by transfusion of stored blood. Transfusion 54:1015-27
Ortiz, Daniel; Briceño, Juan Carlos; Cabrales, Pedro (2014) Microhemodynamic parameters quantification from intravital microscopy videos. Physiol Meas 35:351-67
Mooij, H L; Cabrales, P; Bernelot Moens, S J et al. (2014) Loss of function in heparan sulfate elongation genes EXT1 and EXT 2 results in improved nitric oxide bioavailability and endothelial function. J Am Heart Assoc 3:e001274
Liong, Celine; Ortiz, Daniel; Ao-ieong, Eilleen et al. (2014) Localized increase of tissue oxygen tension by magnetic targeted drug delivery. Nanotechnology 25:265102
Castro, C; Ortiz, D; Palmer, A F et al. (2014) Hemodynamics and tissue oxygenation after hemodilution with ultrahigh molecular weight polymerized albumin. Minerva Anestesiol 80:537-46
Salazar Vázquez, Beatriz Y; Hightower, C Makena; Yalcin, Ozlem et al. (2013) Semisynthetic hybrid biopolymers for non-pharmacological intervention of the microcirculation. Curr Drug Metab 14:540-6
Ortiz, Daniel; Cabrales, Pedro; Briceño, Juan C (2013) Transport of nitric oxide by perfluorocarbon emulsion. Biotechnol Prog 29:1565-72

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