Enhanced oxygenation in vivo by allosteric inhibitors of hemoglobin saturation.
The in vivo effects on hemoglobin (Hb)-O2 affinity and tissue PO2 were investigated after intraperitoneal administration of 2-[4-(((dichloroanilino)-carbonyl)methyl)phenoxyl]-2-methyl propionic acid (RSR4; 150 mg/kg) or its 3,5-dimethyl derivative (RSR13; 300 mg/kg) in C3Hf/Sed mice. The Hb-O2 dissociation curve was plotted from tail vein blood samples using an O2 dissociation analyzer before and up to 160 min after compound administration. Twenty to 40 min after injection, the PO2 at 50% saturation of hemoglobin (Hb P50) increased by a mean of 25% (range 18-31%) after RSR4 and 53% (range 36-76%) after RSR13. Tissue PO2 was continuously measured using an O2 microelectrode in thigh muscle before and up to 40 min after RSR4 or RSR13 injection. Twenty to 40 min after administration, tissue PO2 increased by a mean of 78% (range 30-127%) after RSR4 and 66% (range 39-97%) after RSR13 administration in anesthetized mice. No change in tissue PO2 was seen in anesthetized controls.
Khandelwal
S R
SR
Department of Radiation Oncology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298.
Randad
R S
RS
Lin
P S
PS
Meng
H
H
Pittman
R N
RN
Kontos
H A
HA
Choi
S C
SC
Abraham
D J
DJ
Schmidt-Ullrich
R
R
D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006454:Hemoglobins / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009132:Muscles / Q000378:metabolism; D010100:Oxygen / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D010313:Partial Pressure; D011422:Propionates / Q000494:pharmacology*
D000814:Aniline Compounds; D006454:Hemoglobins; D011422:Propionates; C077066:4-(2-(4-(((3,5-dichloroanilino)carbonyl)methyl)phenoxy)-2-methylpropionic acid); C067396:efaproxiral; D010100:Oxygen