Biomaterial Database

Crosslinked hemoglobin inhibits endothelium-dependent relaxations in isolated canine arteries. 1996

Z S Katusić, and H C Lee, and E T Clambey

Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905, USA.

1. Several previous in vivo studies demonstrated that crosslinked hemoglobin is a potent vasoconstrictor capable of significantly increasing arterial blood pressure following systemic administration. The precise mechanisms underlying the vascular effects of crosslinked hemoglobin are not clear. The present study was designed to determine the effect of crosslinked hemoglobin on the endothelial L-arginine-nitric oxide biosynthesis pathway in isolated canine arteries. 2. Isolated femoral and renal arteries were suspended in organ chambers for isometric tension recordings. Endothelium-dependent relaxations to acetylcholine and calcium ionophore A23187 were studied in the absence or in the presence of crosslinked hemoglobin or hemoglobin. A radioimmunoassay technique was used to determine levels of guanosine 3',5'-cyclic monophosphate (cyclic GMP) and adenosine 3',5'-cyclic monophosphate (cyclic AMP). 3. A nitric oxide synthase inhibitor L-NAME (10(-4)M) selectively inhibited endothelium-dependent relaxations to acetylcholine and calcium ionophore A23187. The inhibitory effect of L-NAME was reversed by L-arginine (3 x 10(-4)M). Crosslinked hemoglobin (10(-7), 10(-6) and 10(-5)M) inhibited endothelium-dependent relaxations to acetylcholine (10(-9)-10(-5)M) or A23187 (10(-9)-10(-6)M). In the same concentration range, purified bovine hemoglobin exerted a similar inhibitory effect on relaxations mediated by activation of endothelial cells. Crosslinked hemoglobin (10(-6)M) significantly reduced basal production of cyclic GMP, but did not affect production of cyclic AMP. Acetylcholine (10(-6)M) stimulated production of cyclic GMP. This effect of acetylcholine was abolished in the presence of crosslinked hemoglobin. 4. These studies demonstrate that crosslinked hemoglobin impairs endothelium-dependent relaxations in isolated large conduit arteries. This effect appears to be mediated by the chemical antagonism of crosslinked hemoglobin against nitric oxide released from the endothelium. Inhibition of the endothelial L-arginine-nitric oxide biosynthesis pathway, with subsequent decrease of cyclic GMP in smooth muscle, may help to explain vasoconstrictor and pressor effects of crosslinked hemoglobin.

UI	MeSH Term	Description	Entries
D009569	Nitric Oxide	A free radical gas produced endogenously by a variety of mammalian cells, synthesized from ARGININE by NITRIC OXIDE SYNTHASE. Nitric oxide is one of the ENDOTHELIUM-DEPENDENT RELAXING FACTORS released by the vascular endothelium and mediates VASODILATION. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic GUANYLATE CYCLASE and thus elevates intracellular levels of CYCLIC GMP.	Endogenous Nitrate Vasodilator,Mononitrogen Monoxide,Nitric Oxide, Endothelium-Derived,Nitrogen Monoxide,Endothelium-Derived Nitric Oxide,Monoxide, Mononitrogen,Monoxide, Nitrogen,Nitrate Vasodilator, Endogenous,Nitric Oxide, Endothelium Derived,Oxide, Nitric,Vasodilator, Endogenous Nitrate
D012077	Renal Artery	A branch of the abdominal aorta which supplies the kidneys, adrenal glands and ureters.	Arteries, Renal,Artery, Renal,Renal Arteries
D001802	Blood Substitutes	Substances that are used in place of blood, for example, as an alternative to BLOOD TRANSFUSIONS after blood loss to restore BLOOD VOLUME and oxygen-carrying capacity to the blood circulation, or to perfuse isolated organs.	Artificial Blood,Artificial Erythrocytes,Artificial Hemoglobin,Blood, Artificial,Erythrocyte Substitutes,Hemoglobin Substitutes,Red Cell Substitutes,Artificial Bloods,Artificial Erythrocyte,Artificial Hemoglobins,Blood Substitute,Bloods, Artificial,Cell Substitute, Red,Cell Substitutes, Red,Erythrocyte Substitute,Erythrocyte, Artificial,Erythrocytes, Artificial,Hemoglobin Substitute,Hemoglobin, Artificial,Hemoglobins, Artificial,Red Cell Substitute,Substitute, Blood,Substitute, Erythrocyte,Substitute, Hemoglobin,Substitute, Red Cell,Substitutes, Blood,Substitutes, Erythrocyte,Substitutes, Hemoglobin,Substitutes, Red Cell
D004285	Dogs	The domestic dog, Canis familiaris, comprising about 400 breeds, of the carnivore family CANIDAE. They are worldwide in distribution and live in association with people. (Walker's Mammals of the World, 5th ed, p1065)	Canis familiaris,Dog
D004305	Dose-Response Relationship, Drug	The relationship between the dose of an administered drug and the response of the organism to the drug.	Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D004730	Endothelium, Vascular	Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components.	Capillary Endothelium,Vascular Endothelium,Capillary Endotheliums,Endothelium, Capillary,Endotheliums, Capillary,Endotheliums, Vascular,Vascular Endotheliums
D004791	Enzyme Inhibitors	Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.	Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D005263	Femoral Artery	The main artery of the thigh, a continuation of the external iliac artery.	Common Femoral Artery,Arteries, Common Femoral,Arteries, Femoral,Artery, Common Femoral,Artery, Femoral,Common Femoral Arteries,Femoral Arteries,Femoral Arteries, Common,Femoral Artery, Common
D006152	Cyclic GMP	Guanosine cyclic 3',5'-(hydrogen phosphate). A guanine nucleotide containing one phosphate group which is esterified to the sugar moiety in both the 3'- and 5'-positions. It is a cellular regulatory agent and has been described as a second messenger. Its levels increase in response to a variety of hormones, including acetylcholine, insulin, and oxytocin and it has been found to activate specific protein kinases. (From Merck Index, 11th ed)	Guanosine Cyclic 3',5'-Monophosphate,Guanosine Cyclic 3,5 Monophosphate,Guanosine Cyclic Monophosphate,Guanosine Cyclic-3',5'-Monophosphate,3',5'-Monophosphate, Guanosine Cyclic,Cyclic 3',5'-Monophosphate, Guanosine,Cyclic Monophosphate, Guanosine,Cyclic-3',5'-Monophosphate, Guanosine,GMP, Cyclic,Guanosine Cyclic 3',5' Monophosphate,Monophosphate, Guanosine Cyclic
D006454	Hemoglobins	The oxygen-carrying proteins of ERYTHROCYTES. They are found in all vertebrates and some invertebrates. The number of globin subunits in the hemoglobin quaternary structure differs between species. Structures range from monomeric to a variety of multimeric arrangements.	Eryhem,Ferrous Hemoglobin,Hemoglobin,Hemoglobin, Ferrous