Abstract

The identity of endothelium-derived relaxing factor (EDRF) is still debated, but several workers believe that it is identical to nitric oxide (NO). Several important drugs such as glyceryl trinitrate (GTN), sodium nitroprusside (SNP) and hydrolazine and some xenobiotics of toxicological or environmental concern including sodium azide, hydroxylamine hydrochloride and sodium nitrate mimic the biological effects of EDRF and NO. It is presumed that these chemicals owe their biological activity to biotransformation to NO in vivo. The proposed research will study the mechanism(s) by which these biotransformations occur. A goal is to screen blood samples from normal human subjects and from subjects who are hypersensitive but receiving drugs other than NO-vasodilators in the hope of obtaining evidence for endogenous NO in for form of EPR signals from NO-hemoglobins. Plans are also to examine blood samples from patients receiving NO-vasodilators for therapeutic purposes, and blood from animals given drugs known to act through EDRF such as acetylcholine, histamine, serotonin and bradykinin.
An aim i s to study the decomposition of SNP by cyclic voltammetry, and during its reactions with hemoglobin, methemoglobin and glutathione and characterize the intermediate products by EPR. The stability of these intermediates will be examined in the presence of cyanide. Cyanide stabilization of a particular intermediate may explain its ability to block the effects of SNP. The reactions of azide, hydrozylamine, nitrite, hydralazine and SNP with catalase will be studied to ascertain if NO is liberated and if catalase inhibitors block the reaction. There are also plans to continue pilot studies on sulfur transferases as they are involved in cyanide biotransformation. The major objective is to clarify the metabolism and mechanism of action of NO-vasodilator drugs and poisons with two goals in mind: to elucidate the mechanism(s) by which tolerance develops to such drugs as GTN and to find ways to intercede in poisonings.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL014127-29
Application #
3334731
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1975-12-01
Project End
1993-03-31
Budget Start
1991-04-01
Budget End
1992-03-31
Support Year
29
Fiscal Year
1991
Total Cost
Indirect Cost

  Institution

Name
Dartmouth College
Department
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755

  Publications

Kam, H Y; Ou, L C; Thron, C D et al. (1999) Role of the spleen in the exaggerated polycythemic response to hypoxia in chronic mountain sickness in rats. J Appl Physiol 87:1901-8
Kruszyna, H; Magyar, J S; Rochelle, L G et al. (1998) Spectroscopic studies of nitric oxide (NO) interactions with cobalamins: reaction of NO with superoxocobalamin(III) likely accounts for cobalamin reversal of the biological effects of NO. J Pharmacol Exp Ther 285:665-71
Kruszyna, R; Smith, R P; Kruszyna, H (1998) Determining sodium azide concentration in blood by ion chromatography. J Forensic Sci 43:200-2
Currie, J L; Mott, L A; Pennisi, S C et al. (1997) Potential for an external vaginal antiitch cream containing benzocaine to cause methemoglobinemia in healthy women. Am J Obstet Gynecol 176:1006-8
Rochelle, L G; Morana, S J; Kruszyna, H et al. (1995) Interactions between hydroxocobalamin and nitric oxide (NO): evidence for a redox reaction between NO and reduced cobalamin and reversible NO binding to oxidized cobalamin. J Pharmacol Exp Ther 275:48-52
Ou, L C; Sardella, G L; Leiter, J C et al. (1994) Role of sex hormones in development of chronic mountain sickness in rats. J Appl Physiol 77:427-33
Wang, Y; Rochelle, L G; Kruszyna, H et al. (1994) An impurity present in some samples of SIN-1 oxidizes it to nitric oxide in anaerobic solutions. Toxicology 88:165-76
Smith, R P; Wilcox, D E (1994) Toxicology of selected nitric oxide-donating xenobiotics, with particular reference to azide. Crit Rev Toxicol 24:355-77
Rochelle, L G; Kruszyna, H; Kruszyna, R et al. (1994) Bioactivation of nitroprusside by porcine endothelial cells. Toxicol Appl Pharmacol 128:123-8
Conrad, K P; Joffe, G M; Kruszyna, H et al. (1993) Identification of increased nitric oxide biosynthesis during pregnancy in rats. FASEB J 7:566-71

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