Abstract
The heavy metal antidotes sodium-2,3-dimercaptopropane-1-sulfonate (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA) were investigated in anaesthetized dogs for their effects on a variety of physiological variables and parameters. In addition, the influence of both dithiols on oxygen consumption and ferrihaemoglobin production was studied in blood and red blood cells in vitro. DMPS (15 and 75 mg/kg i.v.) did not affect respiration, central venous pressure, left ventricular pressure or cardiac output and showed only marginal, statistically non-significant effects on aortic and effective perfusion pressure. In contrast to the slight, non-significant changes due to DMPS (15 mg/kg i.v.), an equimolar dose of DMSA (12 mg/kg i. v.) led to a slight transient decrease in femoral blood pressure with strong reflex tachycardia and increase in blood flow. The higher DMPS dose (75 mg/kg i.v.), however, caused marked decreases in femoral blood pressure and blood flow, strong changes in blood gases and pH, and lactacidosis. Most of the physiological variables and parameters did not return to the initial level by 60 min. The R-spike of the electrocardiogram decreased, and the T-wave increased. Experiments on the denervated hind leg indicate that DMPS may be a direct vasodilator. The fall of blood pressure due to DMPS was markedly reduced when 30% ferrihaemoglobin had been formed by 4-dimethylaminophenol. HCl (DMAP). The highest DMPS dose (150 mg/kg i.v.) provoked circulatory failure and respiratory arrest. Artificial ventilation with room air restored spontaneous respiration, but one of three animals did not survive this dose for more than 90 min. DMPS and DMSA reacted with oxygen. In phosphate buffer, pH 7.4,1 mol O2 appears to be taken up by 2 mol DMPS. The consumption of O2 by DMPS was less in samples of human and canine blood or erythrocyte suspensions than in buffer solution. DMPS caused a greater loss of oxygen than DMSA. DMPS and DMSA alone did not produce ferrihaemoglobin, but the ferrihaemoglobin content of erythrocyte suspensions increased over the time when DMPS was added in the presence of 30% ferrihaemoglobin. Such an action was not observed at the same ferrihaemoglobin content in vivo.
Similar content being viewed by others
References
Aebi H, Frei E (1958) Gekoppelte Oxydation von Formiat und Thiolverbindungen durch Katalase. Helv Chim Acta 41: 361–371
Akera T, Fox AL, Greeff K (1981) Substances possessing inotropic properties similar to cardiac glycosides. IV. Sulfhydryl blocking agents. In: Greef K (ed.) Cardiac glycosides, Part I, Handb Exper Pharmacol, vol 56/1. Springer, Berlin, Heidelberg, New York, pp 464–468
Aposhian HV (1983) DMSA and DMPS — water soluble antidotes for heavy metal poisoning. Ann Rev Pharmacol Toxicol 23: 193–215
Aposhian HV, Tadlock CH, Moon TE (1981) Protection of mice against the lethal effects of sodium arsenite. A quantitative comparison of a number of chelating agents. Toxicol Appl Pharmacol 61: 385–392
Aposhian HV, Mershon MM, Brinkley FB, Hsu CA, Hackley BE (1982) Anti-Lewisite activity and stability of meso-dimercaptosuccinic acid and 2,3-dimercapto-1-propane sulfonic acid. Life Sci 31: 2149–2156
Barron ESG, Miller ZB, Kalnitzky G (1947) The oxidation of dithiols. Biochem J 41: 62–68
Brown DA, Kwiatkowski D (1976) A note on the effect of dithiothreitol (DTT) on the depolarization of isolated sympathetic ganglia by carbachol and bromoacetylcholine. Br J Pharmacol 56: 128–130
Bunn HF, Forget BG (1986) Hemoglobin oxidation: Methemoglobin, methemoglobinemia, and sulfhemoglobinemia. In: Bunn HF, Forget BG (eds) Hemoglobin: molecular, genetic and clinical aspects. W Saunders Company, Philadelphia
Chenoweth MB (1946) The cardio-vascular actions of 2,3-dimercaptopropanol (BAL). J Pharmacol 87: Suppl 41–54
Costa M, Pecci L, Pensa B, Cannella C (1977) Hydrogen peroxide involvement in the rhodanese inactivation by dithiothreitol. Biochem Biophys Res Commun 78: 596–603
Eyer P, Kiese M, Lipowsky G, Weger N (1974) Reactions of 4-dimethylaminophenol with hemoglobin, and autoxidation of 4-dimethylaminophenol. Chem Biol Interact 8: 41–59
Eyer P, Hertle H, Kiese M, Klein G (1975) Kinetics of ferrihemoglobin formation by some reducing agents and the role of hydrogen peroxide. Mol Pharmacol 11: 326–334
Graziano JH, Cuccia D, Friedheim E (1978) Potential usefulness of 2,3-dimercaptosuccinic acid for the treatment of arsenic poisoning. J Pharmacol Exp Ther 207: 1051–1055
Karlin A, Bartels E (1966) Effects of blocking sulphydryl groups and of reducing disulfide bonds on the acetylcholine-activated permeability system of the electroplax. Biochim Biophys Acta 126: 525–535
Klaassen CD (1980) Toxicology. Principles of toxicology. In: Goodman and Gilman's The pharmacological basis of therapeutics 6th edn. MacMillan Publishing Co., Inc., New York, pp 1602–1637
Klimmek R, Fladerer H, Szinicz L, Weger N, Kiese M (1979a) Effects of 4-dimethylaminophenol and Co2EDTA on circulation, respiration, and blood homeostasis in dogs. Arch Toxicol 42: 75–84
Klimmek R, Fladerer H, Weger N (1979b) Circulation, respiration, and blood homeostasis in cyanide-poisoned dogs after treatment with 4-dimethylaminophenol or cobalt compounds. Arch Toxicol 43: 121–133
Klimova LK (1958) Zur Pharmakologie des neuen Antidots Unithiol (Translation from Russian). Farmakol Toksikol 21: 53–59
Kramer K, Kirchhoff HW (1969) Anwendung densitometrischer, thermischer und radiologischer Methoden in der Klinik. 2. Oxymetrie-Symposium 10–12 may 1968. Georg Thieme Verlag, Stuttgart
Luganskij NI, Loboda YI (1960) The effect of unithiol on the distribution, accumulation, and elimination of radioactive arsenic (As76) from rabbits (Translation). Trudy Vseyoyuz Nauch Tekh Konf Pricnen Radioaktiv Stabil. Izotopov i Nauke, 1957. Med Radiobiol, pp 392–397
Luganskij NI, Mizyukova IG, Lokantsev DS (1959) The mechanism of antidotal activity of unithiol in poisoning with arsenic compounds (Translation). Tiolovye Soedinen V. Med Ukrain Nauch-Issledovatel. Sanit-Khim Inst Trudy Nauch Konf Kiev, 1957, pp 115–130
Okonishnikova IE (1965) Experimental therapy and prophylaxis of acute poisoning with arsenic compounds. Gig Tr Prof Zabol 9: 38–43
Rappoport DA, Green JA, Gast JH (1956) Formate oxidation by erythrocytes. Arch Biochem Biophys 63: 343–351
Sanotskij WA, Sotowa MG, Jefimow WI, Rudnitskaja EI, Federowskij LL, Furajewa LP (1967) Möglichkeit der intravenösen Anwendung von Unithiol in hohen Dosen (Translation from Russian). Farmakol Toksikol 30: 480–482
Schad H, Brechteisbauer H, Krainer K (1977) Studies on the suitability of a cyanide dye (Viher-Testr) for indicator dilution technique and its application to the measurement of pulmonary artery and aortic flow. Pflügers Arch 370: 139–144
Smith RP, Gosselin RE (1964) The influence of methemoglobinemia on the lethality of some toxic anions. II. Sulfide. Toxicol Appl Pharmacol 6: 584–592
Stern KG (1932) Über die Hemmungstypen und den Mechanismus der katalatischen Reaktion. 3. Mitteilung über Katalase. Z Physiol Chem 209: 176–206
Stocken LA, Thompson RHS (1946) British Anti-Lewisite. 3. Arsenic and thiol excretion in animals after treatment of Lewisite burns. Biochem J 40: 548–554
Strömme JH (1963) Methemoglobin formation induced by thiols. Biochem Pharmacol 12: 937–948
Szinicz L, Albrecht GJ, Weger N (1981) Effect of various compounds on the reaction of tris-(2-chloroethyl)amine with ribonucleic acid in vitro and on its toxicity in mice. Arzneimittelforschung 31: 1–5
Szinicz L, Wiedemann P, Häring H, Weger N (1983) Effects of repeated treatment with sodium-2,3-dimercaptopropane-1-sulfonate in beagle dogs. Arzneimittelforschung 6: 818–821
Tadlock CH, Aposhian HV (1980) Protection of mice against the lethal effects of sodium arsenite by 2,3-dimercapto-1-propane-sulfonic acid and dimercaptosuccinic acid. Biochem Biophys Res Comm 94: 501–507
Ting KS, Liang YI, Shi J, Chen W, Gu T et al. (1965) Chelate stability of sodium dimercapto-succinate on the intoxications from many metals. Chin Med J 51: 304–307
Torchinsky YM (1981) Sulfur in proteins. Pergamon Press, Oxford
Trotta PP, Pinkus LM, Meister A (1974) Inhibition by dithiothreitol of the utilization of glutamine by carbamyl phosphate synthetase. J Biol Chem 249: 1915–1921
Warburg O (1926) Über den Stoffwechsel von Tumoren. Springer, Berlin
Webb EC, van Heyningen R (1947) The action of British Antilewisite (BAL) on enzyme systems. Biochem J 41: 74–82
West JB (1977) Ventilation/blood flow and gas exchange (3d edn). Blackwell Scientific Publications, Oxford, London, Edinburgh, Melbourne
Wiedemann P, Fichtl B, Szinicz L (1982) Pharmacokinetics of14C-DMPS (sodium-1,3-14C-2,3-dimercaptopropane-1-sulphonate) in beagle dogs. Biopharm Drug Dispos 3: 267–274
Wildenauer DB, Reuther H, Weger N (1982) Interaction of the chelating agent 2,3-dimercaptopropane-1-sulfonate with red blood cells in vitro. I. Evidence for carrier-mediated transport. Chem Biol Interact 42: 165–177
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Klimmek, R., Krettek, C. & Werner, H.W. Acute effects of the heavy metal antidotes DMPS and DMSA on circulation, respiration, and blood homoeostasis in dogs. Arch Toxicol 67, 428–434 (1993). https://doi.org/10.1007/BF01977405
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01977405