In vivo toxic and lethal cardiovascular effects of a synthetic polymeric 1,3-dodecylpyridinium salt in rodents

Journal Article · Mon Aug 15 00:00:00 EDT 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2011.06.003· OSTI ID:21587822

Grandic, Marjana ^[1]; Sepcic, Kristina; Turk, Tom ^[2]; Juntes, Polona ^[3]; Frangez, Robert ^[1]

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1. Institute of Physiology, Pharmacology and Toxicology, Veterinary Faculty, University of Ljubljana, Gerbiceva 60, 1000 Ljubljana (Slovenia)
2. Department of Biology, Biotechnical Faculty, University of Ljubljana, Vecna pot 111, 1000 Ljubljana (Slovenia)
3. Institute of Pathology, Forensic and Administrative Veterinary Medicine, Veterinary Faculty, University of Ljubljana, Gerbiceva 60, 1000 Ljubljana (Slovenia)

APS12-2 is one in a series of synthetic analogs of the polymeric alkylpyridinium salts isolated from the marine sponge Reniera sarai. As it is a potential candidate for treating non small cell lung cancer (NSCLC), we have studied its possible toxic and lethal effects in vivo. The median lethal dose (LD{sub 50}) of APS12-2 in mice was determined to be 11.5 mg/kg. Electrocardiograms, arterial blood pressure and respiratory activity were recorded under general anesthesia in untreated, pharmacologically vagotomized and artificially ventilated rats injected with APS12-2. In one group, the in vivo effects of APS12-2 were studied on nerve-evoked muscle contraction. Administration of APS12-2 at a dose of 8 mg/kg caused a progressive reduction of arterial blood pressure to a mid-circulatory value, accompanied by bradycardia, myocardial ischemia, ventricular extrasystoles, and second degree atrio-ventricular block. Similar electrocardiogram and arterial blood pressure changes caused by APS12-2 (8 mg/kg) were observed in animals pretreated with atropine and in artificially ventilated animals, indicating that hypoxia and cholinergic effects do not play a crucial role in the toxicity of APS12-2. Application of APS12-2 at sublethal doses (4 and 5.5 mg/kg) caused a decrease of arterial blood pressure, followed by an increase slightly above control values. We found that APS12-2 causes lysis of rat erythrocytes in vitro, therefore it is reasonable to expect the same effect in vivo. Indeed, hyperkalemia was observed in the blood of experimental animals. Hyperkalemia probably plays an important role in APS12-2 cardiotoxicity since no evident changes in histopathology of the heart were found. However, acute lesions were observed in the pulmonary vessels of rats after application of 8 mg/kg APS12-2. Predominant effects were dilation of interalveolar blood vessels and lysis of aggregated erythrocytes within their lumina. - Highlights: > LD{sub 50} estimated in mice (11.5 mg/kg) revealed that toxicity of APS12-2 is low. > APS12-2 causes dose dependent hemolysis of rat erythrocytes in vivo and in vitro. > Cardiac arrest by APS12-2 is caused by the high blood potassium concentration. > APS12-2 causes mild acute pulmonary edema.

• OSTI ID: 21587822
• Journal Information: Toxicology and Applied Pharmacology, Vol. 255, Issue 1; Other Information: DOI: 10.1016/j.taap.2011.06.003; PII: S0041-008X(11)00215-8; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANESTHESIA
ANOXIA
ATROPINE
BLOOD PRESSURE
BLOOD VESSELS
EDEMA
ELECTROCARDIOGRAMS
ERYTHROCYTES
HEMOLYSIS
IN VITRO
IN VIVO
ISCHEMIA
LETHAL DOSES
LUNGS
MICE
NEOPLASMS
RATS
TOXICITY
ALKALOIDS
ANEMIAS
ANIMALS
AUTONOMIC NERVOUS SYSTEM AGENTS
BIOLOGICAL MATERIALS
BLOOD
BLOOD CELLS
BODY
BODY FLUIDS
CARDIOVASCULAR DISEASES
CARDIOVASCULAR SYSTEM
CHEMICAL REACTIONS
DECOMPOSITION
DIAGRAMS
DISEASES
DOSES
DRUGS
HEMIC DISEASES
INFORMATION
LYSIS
MAMMALS
MATERIALS
ORGANIC COMPOUNDS
ORGANS
PARASYMPATHOLYTICS
PATHOLOGICAL CHANGES
RESPIRATORY SYSTEM
RODENTS
SYMPTOMS
VASCULAR DISEASES
VERTEBRATES