Effects of drugs which alter blood cell deformability in circulatory shock produced by endotoxin

Yao, Zhenhai
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Pentoxifylline is a xanthine derivative chemically related to theophylline and caffeine. The drug is said to improve tissue oxygenation in chronic vascular occlusive disease by increasing RBC deformability and has been reported to improve survival in experimental hemorrhagic, septic and endotoxic shock. In the present investigation, the effects of pentoxifylline on endotoxin-induced mortality, disseminated intravascular coagulation (DIC), hypotension, and reduction in blood cell deformability were studied in awake rats and compared with the effects produced by two other xanthine compounds, theophylline and caffeine, and by a non-xanthine compound, buflomedil. In control rats, endotoxin (25 mg/kg, i.v.) produced a 92% mortality as well as clinical laboratory signs of DIC. The latter included increased serum fibrin(ogen) degradation products (FDP), prothrombin time. and partial thromboplastin time, and decreased plasma fibrinogen and blood platelet count as well as evidence of gross visceral hemorrhage. Pretreatment with pentoxifylline (25-50 mg/kg), caffeine sodium benzoate (25-200 mg/kg) and buflomedil hydrochloride (2.5-50 mg/kg) produced a dose-dependent reduction in the endotoxin-induced mortality and inhibited most of the manifestations of DIC produced by endotoxin. Pretreatment With theophylline (given in the form of aminophylline, 5-125 mg/kg), did not inhibit the endotoxin-induced DIC and failed to protect against death caused by the lipopolysaccharide. The effects of drugs on blood pressure and heart rate were studied in awake rats With implanted carotid catheters. All four drugs produced a dose-dependent lowering of arterial pressure when administered as a pretreatment. The administration of endotoxin (25 mg/kg) in control animals caused an immediate fall in arterial pressure, followed by a partial recovery and a later progressive decline until death of the animal. All of the control animals in this series died Within 24 hours. Pretreatment with pentoxifylline (50 mg/kg), caffeine sodium benzoate (I00-200 mg/kg) and buflomedil hydrochloride (30-50 mg/kg) significantly reduced the endotoxin-induced hypotension as well as the mortality during the 24-hour period of observation. In contrast, pretreatment With aminophylline (50-100 mg/kg) not only failed to antagonize the hypotension caused by endotoxin but actually had a deleterious effect: post-endotoxin blood pressure in the aminophylline pretreated series was significantly lower than in the saline pretreated endotoxin controls throughout the period of observation. All animals in the aminophylline series died. Vasodilator agents are known to have a protective action in circulatory shock. In the present study, the hypotensive effect produced by aminophylline was comparable to that produced by protective doses of the other agents. The difference in protective efficacy therefore was not related to a difference in vasodilator efficacy. Heart rate measurements showed that there was no correlation between cardiac stimulation produced by the xanthines and protection against endotoxic shock. All three xanthines caused a dose-dependent increase in the heart rate and antagonized the bradycardia caused by endotoxin. However, only pentoxifylline and caffeine increased survival. Buflomedil actually slowed the heart rate but nevertheless inhibited the endotoxin-induced bradycardia and decreased the mortality, Endotoxin (25 mg/kg) was found to cause a reduction in RBC deformability. The in vivo administration of pentoxifylline, caffeine and buflomedil improved the deformability of both erythrocytes and leukocytes and was found to reverse the endotoxin-induced reduction in RBC deformability. In contrast. aminophylline did not have a significant effect on blood cell deformability and did not affect the rheological effect of endotoxin. The present. investigation thus showed that prevention of endotoxin-induced DIC, circulatory shock and death by pentoxifylline, buflomedil and caffeine was positively correlated with an ability of the drugs to improve blood cell deformability. The hypothesis is advanced that a causal relationship may exist between the latter action and the protective action of the three drugs in endotoxic shock.
Thesis (Ph. D.)--University of Hawaii at Manoa, 1991.
Includes bibliographical references (leaves 77-89)
xiv, 89 leaves, bound ill. (some col.) 29 cm
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Theses for the degree of Doctor of Philosophy (University of Hawaii at Manoa). Biomedical Sciences (Pharmacology); no. 2698
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