Effects of propylthiouracil and methimazole on splanchnic hemodynamics in awake and unrestrained rats

Authors

  • Tsunehisa Kawasaki,

    1. Addiction Research Foundation, Clinical Institute, and Departments of Medicine, Anaesthesia
    2. Pharmacology, University of Toronto, and Department of Anaesthesia, Toronto Western Hospital, Toronto, Ontario M5S 2S1, Canada
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  • Frederick J. Carmichael,

    1. Addiction Research Foundation, Clinical Institute, and Departments of Medicine, Anaesthesia
    2. Pharmacology, University of Toronto, and Department of Anaesthesia, Toronto Western Hospital, Toronto, Ontario M5S 2S1, Canada
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  • Gwynne Giles,

    1. Addiction Research Foundation, Clinical Institute, and Departments of Medicine, Anaesthesia
    2. Pharmacology, University of Toronto, and Department of Anaesthesia, Toronto Western Hospital, Toronto, Ontario M5S 2S1, Canada
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  • Victor Saldivia,

    1. Addiction Research Foundation, Clinical Institute, and Departments of Medicine, Anaesthesia
    2. Pharmacology, University of Toronto, and Department of Anaesthesia, Toronto Western Hospital, Toronto, Ontario M5S 2S1, Canada
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  • Yedy Israel,

    1. Addiction Research Foundation, Clinical Institute, and Departments of Medicine, Anaesthesia
    2. Pharmacology, University of Toronto, and Department of Anaesthesia, Toronto Western Hospital, Toronto, Ontario M5S 2S1, Canada
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  • Hector Orrego M.D.

    Corresponding author
    1. Addiction Research Foundation, Clinical Institute, and Departments of Medicine, Anaesthesia
    2. Pharmacology, University of Toronto, and Department of Anaesthesia, Toronto Western Hospital, Toronto, Ontario M5S 2S1, Canada
    • Addiction Research Foundation, 33 Russell St., Toronto, Ontario M5S 2S1, Canada
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Abstract

The treatment of alcoholic liver disease with propylthiouracil is based on its effect of suppressing the ethanol-induced increase in hepatic oxygen consumption. It has been postulated that liver necrosis ensues when the increase in oxygen demand by the liver exceeds oxygen delivery to this organ. Data are now presented which show that propylthiouracil also increases portal blood flow in awake, unrestrained rats.

Liver blood flow was determined using the labeled microsphere technique in rats at various intervals (0.25, 0.5, 1.0, 3.0, 6.0 and 24 hr) after oral propylthiouracil (50 mg per kg). Administration of propylthiouracil (dose range: 6.25 to 100.0 mg per kg) produced a dose-dependent increase in portal blood flow when given either orally or intraarterially. Maximal flows were obtained with 50 mg per kg (controls = 37.8 ± 1.5, oral propylthiouracil = 50.7 ± 2.2 ml ± kg−1-min−1). This increase in portal blood flow was accompanied by a decrease in preportal vascular resistance (controls = 2.61 ± 0.16; propylthiouracil, 50 mg per kg = 1.79 ± 0.09 mmHg per ml ± kg−1 ± min−1). These effects were correlated with the plasma concentrations of propylthiouracil (r = 0.67, n = 68, p ⩽ 0.001). The effect of oral propylthiouracil (50 mg per kg) on portal blood flow started at 0.5 hr and lasted for 6 hr after administration, whereas total liver blood flow was increased for 3 hr. Oral propylthiouracil (50 mg per kg) for 5 days resulted in a 53% increase in thyroid weight, an 85% reduction in 125I thyroid uptake and a 74% decrease in serum thyroxine concentration. This treatment, however, did not modify portal blood flow, nor the response to acute propylthiouracil. Oral administration of equipotent doses of another antithyroid drug, methimazole (10 and 20 mg per kg), had no effect on portal blood flow. Because of the rapid increase in portal blood flow following a single oral or parenteral dose of propylthiouracil and the lack of effect of methimazole, it is concluded that this response of propylthiouracil is independent of its effect on the thyroid gland and of intestinal absorption. The increase in portal blood flow can contribute to the protective effect of propylthiouracil against alcohol-induced liver necrosis by increasing oxygen delivery to the liver.

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