Beneficial effects of a novel anti-hypoxemic agent, TEI-7322, on bleomycin-induced experimental hypoxemia in rats.
Almitrine bismesylate is known to be an anti-hypoxemic agent that acts via the enhancement of hypoxic pulmonary vasoconstriction. However, screening for this class of compounds has been minimal, owing, in part, to a lack of convenient hypoxemic models in small animals. The present study was designed to establish a convenient model of hypoxemia induced by bleomycin and to evaluate anti-hypoxemic agents including a newly synthesized compound. TEI-7322, 2-allylamino-4-tert-butyl-amino-7-methyl-7H-pyrrolo[2,3- d]pyrimidine hydrochloride by using this model. Bleomycin was intratracheally instilled into rats. After 3 weeks, the arterial blood gas pressures were monitored in the animals in the conscious state. Then, prednisolone, doxapram, almitrine or TEI-7322 was administered to the bleomycin-treated rats to monitor changes in arterial blood gas pressures. Bleomycin-treated rats showed a decrease in the arterial blood O2 pressure (PaO2). The blood CO2 pressure (PaCO2) increased, along with an increase in the alveolar-arterial oxygen difference (AaDO2). These blood gas pressures in bleomycin-treated rats were not affected by treatment with prednisolone. Doxapram decreased the PaCO2 but did not change the PaO2. However, administration of almitrine or TEI-7322 significantly improved the PaO2 of bleomycin-treated rats with a decrease in the PaCO2. In conclusion, (1) bleomycin-induced lung injury causes hypoxemia in rats, probably resulting from ventilation-perfusion inequality; thus this model may be useful for evaluating anti-hypoxemic agents; and (2) TEI-7322, as well as almitrine, showed anti-hypoxemic effects in this model with different properties from those of doxapram, possibly due to improvement of ventilation-perfusion inequality, indicating that TEI-7322 may be a potent candidate for the treatment of hypoxemia.
Horiuchi
H
H
Teijin Institute for Bio-Medical Research, Hino, Tokyo, Japan.
Uejima
Y
Y
Sakuma
Y
Y
Kadota
T
T
Okada
N
N
Taniguchi
K
K
Takenouchi
K
K
Yamanaka
Y
Y
Uno
H
H
Komoriya
K
K
D015765:Almitrine / Q000494:pharmacology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D001761:Bleomycin / Q000009:adverse effects*; D001784:Blood Gas Analysis; D000860:Hypoxia / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D008168:Lung / Q000187:drug effects; D008297:Male; D010100:Oxygen / Q000097:blood; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019141:Respiratory System Agents / Q000494:pharmacology*
D000903:Antibiotics, Antineoplastic; D011743:Pyrimidines; D019141:Respiratory System Agents; C098800:TEI 7322; D001761:Bleomycin; D015765:Almitrine; D010100:Oxygen