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, s creening for this class of compounds has been minimal, owing, in part, to a lack of convenient hypoxemic models in small animals. The presen t study was designed to establish a convenient model of hypoxemia indu ced by bleomycin and to evaluate anti-hypoxemic agents including a new ly synthesized compound, TEI-7322, amino-4-tert-butyl-amino-7-methyl-7 H-pyrrolo[2,3-d ]pyrimidine hydrochloride by using this model. Bleomyc in was intratracheally instilled into rats. After 3 weeks, the arteria l blood gas pressures were monitored in the animals in the conscious s tate. Then, prednisolone, doxapram, almitrine or TEI-7322 was administ ered to the bleomycin-treated rats to monitor changes in arterial bloo d gas pressures. Bleomycin-treated rats showed a decrease in the arter ial blood O-2 pressure (PaO2). The blood CO2 pressure (PaCO2) increase d, along with an increase in the alveolar-arterial oxygen difference ( AaDO(2)). 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 wit h a decrease in the PaCO2. In conclusion, (1) bleomycin-induced lung i njury causes hypoxemia in rats, probably resulting from ventilation-pe rfusion 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 o f doxapram, possibly due to improvement of ventilation-perfusion inequ ality, indicating that TEI-7322 may be a potent candidate for the trea tment of hypoxemia.