VASORELAXANT EFFECTS OF SCA40 (A PHOSPHODIESTERASE-III INHIBITOR) IN PULMONARY VASCULAR PREPARATIONS IN RATS

1. The novel phosphodiesterase (PDE) inhibitor SCA40 methylamino)imida zo[1,2-a]pyrazine-2-carbonitrile) was examined for its vasorelaxant ac tivity on isolated pulmonary vascular preparations from rats, 2. SCA40 relaxed ring preparations of main and intralobar pulmonary artery pre contracted submaximally with either phenylephrine or U46619 (thromboxa ne-mimetic). Based on negative log EC50 values, SCA40 was six-to 14-fo ld more potent than the PDE III inhibitor milrinone or the non-selecti ve PDE inhibitor 3-isobutyl-1-methyl xanthine (IBMX). The potency of S CA40 corresponded to its reported potency as a PDE III inhibitor. 3. I n isolated perfused lungs, SCA40 reversed the vasoconstriction induced by alveolar hypoxia, It was 49-fold more potent than IBMX, 4. In main pulmonary artery the vasorelaxation induced by SCA40 was not blocked by the large-conductance calcium-activated potassium channel (BKCa) in hibitors iberiotoxin (50 and 100 nmol/L) or charybdotoxin (100 and 300 nmol/L). This was in contrast to data on guinea-pig trachea, where re sponses to SCA40 were significantly inhibited by charybdotoxin (100 nm ol/L). 5. It is concluded that opening of BKCa channels does not contr ibute to the pulmonary vasorelaxant effects of SCA40 in main pulmonary artery and it is likely that responses reflect the PDE III inhibitory properties of the drug. 6. It is postulated that SCA40 may be useful as a pulmonary vasodilator in disorders such as pulmonary hypertension .