To test whether
E4021, a potent selective cyclic
guanosine 3'-5'-monophosphate (cGMP)
phosphodiesterase inhibitor, causes pulmonary vasodilation and whether it enhances the
vasodilator action of inhaled
nitric oxide (NO), we studied its effects on pulmonary vascular tone and inhaled NO-induced pulmonary vasodilation in isolated perfused rat lungs. Lungs were perfused at a constant flow rate with
salt-
Ficoll solution and ventilated with air plus 5% CO2. After equilibration,
vasodilator responses to either
E4021, inhaled NO, or both were evaluated under conditions of increased perfusion pressure induced by infusion of
U46619.
E4021 had no effect on the baseline perfusion pressure, whereas it caused dose-dependent pulmonary vasodilation when the vasomotor tone was increased by
U46619. Inhaled 1, 5, and 20 ppm NO reduced the increased perfusion pressure by 60+/-5%, 83+/-3%, and 92+/-2%, respectively. Pretreatment with
E4021 significantly potentiated the
vasodilator effect of 1 ppm NO (from 53+/-6% to 71+/-2%; p < 0.05) but did not alter that of 5 ppm NO (from 77+/-3% to 78+/-4%; p > 0.05). In addition, pretreatment with
E4021 significantly augmented the
vasodilator response to
sodium nitroprusside but not to
isoproterenol. These results indicate that
E4021 causes pulmonary vasodilation and potentiates the
vasodilator effect of low concentrations of inhaled NO, probably through a cGMP-dependent mechanism in
salt-
solution perfused rat lungs. We conclude that
E4021 may possibly be useful for the treatment of
pulmonary hypertension, either alone or in combination with inhaled NO.