EFFECT OF DMPPO, A PHOSPHODIESTERASE TYPE 5 INHIBITOR, ON HYPOXIC PULMONARY-HYPERTENSION IN RATS

1 Cyclic guanosine 3'-5'-monophosphate (cyclic GMP) is the second mess enger of important physiologically active mediators controlling the pu lmonary vascular tone. To potentiate the effects of cyclic GMP on the pulmonary vasculature, we used DMPPO, a new selective PDE-5 inhibitor, and examined its action in a rat model of hypoxic pulmonary hypertens ion. 2 Levels of cyclic GMP measured during baseline conditions at 5 a nd 60 min of perfusion were similar in the perfusate of isolated lungs from normoxic and chronically hypoxic rats and did not differ with ti me. Pretreatment with DMPPO (1 mu M) induced a larger increase in cycl ic GMP concentration in the perfusate from chronically hypoxic rat lun gs (319+/- 36 at 5 min to 1821+/-83 pmol ml(-1) at 60 min) than in nor moxic rat lungs (329 +/-20 to 1281 +/- 127 pmol ml(-1), P<0.05). 3 In isolated lungs preconstricted with U-46619, pretreatment with DMPPO (1 mu M) potentiated the vasodilator effects of atrial natriuretic pepti de (100 pM-10 nM) and sodium nitroprusside (1 pM-10 nM), but did not a lter vasodilation to isoproterenol. 4 In conscious rats previously exp osed to 15 days hypoxia and studied under 10% O-2, DMPPO (0.01, 0.05 a nd 0.1 mg kg(-1), i.v. bolus) caused a dose-dependent decrease in pulm onary arterial pressure (Pap) with no change in systemic artery pressu re (Sap) and cardiac output. 5 Continuous infusion of DMPPO (0.1 mg kg (-1) h(-1) i.v. by osmotic pumps) in rats exposed to 10% O-2 during 2- weeks reduced the Pap (P<0.05) and the degree of muscularization of pu lmonary vessels at the alveolar wall (P<0.01) and alveolar duct levels (P<0.05) despite no significant change in right ventricular hypertrop hy. 6 These results suggest that cyclic GMP phosphodiesterase inhibiti on may selectively dilate pulmonary circulation during chronic hypoxia .