alpha-Difluoromethylornithine, an inhibitor of polyamine synthesis, attenuates monocrotaline-induced pulmonary vascular hyperresponsiveness in isolated perfused rat lungs.

Monocrotaline-induced pulmonary hypertension in rats is preceded by an early and prolonged activation of lung ornithine decarboxylase (ODC) and a resultant increase in lung polyamine levels. These changes coincide in time with a transient period of pulmonary vascular hyperresponsiveness to angiotensin II. We therefore tested the hypothesis that enhanced lung ODC activity is necessary for the occurrence of monocrotaline-induced pulmonary vascular hyperresponsiveness. Adult male rats were given a subcutaneous injection of either 105 mg/kg monocrotaline or its vehicle and were treated concurrently with either alpha-difluoromethylornithine (DFMO), a specific, irreversible inhibitor of ODC, or saline. One week post monocrotaline treatment, animals were sacrificed and vascular responsiveness to angiotensin II and KCl was assessed in isolated, buffer perfused lungs. Relative to control preparations, lungs from monocrotaline-treated animals exhibited significantly larger vasoconstrictor responses upon challenge with 0.1 or 0.5 microgram angiotensin II. In contrast, angiotensin II-induced responses in lungs from rats treated with monocrotaline plus DFMO were not different from control. DFMO treatment alone had no impact on angiotensin responses. Vasoconstrictor responses evoked by 30 and 45 mg KCl were not different in lungs from monocrotaline-treated animals relative to control nor were they influenced by concurrent treatment with DFMO. Neither the polyamines (putrescine, spermidine, or spermine) nor DFMO influenced angiotensin II-induced vasoconstriction in normal lungs when added acutely to the perfusate reservoir. These observations suggest that the polyamines, although not serving as regulators of vascular reactivity in the normal pulmonary circulation, are causally related to the evolution of pulmonary vascular hyperresponsiveness observed in lungs from monocrotaline-treated rats.