Pharmacological modification of pulmonary vascular injury: possible role of cAMP.

Experiments were designed to test the hypothesis that drugs which increase adenosine 3',5'-cyclic monophosphate (cAMP) in the lung would prevent the pulmonary hypertension and the increase in vascular permeability caused by the infusion of the oxidant lipid peroxide, tert-butyl hydroperoxide (t-bu-OOH), in isolated rabbit lungs perfused with Krebs-Henseleit buffer. Pretreatment with indomethacin or verapamil was also studied, since these drugs block the increase in pulmonary arterial pressure caused by t-bu-OOH. Indomethacin or verapamil prevented the pulmonary hypertension but did not prevent the increase in permeability caused by t-bu-OOH. Consequently, indomethacin or verapamil treatment partially reduced the gain in lung weight caused by t-bu-OOH. In contrast, pretreatment with isoproterenol, prostaglandin E1, or a cAMP analogue not only prevented the pulmonary hypertension but also inhibited the increase in vascular permeability caused by t-bu-OOH. Consequently, these drugs completely blocked the gain in lung weight caused by t-bu-OOH. Posttreatment with aminophylline or the cAMP analogue also significantly reduced the gain in lung weight caused by t-bu-OOH. These results indicate that pharmacological therapy can reduce the pulmonary hypertension and the increase in vascular permeability caused by the infusion of a lipid hydroperoxide. Since isoproterenol, aminophylline, prostaglandin E1, and a cAMP analogue all had similar effects, the results suggest that the likely common mechanism for their protective effect is an increase in cAMP.