A role for serotonin in alpha-naphthylthiourea-induced pulmonary edema.
alpha-Naphthylthiourea (ANTU) damages the pulmonary capillary endothelium producing a marked pulmonary edema. Since the pulmonary microvasculature regulates the circulating levels of serotonin (5-HT), the role of 5-HT in the pathophysiology of ANTU-induced pulmonary edema was examined. Mice treated with ANTU (10 mg/kg, ip) rapidly developed pulmonary edema which was maximal at 3 hr and was resolved by 12 hr. The lung content of both endogenous 5-HT and a tracer dose of 5-[3H]HT paralleled the time course of the development and resolution of the pulmonary edema. ANTU produced a significant thrombocytopenia (58 to 72%) at all time points, and an elevated platelet content of 5-HT and 5-[3H]HT during the resolution phase (6 to 12 hr). Drugs possessing select effects on 5-HT were shown to alter the edematogenic response to ANTU. Fluoxetine, a selective inhibitor of 5-HT uptake, potentiated the pulmonary edema, while clorgyline, an irreversible inhibitor of type A monoamine oxidase, was without effect. Reserpine which depletes 5-HT stores prevented both thrombocytopenia and pulmonary edema in response to ANTU. Reloading the lung and platelet 5-HT stores of reserpinized animals reestablished the normal response to ANTU. Pretreatment with the selective 5-HT2 receptor antagonist, ketanserin, prevented the thrombocytopenia, the increase in lung content of 5-HT and 5-[3H]HT, and prevented the edematogenic response to ANTU by 70%. These data indicate a major role for 5-HT in the pathophysiology of acute lung microvascular injury produced by ANTU.
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D003010:Clorgyline / Q000494:pharmacology; D004347:Drug Interactions; D005473:Fluoxetine / Q000494:pharmacology; D007650:Ketanserin; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D010880:Piperidines / Q000494:pharmacology; D011654:Pulmonary Edema / Q000139:chemically induced / Q000378:metabolism*; D012110:Reserpine / Q000494:pharmacology; D012701:Serotonin / Q000097:blood / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives* / Q000633:toxicity; D013921:Thrombocytopenia / Q000139:chemically induced
D010880:Piperidines; D012702:Serotonin Antagonists; D005473:Fluoxetine; D012701:Serotonin; D012110:Reserpine; D007650:Ketanserin; D013890:Thiourea; D003010:Clorgyline; C005277:alpha-naphthyl thiourea