The safety of aerosolized diethylenetriamine nitric oxide adduct after single-dose administration to anesthetized piglets and multiple-dose administration to conscious rats.
Diethylenetriamine nitric oxide adduct (DETA/NO) is a slow-release NO donor. It has been shown to be a selective pulmonary vasodilator in acute pulmonary hypertension. However, its potential toxicity after inhalation is unknown. This study investigated the potential toxicity of aerosolized DETA/NO after single- and multiple-dose exposure in animals. In the first part of the study, a single dose of DETA/NO (60 micromol) or placebo was aerosolized into the lungs of anesthetized piglets. Arterial methemoglobin and serum nitrite (NO2-) concentrations were measured after exposure. In the second part of the study, rats were exposed to aerosolized DETA/NO (60 micromol) or placebo for 7 days, and animals were euthanized 1, 3, 7, and 14 days after the first exposure. Serum NO2- and plasma surfactant protein B (SP-B) concentrations were measured. In both studies, acute lung inflammation was evaluated histopathologically (polymorphonuclear leucocytes (PMN) infiltration) and by measuring lung wet to dry weight ratio (LWDR). The tracheas of rats, which had the highest exposure, were further examined for ultrastructural changes using electron microscopy. In both rats and pigs, serum NO2- concentrations were elevated in all the DETA/NO-treated animals, indicating significant exposure to DETA/NO. Arterial methemoglobin was not increased by DETA/NO treatment. In the rats, plasma SP-B was not elevated by DETA/NO treatment. In addition, DETA/NO had no effects on PMN infiltration or LWDR in either animal model nor on the ultrastructure of large airways in rats. This study shows no evidence of pulmonary or hematological toxicity following single or repeated doses of DETA/NO in animals.
Lam
Chen-Fuh
CF
Pharmacology Unit, School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia.
Caterina
Paul
P
Filion
Pierre
P
Ilett
Kenneth F
KF
van Heerden
Peter V
PV
D000280:Administration, Inhalation; D000336:Aerosols; D000758:Anesthesia; D000818:Animals; D006168:Guinea Pigs; D008171:Lung Diseases / Q000139:chemically induced / Q000473:pathology; D008297:Male; D008706:Methemoglobin / Q000378:metabolism; D017348:Microscopy, Electron, Scanning Transmission; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000737:chemistry*; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D009573:Nitrites / Q000097:blood; D009929:Organ Size / Q000187:drug effects; D011073:Polyamines / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D037701:Pulmonary Surfactant-Associated Protein B / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013552:Swine; D014132:Trachea / Q000187:drug effects / Q000473:pathology
D000336:Aerosols; D020030:Nitric Oxide Donors; D009573:Nitrites; D011073:Polyamines; D037701:Pulmonary Surfactant-Associated Protein B; C005391:diethylenetriamine; D009569:Nitric Oxide; D008706:Methemoglobin