Evidence for the extrapulmonary localization of inhaled nitric oxide

Inhaled nitric oxide (NO) has emerged as a promising pulmonary vasodilator to treat pulmonary hypertension associated with heart disease and ventilation/perfusion mismatching. However, the pharmacokinetics of inhaled NO still remains obscure and its cardiopulmonary selectivity appears to be increasingly under debate. In the present study measured NO content and levels of cyclic guanosine 3',5'monophosphate (cGMP), a mediator of NO-induced vasodilation, in a variety of organs from rats subjected to NO inhalation. Electron spin resonance spectroscopy associated to a spin trapping technique using N-methyl D-glucamine dithiocarbamate (FeMGD) was used to directly quantify NO levels in the lung, kidney, liver, aorta, and heart from anesthetized Wistar rats subjected to various doses (0, 20, 50, 100, or 200 ppm) and various times (0, 30, 45, or 75 minutes) of inhaled NO. Inhaled NO at a dose of 100 and 200 ppm significantly increased the NO-FeMGD complex in all organs studied. An increase of cGMP was detected in the lung and the aorta after inhaled NO for 45 minutes at the dose of 50 ppm. No changes in NO levels and its metabolites were shown between 30 and 75 minutes of inhaled NO. The results show that inhaled NO at a dose of 100 ppm or more increases NO levels in other organs beside the lung, strongly suggesting that inhaled NO would be more than a pulmonary vasodilator and its selectivity remains to be reconsidered when used for therapeutic purposes.