Effect of inhalation of dinitrosyl iron complexes with N-acetyl-L-cysteine on systemic and pulmonary circulation in healthy rats and animals with pulmonary hypertension

Previous preclinical and clinical studies of dinitrosyl iron complexes with glutathione (DNIC) demonstrated high safety and hypotensive efficacy in patients with uncomplicated hypertensive crises. However, bioavailability through the skin and pulmonary surfactant was extremely limited due to the properties of glutathione as a DNIC ligand. Objective. To investigate hypotensive effect of DNIC with amphiphilic ligand N-acetyl-L-cysteine in systemic and pulmonary circulations after inhalation. Material and methods. Experiments were conducted in healthy Wistar rats and animals with pulmonary hypertension induced by monocrotaline (60 mg/kg). Anesthesia was achieved using a combination of tiletamine 250 mg and zolazepam 250 mg dissolved in saline solution (5 ml) (dose 5—7 mg/kg depending on weight and depth of anesthesia). We measured mean arterial pressure and heart rate in aortic arch using a Millar catheter in the left carotid artery. Right ventricular pressure was analyzed using a curved guidewire inserted in the right ventricle via the right jugular vein. DNIC-ACC was inhaled using an Omron U-22 ultrasonic nebulizer for 12 min at two doses: low dose (0.25 μmol) and, after a 15-minute recovery, double dose (0.50 μmol). Results. Systemic and pulmonary pressure decreased after 3-minute inhalation. In animals with pulmonary hypertension, right ventricular pressure decreased by 30% within 10 minutes, in control animals - by only 6%. Systemic pressure decreased in control animals (by 30%) and animals with pulmonary hypertension (by 26%). Conclusion. Inhalation of DNIC-ACC in control animals and animals with pulmonary hypertension decreased systemic and pulmonary pressure. Pulmonary pressure decrease was significantly greater in animals with monocrotoline-induced pulmonary hypertension compared to control animals. These results indicate the need for further research to adjust doses for less hypotensive effect in systemic circulation.