H2S releasing sodium sulfide protects against pulmonary hypertension by improving vascular responses in monocrotaline-induced pulmonary hypertension

Abstract

Pulmonary arterial hypertension is caused by complex structural and functional changes in the endothelial and smooth muscle cells of pulmonary arteries. Hydrogen sulfide (H₂S), a gasotransmitter, can potentially treat pulmonary hypertension by relaxing the pulmonary arteries and decreasing bronchial pressure. Although the role of H₂S in systemic circulation has been examined, the H₂S levels in pulmonary arteries, the role of H₂S in endothelium-dependent vasorelaxation and the L-cysteine/H₂S pathway in monocrotaline-induced pulmonary arterial hypertension have not been investigated. The rats were divided into control, monocrotaline, monocrotaline + Na₂S, and Na₂S groups. The right ventricular pressure and hypertrophy were evaluated. KCl, acetylcholine, and L-cysteine responses were obtained in the main pulmonary arteries by wire myograph. H₂S levels were measured in pulmonary arteries and lungs by methylene blue assay. Right ventricular pressure and hypertrophy were increased by monocrotaline and ameliorated by Na₂S. The KCl-induced contractions and relaxing responses to acetylcholine and L-cysteine in pulmonary arteries and H₂S production in the lungs and pulmonary arteries were significantly attenuated in the monocrotaline group and augmented in the monocrotaline + Na₂S group. These findings suggest that H₂S levels were reduced, and L-cysteine-induced and endothelium-dependent relaxations were impaired in the pulmonary arteries in monocrotaline-induced pulmonary arterial hypertension. The H₂S donor, Na₂S, prevented endothelial dysfunction and increased pulmonary artery pressure and hypertrophy. Also, Na₂S enhanced the L-cysteine-mediated responses and restored the diminished H₂S levels in pulmonary arteries and the lungs. The treatments targeting H₂S might be beneficial for promoting vascular alterations, i.e. endothelial dysfunction and impaired H₂S-mediated relaxation in pulmonary arterial hypertension.

Keywords: Endothelial dysfunction; Hydrogen sulfide; L-cysteine; Pulmonary arterial hypertension; Vascular response.