P07 Hydrogen sulfide relaxes intrapulmonary airways by inhibiting Ca2+ release through InsP3 receptors and Ca2+ oscillations in smooth muscle cells

Abstract

Hydrogen sulfide (H 2 S) is a signaling molecule that regulates diverse cell physiological process in several organs and systems including vascular and airway smooth muscle cell (SMC) contraction. Decreases in endogenous H 2 S synthesis have been associated with the development of cardiovascular diseases and asthma. Here we investigated the mechanism of airway SMC relaxation induced by H 2 S in small intrapulmonary airways using mouse lung slices and confocal and phase-contrast video microscopy. Exogenous H 2 S (100 μ M) reversibly inhibited Ca 2+ release and airway contraction evoked by inositol-1,4,5-trisphosphate (InsP 3 ) uncaging in airway SMCs. Similarly, InsP 3 -evoked Ca 2+ release and contraction was inhibited by endogenous H 2 S precursor L-cysteine (10 mM) but not by L-serine (10 mM) or either amino acid in the presence of DL-propargylglycine (PPG). Consistent with the inhibition of Ca 2+ release through InsP 3 receptors (InsP 3 R), H 2 S reversibly inhibited acetylcholine (ACh)-induced Ca 2+ oscillations in airway SMCs. In addition, exogenous H 2 S and L-cysteine caused relaxation of airways pre-contracted with either ACh or 5-hydroxytriptamine (5-HT). The effects of H 2 S on InsP 3 -evoked Ca 2+ release and contraction as well as on the relaxation of agonist-contracted airways were mimicked by the thiol-reducing agent dithiothreitol (DTT, 10 mM) and inhibited by the oxidizing agent diamide (30 μ M). These studies indicate that H 2 S causes airway SMC relaxation by inhibiting Ca 2+ release through InsP 3 R and consequent reduction of agonist-induced Ca 2+ oscillations in SMCs. These results suggest a novel role for endogenously produced H 2 S that involves the modulation of InsP 3 -evoked Ca 2+ release —a cell-signaling system of critical importance for many physiological and pathophysiological processes.