Mechanisms Underlying the Biphasic Effects of Hydrogen Sulfide in Rat Intrapulmonary Arteries.

Abstract

Background/Objectives: Hydrogen sulfide (H₂S) is an important regulator of pulmonary vascular tone; however, the mechanisms underlying its biphasic contractile and relaxant effects, as well as the distinct contributions of endogenous and exogenous H₂S to nitric oxide (NO) signaling, remain incompletely understood. This study investigated the roles of endogenous and exogenous H₂S in regulating pulmonary vascular responses under physiological and oxidative stress conditions. Methods: Rat intrapulmonary arteries were studied using wire myography and simultaneous measurements of vascular force and intracellular Ca²⁺. Pharmacological inhibitors were used to examine the contribution of endogenous H₂S synthesis, NO synthase, soluble guanylate cyclase (sGC), K_ATP channels, and oxidative stress to vascular responses. Results: Sodium hydrogen sulfide (NaHS) produced biphasic concentration-dependent responses, with contraction at low concentrations followed by relaxation at higher concentrations. Simultaneous measurements of vascular force and intracellular Ca²⁺ showed that the initial contractile response to low concentrations of NaHS was not accompanied by a clear increase in intracellular Ca²⁺, whereas relaxation developed despite maintained or increasing intracellular Ca²⁺, indicating that NaHS-induced relaxation cannot be explained solely by reduced intracellular Ca²⁺ levels. Inhibition of endogenous H₂S synthesis reduced vascular responsiveness to the NO donor sodium nitroprusside, whereas relaxation induced by exogenous NaHS was largely preserved after inhibition of NO synthase or sGC, indicating distinct roles of endogenous and exogenous H₂S. Oxidative stress impaired acetylcholine- and riociguat-induced relaxation, while NaHS partially restored endothelial function. Conclusions: Endogenous and exogenous H₂S regulate pulmonary vascular tone through distinct mechanisms. Endogenous H₂S supports vascular responsiveness to NO, whereas exogenous H₂S induces relaxation largely independently of NO-sGC signaling. Furthermore, NaHS-induced relaxation occurs despite maintained intracellular Ca²⁺, suggesting an important contribution of Ca²⁺-independent mechanisms, and partially preserves endothelial function under oxidative stress.