Abstract
Application of H2S (“sulfide”) elicits a complex contraction in rat pulmonary arteries (PAs) comprising a small transient contraction (phase 1; Ph1) followed by relaxation and then a second, larger, and more sustained contraction (phase 2; Ph2). We investigated the mechanisms causing this response using isometric myography in rat second-order PAs, with Na2S as a sulfide donor. Both phases of contraction to 1,000 μM Na2S were attenuated by the pan-PKC inhibitor Gö6983 (3 μM) and by 50 μM ryanodine; the Ca2+ channel blocker nifedipine (1 μM) was without effect. Ph2 was attenuated by the mitochondrial complex III blocker myxothiazol (1 μM), the NADPH oxidase (NOX) blocker VAS2870 (10 μM), and the antioxidant TEMPOL (3 mM) but was unaffected by the complex I blocker rotenone (1 μM). The bath sulfide concentration, measured using an amperometric sensor, decreased rapidly following Na2S application, and the peak of Ph2 occurred when this had fallen to ~50 μM. Sulfide caused a transient increase in NAD(P)H autofluorescence, the offset of which coincided with development of the Ph2 contraction. Sulfide also caused a brief mitochondrial hyperpolarization (assessed using tetramethylrhodamine ethyl ester), followed immediately by depolarization and then a second more prolonged hyperpolarization, the onset of which was temporally correlated with the Ph2 contraction. Sulfide application to cultured PA smooth muscle cells increased reactive oxygen species (ROS) production (recorded using L012); this was absent when the mitochondrial flavoprotein sulfide-quinone oxoreductase (SQR) was knocked down using small interfering RNA. We propose that the Ph2 contraction is largely caused by SQR-mediated sulfide metabolism, which, by donating electrons to ubiquinone, increases electron production by complex III and thereby ROS production.
Highlights
Hydrogen sulfide (H2S, hereafter referred to as sulfide) typically acts as a vasodilator but in some arteries causes constriction or a complex response that exhibits both constricting and dilating phases [26]
We have presented evidence in abstract form that the second sulfide-induced contraction of rat pulmonary arteries (PAs) is abolished by the complex III blocker myxothiazol and is associated with mitochondrial hyperpolarization, leading us to propose that it is caused by an increased flux of electrons through the distal electron transport chain (ETC), which results in an increased generation of reactive oxygen species (ROS) by complex III [1, 8, 31]
This consisted of an initial brief contraction [phase 1 (Ph1)], followed by a relaxation and a second increase in tension [phase 2 (Ph2)], which waned with time
Summary
Hydrogen sulfide (H2S, hereafter referred to as sulfide) typically acts as a vasodilator but in some arteries causes constriction or a complex response that exhibits both constricting and dilating phases [26]. A study in perfused trout gills [35] showed that the constriction evoked by 100 M sulfide was strongly suppressed by blockers of mitochondrial complexes I, III, and IV and by the antioxidant diethyldithiocarbamate, leading the authors to propose a role for mitochondrially derived reactive oxygen species (ROS). It has been reported [25] that 1 mM NaHS depolarized bovine PA smooth muscle, which would be predicted to cause contraction by opening voltage-gated Ca2ϩ channels. Evidence has been presented that low concentrations of sulfide constricted rat aorta and increased blood pressure by scavenging nitric oxide [2]
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