15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and sodium-bisulfide

Adipose tissue releases an "adipocyte-derived relaxing factor" (ADRF) lowering tone of isolated arteries. The potential influence of hypoxia on the vasorelaxing properties of adipose tissue was investigated. Aortas from male Swiss mice with or without adherent adipose tissue were mounted in a wire myograph for isometric tension recording. Hypoxia (bubbling with 95% N(2), 5% CO(2)) relaxed precontracted (norephinephrine, 5 microM) aorta with adipose tissue while only a minimal vasorelaxing effect was observed in arteries without adipose tissue. This effect was also seen after precontraction with prostaglandin F(2alpha) (30 microM) or U-46619 (10 nM). Precontraction with 60 or 120 mM K(+), incubation with tetraethylammoniumchloride (3 mM) or glibenclamide (30 microM) significantly impaired the hypoxic response. Glibenclamide (30 microM) enhanced the vasorelaxing effect of NaHS (except at high concentrations of NaHS). Lactate (10 nM to 1 mM) had no effect on preparations with or without adipose tissue. 8-(p-sulfophenyl)theophylline (0.1 mM), zinc protoporphyrin IX (10 microM), 1 H-[1, 2, 4]oxadiazolo[4,3-A]quinoxalin-1-one (10 microM) and removal of the endothelium did not influence the hypoxic relaxation. Our findings indicate that hypoxia has a relaxing influence on mice aorta that is dependent on the presence of adherent adipose tissue. This relaxation is partly mediated by opening K(ATP) channels and independent of the endothelium and soluble guanylyl cyclase. Neither lactate, adenosine, CO nor H(2)S seems to be involved in this hypoxic response. However, the involvement of the as yet unidentified "adipocyte-derived relaxing factor" (ADRF) cannot be excluded.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenosine; Adipose Tissue; Animals; Aorta, Thoracic; Arteries; Cell Hypoxia; Dinoprost; Glyburide; Guanylate Cyclase; Male; Mice; Norepinephrine; Potassium; Prostaglandins; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase; Sulfides; Tetraethylammonium; Theophylline; Vasodilation

The activity of NADPH oxidase (NOX) is blocked by nitric oxide (NO). Hydrogen sulfide (H(2)S) is also produced by blood vessels. It is reasonable to suggest that H(2)S may have similar actions to NO on NOX. In order to test this hypothesis, the effect of sodium hydrosulfide (NaHS) on O(2)(-) formation, the expression of NOX-1 (a catalytic subunit of NOX) and Rac(1) activity (essential for full NOX activity) in isolated vascular smooth muscle cells (hVSMCs) was investigated. hVSMCs were incubated with the thromboxane A(2) analogue U46619 +/- NaHS for 1 or 16 h, and O(2)(-) formation, NOX-1 expression and Rac(1) activity were assessed. The possible interaction between H(2)S and NO was also studied by using an NO synthase inhibitor, L-NAME, and an NO donor, DETA-NONOate. The role of K(ATP) channels was studied by using glibenclamide. NaHS inhibited O(2)(-) formation following incubation of 1 h (IC(50), 30 nM) and 16 h (IC(50), 20 nM), blocked NOX-1 expression and inhibited Rac(1) activity. These inhibitory effects of NaHS were mediated by the cAMP-protein-kinase-A axis. Exogenous H(2)S prevents NOX-driven intravascular oxidative stress through an a priori inhibition of Rac(1) and downregulation of NOX-1 protein expression, an effect mediated by activation of the adenylylcyclase-cAMP-protein-kinase-G system by H(2)S.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenylyl Cyclases; Cells, Cultured; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP-Dependent Protein Kinases; Dose-Response Relationship, Drug; Enzyme Inhibitors; Glyburide; Humans; Hydrogen Sulfide; KATP Channels; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; NADPH Oxidase 1; NADPH Oxidases; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitroso Compounds; Potassium Channel Blockers; rac1 GTP-Binding Protein; Signal Transduction; Sulfides; Superoxides; Time Factors