Abstract
Introduction: Glucocorticoid (GC) excess is related to hypertension. The deletion of endothelial GC-receptors abrogates the blood pressure increase, suggesting GC-induced hypertension is endothelium-dependent. In response to shear stress endothelium releases nitric oxide, endothelial derived hyperpolarizing factor (EDHF) and prostacyclin. Recently H2S has been proposed as a candidate for EDHF. H2S is mainly produced by the enzymes cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) from L-cysteine. The aim of this study was to investigate the EDHF/H2S signaling in GC-hypertension. Methods: Male Wistar rats were treated with DEX (1.5 mg/kg/sc) or vehicle (VEH) for 8 days. Systolic blood pressure (SBP) was monitored every 2 days. EDHF was evaluated in mesenteric plexus and carotid artery performing a concentration-effect curve of acetylcholine in presence of indomethacin (INDO) and nitro-L-arginine methyl ester (L-NAME). Apamin (APA) plus charibdotoxin (CTX), SKCa and BKCa inhibitors, or propargylglycine (PAG), CSE inhibitor, were used. CBS and CSE levels were analyzed by immunoblot. H2S levels were measured by a colorimetric assay. Results: DEX treatment significantly increased SBP compared to VEH (*p<0.05, **p<0.01, ***p<0.001 at days 2-4, 6, 8 respectively). EDHF-mediated relaxation of mesenteric bed or carotid artery was markedly reduced in DEX group compared to VEH (***p<0.001). APA and CTX as well as PAG abolished EDHF-mediated relaxation in DEX or VEH group (***,°°°p<0.001 respectively). CBS and CSE levels were significantly reduced in mesenteric plexus and carotid artery in DEX group (*p<0.05). The H2S production was markedly reduced in mesenteric plexus and carotid artery (*p<0.05, **p<0.01 respectively) as well as plasmatic H2S levels (*p<0.05) in DEX rats compared to VEH. Conclusions: Our data demonstrate that GC-excess induces an impairment of H2S/EDHF signaling indicating an additional cause of GC-mediated hypertension.
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