title: Upregulation of inducible nitric oxide synthase contributes to attenuated cutaneous vasodilation in essential hypertensive humans.
abstract: Essential hypertension is a proinflammatory, proconstrictor disease coinciding with endothelial dysfunction and inward vessel remodeling. Using the skin circulation, our aim was to determine whether inducible NO synthase (iNOS) upregulation attenuates NO-dependent cutaneous vasodilation in hypertensive humans. We hypothesized that, with hypertension, localized iNOS inhibition would restore vasodilation in response to NO-dependent stimuli, and iNOS expression would be increased and phosphorylated vasodilator-stimulated phosphoprotein would be decreased. For, in vivo protocols, 4 intradermal microdialysis fibers were placed in 9 hypertensive and 10 normotensive men and women (systolic blood pressure: 146±4 versus 113±2 mm Hg; P<0.001). Microdialysis fibers served as control, iNOS inhibited (1400 W), neuronal NO synthase inhibited (N(ω)-propyl-l-arginine), and nonselective NOS inhibited (N(G)-nitro-l-arginine methyl ester). Cutaneous vascular conductance was calculated (percentage of sodium nitroprusside) during standardized local heating (42°C) and acetylcholine dose-response protocols (0.01, 0.10, 1.00, 5.00, 10.00, 50.00, 100.00 mmol/L). The NO-dependent local heating response was attenuated at control (95±2% versus 76±2% cutaneous vascular conductance; P<0.05) and neuronal NO synthase-inhibited sites (94±4% versus 77±3% cutaneous vascular conductance; P<0.01) in hypertensives. iNOS inhibition augmented the NO-dependent local heating response (93±2% versus 89±10% cutaneous vascular conductance). Acetylcholine-induced vasodilation was attenuated in control sites at doses ≥0.1 mmol/L of acetylcholine in hypertensives and was restored with iNOS inhibition (0.1 mmol/L, P<0.05; 1, 5, and 10 mmol/L, P<0.001; 50 and 100 mmol/L, P<0.01). In vitro iNOS expression was increased (P=0.006) and phosphorylated vasodilator-stimulated phosphoprotein was decreased in skin from hypertensive humans (P=0.04). These data suggest that iNOS is upregulated in essential hypertensive humans and contributes to reduced NO-dependent cutaneous vasodilation.
authors.affiliation: Department of Kinesiology, Pennsylvania State University, University Park, PA, USA.
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Smith
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Santhanam
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Bruning
authors.forename: Anna
authors.initials: A
authors.lastname: Stanhewicz
authors.forename: Dan E
authors.initials: DE
authors.lastname: Berkowitz
authors.forename: Lacy A
authors.initials: LA
authors.lastname: Holowatz
mesh_terms: D000279:Administration, Cutaneous; D000704:Analysis of Variance; D015153:Blotting, Western; D016022:Case-Control Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006973:Hypertension / Q000201:enzymology* / Q000503:physiopathology; D017078:Laser-Doppler Flowmetry; D008297:Male; D008875:Middle Aged; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology; D012016:Reference Values; D012039:Regional Blood Flow / Q000187:drug effects; D012867:Skin / Q000098:blood supply* / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: D009599:Nitroprusside; D052247:Nitric Oxide Synthase Type II; D019331:NG-Nitroarginine Methyl Ester