title: Autonomic Blockade Reverses Endothelial Dysfunction in Obesity-Associated Hypertension.
abstract: Impaired nitric oxide (NO) vasodilation (endothelial dysfunction) is associated with obesity and thought to be a factor in the development of hypertension. We previously found that NO synthesis inhibition had similar pressor effects in obese hypertensives compared with healthy control during autonomic blockade, suggesting that impaired NO vasodilation is secondary to sympathetic activation. We tested this hypothesis by determining the effect of autonomic blockade (trimethaphan 4 mg/min IV) on NO-mediated vasodilation (increase in forearm blood flow to intrabrachial acetylcholine) compared with endothelial-independent vasodilation (intrabrachial sodium nitroprusside) in obese hypertensive subjects (30<body mass index<40 kg/m(2)). Acetylcholine and sodium nitroprusside were given at equipotent doses (10, 30, and 50 μg/min and 1, 2, and 3 μg/min, respectively) to 14 obese subjects (49±3.6 years, 34±1 kg/m(2), 165/94±7/6 mm Hg), on separate occasions 1 month apart, randomly assigned. Autonomic blockade increased basal forearm blood flow (from 3.9±0.7 to 5.2±1.2 mL/100 mL per minute, P=0.078). As expected, NO-mediated vasodilation was blunted on the intact day compared with NO-independent vasodilation; forearm blood flow increased from 3.6±0.6 to 10.1±1.1 with the highest dose of nitroprusside, but only from 3.7±0.4 to 7.2±0.8 mL/100 mL per minute with the highest dose of acetylcholine, P<0.05. In contrast, forearm blood flow responses to acetylcholine were restored by autonomic blockade and were no longer different to nitroprusside (from 6.2±1.1 to 11.4±1.6 mL/100 mL per minute and from 5.2±0.9 to 12.5±0.9, respectively, P=0.58). Our results support the concept that sympathetic activation contributes to the impairment in NO-mediated vasodilation seen in obesity-associated hypertension and provides further rationale to explore it as a therapeutic target.
authors.affiliation: From the Division of Clinical Pharmacology (A.G., R.F., S.Y.P., G.F., A.D., I.B.), Departments of Medicine (A.G., R.F., S.Y.P., G.F., A.D., I.B.), and Pharmacology (I.B.), Vanderbilt University, Nashville, TN. alfredo.gamboa@vanderbilt.edu.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Gamboa
authors.affiliation: From the Division of Clinical Pharmacology (A.G., R.F., S.Y.P., G.F., A.D., I.B.), Departments of Medicine (A.G., R.F., S.Y.P., G.F., A.D., I.B.), and Pharmacology (I.B.), Vanderbilt University, Nashville, TN.
authors.forename: Rocío
authors.initials: R
authors.lastname: Figueroa
authors.affiliation: From the Division of Clinical Pharmacology (A.G., R.F., S.Y.P., G.F., A.D., I.B.), Departments of Medicine (A.G., R.F., S.Y.P., G.F., A.D., I.B.), and Pharmacology (I.B.), Vanderbilt University, Nashville, TN.
authors.forename: Sachin Y
authors.initials: SY
authors.lastname: Paranjape
authors.affiliation: From the Division of Clinical Pharmacology (A.G., R.F., S.Y.P., G.F., A.D., I.B.), Departments of Medicine (A.G., R.F., S.Y.P., G.F., A.D., I.B.), and Pharmacology (I.B.), Vanderbilt University, Nashville, TN.
authors.forename: Ginnie
authors.initials: G
authors.lastname: Farley
authors.affiliation: From the Division of Clinical Pharmacology (A.G., R.F., S.Y.P., G.F., A.D., I.B.), Departments of Medicine (A.G., R.F., S.Y.P., G.F., A.D., I.B.), and Pharmacology (I.B.), Vanderbilt University, Nashville, TN.
authors.forename: Andre
authors.initials: A
authors.lastname: Diedrich
authors.affiliation: From the Division of Clinical Pharmacology (A.G., R.F., S.Y.P., G.F., A.D., I.B.), Departments of Medicine (A.G., R.F., S.Y.P., G.F., A.D., I.B.), and Pharmacology (I.B.), Vanderbilt University, Nashville, TN.
authors.forename: Italo
authors.initials: I
authors.lastname: Biaggioni
mesh_terms: D001340:Autonomic Nerve Block / Q000379:methods*; D001795:Blood Pressure Determination; D015992:Body Mass Index; D015897:Comorbidity; D018592:Cross-Over Studies; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006973:Hypertension / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology*; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D009599:Nitroprusside / Q000008:administration & dosage*; D009765:Obesity / Q000453:epidemiology* / Q000503:physiopathology; D018570:Risk Assessment; D012720:Severity of Illness Index
chemical_list: D009599:Nitroprusside; D009569:Nitric Oxide
keywords: autonomic nervous system; hypertension; nitric oxide; obesity; vasodilation