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(Circulation. 2000;102:552.)
© 2000 American Heart Association, Inc.

Clinical Investigation and Reports

Noradrenergic Vascular Hyper-Responsiveness in Human Hypertension Is Dependent on Oxygen Free Radical Impairment of Nitric Oxide Activity

Presented in part at the 52nd Annual Fall Conference and Scientific Sessions of the Council for High Blood Pressure Research, Philadelphia, Penn, September 15–18, 1998.

Giuseppe Lembo, MD, PhD; Carmine Vecchione, MD; Raffaele Izzo, MD; Luigi Fratta, MD; Dario Fontana, MD; Gennaro Marino, MD; Giovanni Pilato, MD; Bruno Trimarco, MD

From Istituto di Ricovera e Cura a Carattere Scientifico Neuromed, Pozzilli (G.L., C.V., L.F., B.T.) and the Department of Internal Medicine (R.I., D.F., G.M., G.P., B.T.), "Federico II" University of Naples, Italy.

Correspondence to Giuseppe Lembo, MD, PhD, IRCCS Neuromed, Località Camerelle, 86077 Pozzilli (IS), Italy. E-mail lembo{at}neuromed.it

Background—Noradrenergic vascular hyper-responsiveness is a hallmark of essential hypertension. To evaluate whether nitric oxide plays a role in the enhanced vascular response to norepinephrine in hypertension, we examined 32 hypertensives and 28 normotensives who were distributed in 3 experimental series.

Methods and Results—In the first series, we measured the forearm blood flow (FBF) response to a norepinephrine infusion under control conditions and during the infusion of L-N-monomethylarginine (L-NMMA). Norepinephrine evoked dose-dependent vasoconstriction that was greater in hypertensives than in normotensives (maximum FBF, -61±1 versus -51±1%; P<0.01). During L-NMMA infusion, norepinephrine vasoconstriction was not modified in hypertensives; however, it was potentiated in normotensives (maximum FBF, -64±2%; P<0.01). In the second series, we tested whether norepinephrine vasoconstriction could be affected by an antioxidant such as ascorbic acid. Norepinephrine vasoconstriction was blunted by ascorbic acid administration only in hypertensives (maximum FBF, -49±3 versus -63±2%; P<0.01); the vasoconstriction became similar to that observed in normotensives. During ascorbic acid plus L-NMMA administration, the vascular response to norepinephrine increased to a similar extent in both study groups. To rule out the possibility that the effect of ascorbic acid on norepinephrine vasoconstriction could depend on adrenergic receptor–induced nitric oxide release, in the last series we inhibited endogenous nitric oxide and replaced it with an exogenous nitric oxide donor (sodium nitroprusside). Even in these conditions, ascorbic acid attenuated norepinephrine vasoconstriction only in hypertensives (maximum FBF, -50±2 versus -62±1%; P<0.01).

Conclusions—Our data demonstrate that noradrenergic vascular hyper-responsiveness in hypertension is dependent on an impairment of nitric oxide activity that is realized through norepinephrine-induced oxygen free radical production.

Key Words: norepinephrine • hypertension • blood flow • endothelium • antioxidants

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