Cyclooxygenase Inhibition Restores Nitric Oxide Activity in Essential Hypertension

Abstract

To evaluate whether cyclooxygenase constrictor substances can impair nitric oxide-mediated vasodilation in essential hypertension, in seven normotensive subjects (43.3±4.1 years; BP, 117±6/81±2 mm Hg) and seven essential hypertensive patients (47.1±5.2 years; BP, 151±8/98±4 mm Hg) we studied forearm blood flow (strain-gauge plethysmography) modifications induced by intrabrachial acetylcholine (0.15,0.45, 1.5, 4.5, 15 μg·100 mL ⁻¹ ·min ⁻¹ ) in basal conditions, during infusion of N ^G -monomethyl- l -arginine (L-NMMA; 100 μg·100 mL ⁻¹ ·min ⁻¹ ), a nitric oxide synthase inhibitor, or indomethacin (50 μg·100 mL ⁻¹ ·min ⁻¹ ), a cyclooxygenase inhibitor, or simultaneous indomethacin and L-NMMA. In normotensives, vasodilation to acetylcholine was blunted by L-NMMA (maximum flow increase: 671±64% and 386±42%, respectively; P <.01), and this effect was unchanged by indomethacin. In contrast, in hypertensive patients, vasodilation to acetylcholine (maximum flow increase: 458±33%) was unchanged by L-NMMA. Indomethacin significantly ( P <.01) increased the response to acetylcholine (maximum flow increase: 635±53%) and restored the inhibitory effect of L-NMMA (maximum flow increase: 445±36%; P <.01 versus indomethacin alone). In an adjunctive seven normotensives (51.4±4.2 years; BP, 114±5/79±3 mm Hg) and seven essential hypertensives (53.2±7.6 years; BP, 153±9/100±3 mm Hg) we repeated the same protocol by replacing L-NMMA with l -arginine (200 μg·100 mL ⁻¹ ·min ⁻¹ ), the substrate for NO synthase. In normotensives, vasodilation to acetylcholine was increased by l -arginine (maximum flow increase: 539±48% and 806±61%, respectively) and this effect was unchanged by indomethacin. In hypertensive patients, vasodilation to acetyl-choline (maximum flow increase: 339±32%) was unchanged by l -arginine but was significantly ( P <.01) increased by indomethacin (maximum flow increase: 592±38%). Moreover, indomethacin restored the facilitatory effect of l -arginine (maximum flow increase: 804±56%; P <.01 versus indomethacin alone). Therefore, cyclooxygenase inhibition restores nitric oxide-mediated vasodilation in essential hypertension, suggesting that cyclooxygenase-dependent substances can impair nitric oxide production.