SELECTIVE DEFECT IN NITRIC-OXIDE SYNTHESIS MAY EXPLAIN THE IMPAIRED ENDOTHELIUM-DEPENDENT VASODILATION IN PATIENTS WITH ESSENTIAL-HYPERTENSION

Background-Patients with essential hypertension have impaired endothel ial NO activity, but the mechanism underlying this abnormality is unkn own. Methods and Results-To investigate whether the endothelial dysfun ction of hypertensive patients is related to a selective defect in NO synthesis, we studied the forearm blood now responses to intra-arteria l infusion of acetylcholine (7.5 to 30 mu g/min), an endothelial agoni st linked to NO synthase through the Ca2+ signaling pathway, and isopr oterenol (50 to 200 ng/min), a beta-adrenoceptor agonist that stimulat es NO production by increasing intracellular cAMP, in 12 normotensive subjects and 12 hypertensive patients. The infusion of isoproterenol w as repeated during the concurrent blockade of NO synthesis by N-G-mono methyl-L-arginine (L-NMMA; 4 mu mol/min). The vasodilator response to acetylcholine was significantly reduced in hypertensives compared with normotensives (maximum blood flow: 10.4+/-4.6 versus 14.4+/-3.7 mL . min(-1) . dL(-1); P=.008). However, the vasodilator effect of isoprote renol was similar in normotensives and hypertensives (maximum blood no w: 14.4+/-5.4 versus 13.5+/-5 mL . min(-1) . dL(-1); P=.56) and was si gnificantly (both P<.01) and equally blunted by L-NMMA in both groups (maximum blood now: 11+/-3 mL . min(-1). dL(-1) in normotensives versu s 10.8+/-3.9 mL . min(-1) . dL(-1) in hypertensives; P=.77). The vasod ilator response to sodium nitroprusside (0.8 to 3.2 mu g/min), an exog enous NO donor, was similar in both groups and was not modified by L-N MMA. Conclusions-Hypertensive patients have impaired endothelium-depen dent vasodilation in response to acetylcholine but preserved NO activi ty in response to beta-adrenergic stimulation. These findings suggest that the endothelial dysfunction in essential hypertension is due to a selective abnormality of NO synthesis, probably related to a defect i n the phosphatidylinositol/Ca2+ signaling pathway.