660 DIABETES, VOL. 47, APRIL 1998 Early Activation of Vascular Endothelium in Nonobese, Nondiabetic Essential Hypertensive Patients With Multiple Metabolic Abnormalities Claudio Ferri, Giovambattista Desideri, Roberta Baldoncini, Cesare Bellini, Claudio De Angelis, Clarita Mazzocchi, and Anna Santucci Circulating soluble E-selectin, intercellular adhesion molecule-1 ( ICAM-1) , and vascular adhesion molecule- 1 (VCAM-1) concentrations were evaluated in 93 nonobese essential hypertensive patients, of whom 16 had impaired glucose tolerance and hyperlipidemia (group I) ; 25 had impaired glucose tolerance (group II) ; 28 had hyperlipidemia (group III); and 24 had no metabolic abnormalities (group IV). A group of 22 healthy volunteers served as a control group. All groups were without clinical or ultrasound evidence of vascular lesion and were matched for age, sex, and BMI. Endothelial soluble adhesion molecules were measured at baseline, during an oral glucose tolerance test, and after 12 weeks of either enalapril or placebo treatments. Plasma soluble E-selectin, ICAM-1, and VCAM-1 were higher ( P < 0.05) in group I and II than in the other groups (group I: E-selectin, 96.1 ± 27.1; ICAM-1, 304.0 ± 102.1; VCAM-1, 626.1 ± 156.2 μg/l. Group II: E-selectin, 88.0 ± 18.0; ICAM-1, 268.0 ± 84.1; VCAM-1, 594.1 ± 140.9 μg/l. Group III: E-selectin, 70.1 ± 18.1; ICAM-1, 195.1 ± 68.0; VCAM-1, 495.9 ± 110.1 μg/l. Group IV: E-selectin, 65.1 ± 16.1; ICAM-1, 168.1 ± 64.0; VCAM-1, 472.1 ± 108.2 μg/l). Soluble adhesins lev- els were not higher than normal in groups III and IV. Plasma soluble ICAM-1 concentrations increased in group I after glucose administration and were directly correlated with 2-h insulin levels ( r = 0.648, P = 0.007). Compared with placebo, 12 weeks of enalapril treatment significantly ( P < 0.0001) reduced soluble E-selectin, ICAM-1, and VCAM-1. Decrements of soluble adhesins were not dependent on enalapril-related blood pres- sure changes. Therefore, an early endothelial activation was present in essential hypertensive patients with impaired glucose tolerance, regardless of the presence of hyperlipidemia. ACE inhibition counteracted such endothelial activation. Diabetes 47:660–667, 1998 A dhesion molecules of the selectin family (E- selectin) (1) and the immunoglobulin superfam- ily (intercellular adhesion molecule-1 [ICAM-1] and vascular adhesion molecule-1 [VCAM-1]) (2) are poorly expressed by the resting endothelium. In contrast, they are upregulated during acute infections (2), granulo- matous diseases (2), and atherogenesis (3). Thus, endothelial adhesion molecules allow both acute responses against pathogens (4) and chronic inflammatory processes, such as those leading to progressive formation of atherosclerotic plaques (3). Upregulation of endothelial adhesion molecules is accom- panied by the release of their soluble fractions into the blood- stream (5). As a consequence, elevated plasma levels of sol- uble endothelial adhesins have been suggested as the only available indexes of increased adhesion molecule expression by the intact vascular endothelium in vivo (5). Accordingly, some recent data indicate that adhesion receptors are upreg- ulated in patients with a high risk of developing atheroscle- rosis. In particular, circulating levels of soluble E-selectin (6), ICAM-1, and VCAM-1 (7) were elevated in type 2 diabetic patients. Similarly, mild essential hypertensive patients man- ifested increased plasma concentrations of soluble E-selectin (8). As a consequence, it does not seem arbitrary to speculate that an early endo thelial activation might be present in uncomplicated diabetes and hypertension, thus favoring the development of overt vascular lesions. In keeping to this hypothesis, the vascular endothelium from type 1 diabetic (9), type 2 diabetic (10), and obese patients (11) exaggeratedly releases other endothelium-derived substances that have been indicated as markers of endothelial damage, i.e., vo n Willebrand factor (vWF; 9) and endothelin-1 (10,11). In this context, we recently demonstrated a significant ele- vation of plasma endothelin-1 levels in nonobese, essential hypertensive patients with impaired glucose tolerance, par- ticularly when hyperdyslipidemia was simultaneously pres- ent (12). Therefore, we hypothesized that an early endothe- lial activation preceded the onset of overt vascular damage in hypertensive patients with multiple metabolic abnormali- ties (13) and was responsible for the increased release of endothelin-1 into the bloodstream (12). To verify this hypothesis, we measured plasma soluble E- selectin, ICAM-1, VCAM-1, and vWF levels in these patients. Because changes of circulating soluble adhesins have been recently described after ACE inhibition (14) and oral glu- From the Andrea Cesalpino Foundation (C.F., G.D., R.B., C.D.A.), Univer- sity “La Sapienza,” Rome; and the Departments of Experimental (C.B.) and Internal Medicine (C.M., A.S.), the University of L’Aquila, L’Aquila, Italy. Address correspondence and reprint requests to Dr. Claudio Ferri, Uni- versità “La Sapienza,” Cattedra di I Clinica Medica, Fondazione Andrea Cesalpino , 00161 Rome, Italy. E-mail: clferri@ axrma.uniroma1.it. Received for publication 15 August 1997 and accepted in revised form 18 December 1997. ICAM-1, intercellular adhesion molecule-1; VCAM-1, vascular adhesion molecule-1; vWF, von Willebrand factor.