Journal of Human Hypertension (2002) 16, 557–562 2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh ORIGINAL ARTICLE Circulating intercellular cell adhesion molecule-1, endothelin-1 and von Willebrand factor-markers of endothelial dysfunction in uncomplicated essential hypertension: the effect of treatment with ACE inhibitors Z Hlubocka´1, V Umnerova´ 1, S Heller1, J Peles¯ka1, A Jindra1,MJa´chymova´1, J Kvasnic¯ka2, K Horky´ 1 and M Aschermann1 1Second Department of Internal and Cardiovascular Medicine, First School of Medicine, Charles University, Prague, Czech Republic; 2Department of Clinical Hematology, First School of Medicine, Charles University, Prague, Czech Republic The aim of the study was to examine whether the circul- tensive patients with quinapril led to a significant ating cell adhesion molecules, von Willebrand factor decrease in the levels of endothelin-1 (5.76 vs (vWf) and endothelin-1, are elevated in patients with 5.28 fmol/ml, P Ͻ 0.01). We did not observe significant essential hypertension with no other risk factors for changes in the levels of adhesion molecules and vWf atherosclerosis and thus may serve as a markers of after ACE inhibitor treatment, although a trend toward a endothelial dysfunction in uncomplicated hypertension. decrease was apparent with all these parameters. Furthermore, the effect of treatment with the ACE inhibi- Patients with uncomplicated hypertension with no other tor, quinapril, on levels of endothelial dysfunction mark- risk factors of atherosclerosis had significantly elevated ers were studied. The levels of adhesion molecules levels of ICAM-1, vWf, and endothelin-1. Our data sug- (intercellular cell adhesion molecule-1 [ICAM-1], E-sel- gest that these factors may serve as markers of endo- ectin, P-selectin), von Wilebrand factor (vWf) and endo- thelial damage even in uncomplicated hypertension. In thelin-1 were measured in patients with hypertension hypertensive patients, treatment with the ACE inhibitor without any other risk factors of atherosclerosis before quinapril resulted in a significant decrease in endo- and after treatment with quinapril (n = 22) and in normo- thelin-1 levels. These findings indicate a beneficial tensive controls (n = 22). Compared with normotensive effect of ACE inhibitors on endothelial dysfunction in subjects, the hypertensive patients had significantly hypertensive patients. higher levels of ICAM-1 (238 vs 208 ng/ml, P = 0.02), vWf Journal of Human Hypertension (2002) 16, 557–562. (119 vs 105 IU/dl, P Ͻ 0.05) and endothelin-1 (5.76 vs doi:10.1038/sj.jhh.1001403 5.14 fmol/ml, P Ͻ 0.05). Three-month treatment of hyper- Keywords: soluble adhesion molecules; von Willebrand factor; endothelin-1; endothelial dysfunction Introduction step in the development of atherosclerosis is impair- ment of the physiological function of vascular endo- Hypertension is one of the main risk factors for car- thelium referred to as endothelial dysfunction. Cell diovascular diseases and accelerated development adhesion molecules play an important role in this of atherosclerosis and its complications. The first initial phase of development of atherosclerosis. Endothelial dysfunction in hypertensive individ- uals is characterised by impaired vasorelaxation Correspondence: Z Hlubocka´, MD, Second Department of Internal mediated by endothelium (in the presence of a and Cardiovascular Medicine, First School of Medicine, Charles decreased activity of vasodilators, endothelium- University, U nemocnice 2, 128 08 Prague 2, Czech Republic. E-mail: zmareȰhotmail.com derived relaxant factor/nitric oxide (EDRF/NO) in Received 12 July 2001; revised 3 February 2002; accepted 7 Feb- particular, and an increased activity of vasoconstric- ruary 2002 tor factors as endothelin), increased adhesion and Markers of endothelial dysfunction in hypertension Z Hlubocka´ et al 558 permeability of endothelial cells and structural levels.14 By contrast, a previous study described changes of the vascular wall. only slight, statistically non-significant increments Endothelial dysfunction has been associated with (11%) of soluble ICAM-1, E-selectin and VCAM-1 increased expression of glycoprotein adhesion mol- levels in healthy volunteers during graded 4-h ecules of the selectin group1 (E-selectin and P- infusion of angiotensin II at doses up to selectin) and immunoglobulin group (intercellular 20 ng/kg/min (average dose 8 ng/kg/min).15 The rea- cell adhesion molecule-1 (ICAM-1) and vascular cell son for this discrepancy is unclear. adhesion molecule-1 (VCAM-1). These surface mol- Apart from the decrease in BP, one of the aims of ecules allow leukocytes to adhere to the endothelial antihypertensive therapy is the reversal of endo- surface and subsequently to migrate into the vessel thelial dysfunction. The studies described above wall. Subendothelial accumulation of inflammatory indicate that angiotensin-converting enzyme (ACE) cells with subsequent formation of foam cells is the inhibitors, through their comprehensive action on first step in the development of atherosclerosis.2 the RAA system may improve impaired endothelial Increased expression of cell adhesion molecules function in hypertensive subjects; one of the mech- ICAM-1, VCAM-1 and E-selectin has been observed anisms of action of ACE inhibitors seems to be in human atherosclerotic plaques.3,4 downregulation of cell adhesion molecules. Furthermore, the amount of soluble ICAM-1 and The present study focuses on whether plasma lev- E-selectin released into the circulation has been els of adhesion molecules, vWf and endothelin-1 demonstrated to directly correlate with the surface may serve as markers of endothelial dysfunction in expression of ICAM-1 and E-selectin in a culture of hypertensive patients who have no other risk factor endothelial cells.5 Upregulation of adhesion mol- of atherosclerosis. ecule genes leads to the expression of membrane- associated adhesion molecules and release of their soluble forms. Based on these findings, we assume Aims of the study that circulating soluble adhesion molecules levels Increased levels of soluble adhesion molecules have may act as markers of adhesion molecules been reported in a number of studies in patients expression in vivo.6,7 with overt atherosclerosis or with accumulation of Increased plasma levels of E-selectin have been risk factors of atherosclerosis8–11 and are thought to demonstrated in conditions associated with an be markers of endothelial dysfunction in the early increased risk for the development of atheroscler- stages of atherosclerosis. 8 osis, eg, in type-2 diabetes mellitus and in essential The aim of our study was to establish whether 9 hypertension. Patients with hypertension associa- patients with uncomplicated essential hypertension ted with other risk factors for atherosclerosis have with no other risk factors of atherosclerosis have been shown to exhibit elevated plasma levels of increased levels of soluble adhesion molecules (E- soluble ICAM-1, VCAM-1, E-selectin and von selectin, P-selectin, and ICAM-1) and other potential Willebrand factor (vWf).10,11 Elevated levels of sol- markers of endothelial dysfunction (vWF, endo- uble P-selectin were associated with increased risk thelin-1). A secondary aim was to assess the effect of future myocardial infarction and cardiovascular of antihypertensive therapy with the ACE inhibitor, death in apparently healthy women.12 Increase quinapril, on levels of adhesion molecules and other plasma levels of P-selectin were also reported in endothelial dysfunction markers. patients with renovascular and malignant hyperten- sion while the authors did not observe statistically significant changes in P-selectin levels in patients Subjects and methods 13 with primary hypertension. Subjects The pathogenesis of arterial hypertension and its complications includes both mechanical factors In the period from March 1999 through January 2001 (increase in blood pressure (BP), increased periph- we examined at the Second Department of Internal eral vascular resistance, and shear stress), and hor- and Cardiovascular Medicine, General University monal factors (renin-angiotensin-aldosterone (RAA) Hospital in Prague, Czech Republic, a total of 22 system, catecholamines, etc). Increased activity of middle-aged men (35–66 years, mean age 50 ± 10 the renin-angiotensin system is an important factor years) with mild essential hypertension (mean sys- in the pathogenesis of arterial hypertension. tolic BP 143 ± 18 mm Hg, mean diastolic BP 94 ± 8 Recently, it has been shown that intravenous angio- mm Hg) with no other risk factors of atherosclerosis. tensin II infusion (at an initial dose of 1 ng/kg/min, They were either newly diagnosed patients, without increased each 30 min by 2 ng/kg/min to the final any treatment, or hypertensive individuals exam- dose of 7 ng/kg/min) increases plasma ICAM-1 con- ined after a 3-week discontinuation of antihyperten- centrations in healthy volunteers and subjects with sive therapy. A control group comprised 22 healthy essential hypertension,14 thereby enhancing leuko- age-matched men (34–65 years, mean age 46 ± 7 cyte adhesion and migration to the vascular wall. years) with normal BP values (BP below 140/90 Selective blockade of the AT-1 receptor for angioten- mm Hg, mean systolic BP 122 ± 11 mm Hg, diastolic sin II then resulted in a decrease in serum ICAM-1 BP 83 ± 6 mm Hg), without any risk factors of athero- Journal of Human Hypertension Markers of endothelial dysfunction in hypertension Z Hlubocka´