Impaired Mechanisms of Leukocyte Adhesion In Vitro by the Calcium ...

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In this issue of Cardiovascular Drugs and Therapy,. Nebe et al. [1] have demonstrated that the T-type. Ca2+-channel blocker mibefradil, but not the L-type.
Cardiovascular Drugs and Therapy 16 179–180 2002 C 2002 Kluwer Academic Publishers. Manufactured in The Netherlands 

EDITORIAL

Impaired Mechanisms of Leukocyte Adhesion In Vitro by the Calcium Channel Antagonist Mibefradil Paul J. Lijnen Hypertension and Cardiovascular Rehabilitation Unit, Department of Molecular and Cardiovascular Research, University of Leuven (K.U. Leuven), Belgium

I n this issue of Cardiovascular Drugs and Therapy, Nebe et al. [1] have demonstrated that the T-type Ca2+ -channel blocker mibefradil, but not the L-type Ca2+ -channel blockers amlodipine and verapamil, attenuated leukocyte adhesion in vitro. They also observed that mibefradil reduced the surface expression of β2 integrins and L-selectin and inhibited the fMLP induced calcium rise, indicating that mibefradil interferes with the integrin signaling through blocking the intracellular Ca2+ rise. It is well established that enhanced adhesion to the vascular endothelium and excessive trafficking to extravascular locations can lead to serious tissue injury and destructions. Therefore, studies interfering with the molecular mechanisms of leukocyte athesion to the vascular endothelium, as performed by Nebe et al. [1], are an important goal to block diseases such as atherosclerosis and chronic inflammations. Indeed, it has been shown that mibefradil also exhibited a more pronounced inhibition of the proliferation of human peripheral blood mononuclear cells than nifedipine [2]. The fact that mibefradil had an antiproliferative effect, by contrast with verapamil or amlodipine [3] and that mibefradil had a more pronounced inhibitory effect on the lymphoproliferative response than nifedipine [2] suggests that the blockade of T-type Ca2+-channels could play an important role. T-channels seems to mediate the increase of inracellular Ca2+ induced by angiotensin II [4], endothelin [5] and platelet derived growth factor [6]. It has even been shown that blockade of T-channels with nordihydroguiaretic acid could prevent the proliferative effect of platelet derived growth factor [6]. In vivo, the blood pressure lowering effect of mibefradil is also accompanied by a decrease in intracellular free Ca2+ concentrations and by a reduction in 3 H-thymidine incorporation [7], indicating an inhibition of their proliferation. Following nifedipine administration in healthy volunteers (a single oral dose of 10 mg) Morgano et al. [8] found a decreased blastogenesis. The incorporation of 3 H-thymidine by concanavalin A-stimulated PBMC of patients treated with 300 mg verapamil daily for 2 weeks was also significantly lower (−57%) than that of controls [9].

An in vivo antiproliferative effect of calcium channel blockers has also been described in various animal studies. Indeed, administration of nifedipine orally to balloon-catheterized rats or rabbits, inhibited aortic smooth muscle cell proliferation, measured 48 h after injury [10]. Betz [11] reported that flunarizine and verapamil reduce intimal proliferation in rabbit carotid arteries stimulated with electrical impulses. The antiproliferative effect of lacidipine has also been studied in vivo, by examining its effect on hyperplasia induced by perivascular manipulation of the hypercholesterolaemic rabbit carotid arteries. In treated (3 mg/kg per day for 2 weeks) animals, lacidipine decreased the intima-to-media ratio, indicating a potent effect on smooth muscle cell migration and/or proliferation [12]. Unkelback et al. [13] also reported that long-term calcium entry blockade with isradipine for 6 weeks (60 mg/kg per day) in 6- to 8-week old Wistar rats reduced aortic media thickness and increased media smooth muscle cell density, indicating that the reduced media thickness is caused by cellular smooth muscle hypotrophy (thus mainly by a decrease in mean cellular volume). In DOCA-salt hypertensive rats treated with mibefradil, resorption of hypertrophy and fibrosis appeared to be related to a direct action on cardiomyocyte and fibroblast growth [14]. In addition, mibedradil prevented the infiltration of monocytes in the subendothelium of the aorta of spontaneously hypertensive rats [15]. Schmitt et al. [3] have also demonstrated that mibefradil decreases the area of neointima formed 14 days after balloon injury of the carotid artery in rats; in contrast neither verapamil nor amlodipine had an effect. This in vivo effect of mibefradil was indeed an inhibition of smooth muscle cell proliferation as shown by a decrease in 3 H-thymidine incorporation. Mibedradil (30 mg/kg−1 per day) given orally to young salt-loaded stroke-prone spontaneously hypertensive rats (SHR-SP) from age 5 weeks to 20 weeks,

Address for correspondence: Dr. P. Lijnen, Hypertension Unit, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. Tel.: 32/16/34.57.66; Fax: 32/16/34.62.03; E-mail: paul.lijnen@ med.kuleuven.ac.be

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also abolished vascular fibrinoid necrosis formation in the brain and reduced arterial thickening in the cerebral artery as well as in the aorta [16]. In a rat model of chronic heart failure Mulder et al. [17] showed that long-term administration of mibefradil for 9 months increased survival (to the same extent as the ACE inhibitor cilazapril) without impairing left ventricular (LV) function, and was associated with a reduction in LV weight and fibrosis (or LV collagen density). In contrast to mibefradil, calcium antagonists that act primarly on the L-type Ca2+ channel such as verapamil [3], amlodipine [16] and felodipine [18] did not prevent neointima formation at doses producing a similar blood pressure decrease. Thus, the antiproliferative effects of mibefradil may derive, at least partly, from its specific blockade of T-type Ca2+ channels, although it also has effects on the L-type channels. A role for T-type Ca2+ channels in proliferation and growth has indeed been suggested [19] as well as in the prevention of excessive adhesion of leukocytes [1] and the reduction in the transmigration of leukocytes in the tissue [1,20].

Acknowledgments The authors gratefully acknowledge the secretarial assistance of Mrs. Y. Toremans. Prof. Dr. P. Lijnen is holder of the Boehringer Ingelheim Chair in Hypertension.

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