AMLODIPINE AND VASCULAR HYPERTROPHY

In both atherosclerosis and arterial hypertension, structural and func tional abnormalities result in vascular hypertrophy that is associated with an increased ratio of vascular media thickness to lumen diameter and hyperreactivity of vascular smooth muscle cells (VSMCs), resultin g in uncontrolled cell migration and growth in vivo. In culture, VSMCs isolated from the spontaneously hypertensive rat (SHR) also display e xaggerated growth and/or proliferation compared to VSMCs isolated from normotensive control Wistar Kyoto (WKY) rats. In vitro studies of cul tured VSMCs can therefore be used as a model to investigate the mechan isms whereby a drug such as amlodipine can exert its antihypertensive and antiatherogenic effects. The present in vitro investigations exami ne the mechanisms whereby amlodipine reduces VSMC growth/proliferation promoted by basic fibroblast growth factor (bFGF), a peptide growth f actor likely to participate in the vascular smooth muscle hypertrophy of the SHR. VSMCs from SHR and/or WKY rat aortae were isolated, passag ed, and cultured. The influence of amlodipine on VSMC growth/prolifera tion was studied by measuring DNA synthesis and cell number under expe rimental conditions, which allowed us to determine the cell cycle phas e in which amlodipine exerts its effects. Amlodipine was found to inhi bit growth and bFGF-induced DNA synthesis in a concentration-dependent manner. Delayed addition of amlodipine showed that the drug exerts it s effect early in the G(1) phase, a result that was confirmed by the f inding that amlodipine could not inhibit bFGF-induced DNA synthesis in VSMCs arrested at the G(1)/S boundary. In comparative experiments, th e inhibitory effect of amlodipine on both cell growth and DNA synthesi s was found to be of similar magnitude in SHR- and WKY-derived VSMCs. It is therefore likely that by modulating cell growth/proliferation in duced by bFGF, amlodipine may reduce the vascular hypertrophy of the S HR. Since amlodipine also has been found to inhibit VSMC migration, on e may reasonably envisage that these characteristics are important com ponents of the antiatherogenic properties of the drug. (C) 1997 Elsevi er Science Ireland Ltd.