CALCIUM ANTAGONISM IN VASCULAR SMOOTH-MUSCLE CELLS

Ca2+ ions play critical roles in physiological and pathological signal transduction in vascular smooth muscle cells (VSMC). The control of C a2+ homeostasis is an important means for modulating excitability and response. A pathological increase of Ca2+-dependent vascular tone caus es vasospasm and arterial hypertension. Moreover, Ca2+-mediated migrat ion, proliferation, matrix production and necrotization of VSMC are im portant components of atherogenic plaque formation. At least two physi ological Ca2+ antagonists are known that compete for Ca2+ binding site s at VSMC: H+ and Mg2+. Effective pharmacological control of Ca2+ home ostasis is exerted by organic Ca2+ antagonists. The prototypical compo unds verapamil, nifedipine and diltiazem and their derivatives represe nt three separate structural categories of drugs that block transsarco lemmal Ca2+ influx by specific interaction at a set of binding sites a ssociated with the alpha 1-subunit of the L-type, voltage-gated Ca2+ c hannel protein. Selectivity of action of the Ca2+ antagonists may aris e from pharmacokinetics, class and subclass of the Ca2+ channel activa ted, state-dependent interactions or pathological alterations. In huma n therapy they are the drugs of choice in the treatment of arterial sp asms and hypertension. The extent to which their antiatherogenic prope rties are related to Ca2+ channel antagonism at VSMC remains to be elu cidated further.